An extension of the FRI framework for calcium transient detection

Two-photon calcium imaging of the brain allows the spatiotemporal activity of neuronal networks to be monitored at cellular resolution. In order to analyse this activity it must first be possible to detect, with high temporal resolution, spikes from the time series corresponding to single neurons. Previous work has shown that finite rate of innovation (FRI) theory can be used to reconstruct spike trains from noisy calcium imaging data. In this paper we extend the FRI framework for spike detection from calcium imaging data to encompass data generated by a larger class of calcium indicators, including the genetically encoded indicator GCaMP6s. Furthermore, we implement least squares model-order estimation and perform a noise reduction procedure ('pre-whitening') in order to increase the robustness of the algorithm. We demonstrate high spike detection performance on real data generated by GCaMP6s, detecting 90% of electrophysiologically-validated spikes

The role of thalamic group II mGlu receptors in health and disease

The thalamus plays a pivotal role in the integration and processing of sensory, motor, and cognitive information. It is therefore important to understand how the thalamus operates in states of both health and disease. In the present review, we discuss the function of the Group II metabotropic glutamate (mGlu) receptors within thalamic circuitry, and how they may represent therapeutic targets in treating disease states associated with thalamic dysfunction

Factors associated with alcohol reduction in harmful and hazardous drinkers following alcohol brief intervention in Scotland: a qualitative enquiry

Background: Alcohol Brief Intervention (ABI) uses a motivational counselling approach to support individuals to reduce excessive alcohol consumption. There is growing evidence on ABI’s use within various health care settings, although how they work and which components enhance success is largely unknown. This paper reports on the qualitative part of a mixed methods study. It explores enablers and barriers associated with alcohol reduction following an ABI. It focuses on alcohol’s place within participants’ lives and their personal perspectives on reducing consumption. There are a number of randomised controlled trials in this field though few ABI studies have addressed the experiences of hazardous/harmful drinkers. This study examines factors associated with alcohol reduction in harmful/hazardous drinkers following ABI. Methods: This qualitative study was underpinned by a realist evaluation approach and involved semistructured interviews with ten harmful or hazardous alcohol drinkers. Participants (n = 10) were from the intervention arm of a randomised controlled trial (n = 124). All had received ABI, a 20 min motivational counselling interview, six months previously, and had reduced their alcohol consumption. Interviews were recorded, transcribed verbatim and thematically analysed. Results: Participants described their views on alcohol, its’ place in their lives, their personal perspectives on reducing their consumption and future aspirations. Conclusions: The findings provide an insight into participants’ views on alcohol, ABI, and the barriers and enablers to change. Participants described a cost benefit analysis, with some conscious consideration of the advantages and disadvantages of reducing intake or abstaining from alcohol. Findings suggest that, whilst hospital admission can act as a catalyst, encouraging individuals to reflect on their alcohol consumption through ABI may consolidate this, turning this reflective moment into action. Sustainability may be enhanced by the presence of a ‘significant other’ who encourages and experiences benefit. In addition having a purpose or structure with activities linked to employment and/or social and leisure pursuits offers the potential to enhance and sustain reduced alcohol consumption. Trial registration: Trial registration number TRN NCT00982306 September 22nd 200

Group II metabotropic glutamate receptor modulation of sensory responses in the ventrobasal thalamus

The functional integrity of the thalamic reticular nucleus (TRN) is thought to be key in the control of selective attention (Crick, 1984; Pinault, 2004). This GABAergic structure (Houser et al., 1980) is responsible for ensuring synchronous activity within the appropriate thalamocortical circuits required for either sensory perception or for the preparation and execution of distinct motor and/or cognitive tasks. It is therefore imperative to ascertain the exact nature of how inhibitory innervation from the TRN to thalamic nuclei is controlled in order to understand how neurophysiological disease states associated with TRN malfunction (Huguenard, 1999; Rub et al., 2003; Barbas and Zikopoulos, 2007; Pinault, 2011) precipitate. I t has been previously demonstrated that the Group II metabotropic glutamate receptors (mGlu2/3) can modulate physiologically-evoked responses in the VB (Salt and Turner, 1998) by reducing inhibition from the TR N (Turner and Salt, 2003). However, it is not yet known what the relative contributions are of the two subtypes to this modulation, nor to what extent these receptors may be activated under physiological conditions during this process. Using single-neurone recording in the rat ventrobasal thalamus (VB) in vivo with local iontophoretic application of selective Group II mGlu receptor compounds, my findings were threefold. Firstly, I found that both mGlu2 and mGlu3 receptors contribute a component to the overall Group II mGlu receptor effect on sensory responses in the VB. Secondly, I was able to demonstrate that both Group II mGlu receptor subtypes are likely activated by endogenous ‘glutamate spillover’ from the synapses formed between excitatory sensory afferents and VB neurones following physiological sensory stimulation, and that this can lead to a reduction in sensory-evoked inhibition arising from the TRN. I propose that this potential Group II mGlu receptor modulation of inhibition could play an important role in discerning relevant information from background activity upon physiological sensory stimulation: a novel mechanism that could be of importance in attention and cognitive processes, whose malfunction could result in maladaption of sensory perception, such as that which can occur in psychiatric disease. Thirdly, I was able to provide evidence that mGlu2 receptors are likely located on astrocytic processes surrounding the VB- TR N synapse, and are able to mediate a n a st rocyti c mechanism of action that reduces inhibitory synaptic transmission from the TRN to the VB. To the best of my knowledge this provides the first evidence that mGlu2 receptors are able to activate astrocytes, and of the involvement of astrocytes in the modulation of heterosynaptic transmission. As VB astrocytes are able to respond to synaptic stimulation (Parri et al., 2010), maladaption of mGlu2 receptor-mediated endogenous astrocytic activation may therefore have functional implications for the processing of somatosensory information and for the preparation and execution of distinct motor and/or cognitive tasks. Finally, I also investigated the action of the putative endogenous selective Group II mGlu receptor agonist Xanthurenic Acid (XA), which is a metabolite of the kynurenine pathway. Changes in both of these systems have been implicated in the pathophysiology of schizophrenia and other psychiatric disorders, however little is known regarding the mechanism of action of XA. I therefore investigated the effects of XA in modulating inhibition in the VB from the TRN using the same in vivo electrophysiology preparation as described above, and also evaluated the ability of XA to bind to and activate mGlu2 receptors using in vitro molecular pharmacological methods. Selective Group II mGlu receptor compounds that exploit this novel mechanism of endogenous activation may therefore be of importance in the modulation of sensory, attentional and cognitive processes for therapeutic strategies

Opioid-related deaths during hospital admissions or shortly after discharge in the United Kingdom: A thematic framework analysis of coroner reports

BACKGROUND: People who use heroin and other illicit opioids are at high risk of fatal overdose in the days after hospital discharge, but the reasons for this risk have not been studied. METHODS: We used the National Programme on Substance Abuse Deaths, a database of coroner reports for deaths following psychoactive drug use in England, Wales, and Northern Ireland. We selected reports where the death occurred between 2010 and 2021, an opioid was detected in toxicology testing, the death was related to nonmedical opioid use, and death was either during an acute medical or psychiatric hospital admission or within 14 days after discharge. We used thematic framework analysis of factors that may contribute to the risk of death during hospital admission or after discharge. RESULTS: We identified 121 coroners’ reports; 42 where a patient died after using drugs during hospital admission, and 79 where death occurred shortly after discharge. The median age at death was 40 (IQR 34–46); 88 (73%) were male; and sedatives additional to opioids were detected at postmortem in 88 cases (73%), most commonly benzodiazepines. In thematic framework analysis, we categorised potential causes of fatal opioid overdose into three areas: (a) hospital policies and actions. Zero-tolerance policies mean that patients conceal drug use and use drugs in unsafe places such as locked bathrooms. Patients may be discharged to locations such as temporary hostels or the street while recovering. Some patients bring their own medicines or illicit opioids due to expectations of low-quality care, including undertreated withdrawal or pain; (b) high-risk use of sedatives. People may increase sedative use to manage symptoms of acute illness or a mental health crisis, and some may lose tolerance to opioids during a hospital admission; (c) declining health. Physical health and mobility problems posed barriers to post-discharge treatment for substance use, and some patients had sudden deteriorations in health that may have contributed to respiratory depression. CONCLUSION: Hospital admissions are associated with acute health crises that increase the risk of fatal overdose for patients who use illicit opioids. Hospitals need guidance to help them care for this patient group, particularly in relation to withdrawal management, harm reduction interventions such as take-home naloxone, discharge planning including continuation of opioid agonist therapy during recovery, management of poly-sedative use, and access to palliative care

The age of anxiety? It depends where you look: changes in STAI trait anxiety, 1970–2010

Purpose Population-level surveys suggest that anxiety has been increasing in several nations, including the USA and UK. We sought to verify the apparent anxiety increases by looking for systematic changes in mean anxiety questionnaire scores from research publications. Methods We analyzed all available mean State–Trait Anxiety Inventory scores published between 1970 and 2010. We collected 1703 samples, representing more than 205,000 participants from 57 nations. Results Results showed a significant anxiety increase worldwide, but the pattern was less clear in many individual nations. Our analyses suggest that any increase in anxiety in the USA and Canada may be limited to students, anxiety has decreased in the UK, and has remained stable in Australia. Conclusions Although anxiety may have increased worldwide, it might not be increasing as dramatically as previously thought, except in specific populations, such as North American students. Our results seem to contradict survey results from the USA and UK in particular. We do not claim that our results are more reliable than those of large population surveys. However, we do suggest that mental health surveys and other governmental sources of disorder prevalence data may be partially biased by changing attitudes toward mental health: if respondents are more aware and less ashamed of their anxiety, they are more likely to report it to survey takers. Analyses such as ours provide a useful means of double-checking apparent trends in large population surveys

A Survey on Continuous Time Computations

We provide an overview of theories of continuous time computation. These theories allow us to understand both the hardness of questions related to continuous time dynamical systems and the computational power of continuous time analog models. We survey the existing models, summarizing results, and point to relevant references in the literature

Male reproductive health and environmental xenoestrogens

EHP is a publication of the U.S. government. Publication of EHP lies in the public domain and is therefore without copyright. Research articles from EHP may be used freely; however, articles from the News section of EHP may contain photographs or figures copyrighted by other commercial organizations and individuals that may not be used without obtaining prior approval from both the EHP editors and the holder of the copyright. Use of any materials published in EHP should be acknowledged (for example, "Reproduced with permission from Environmental Health Perspectives") and a reference provided for the article from which the material was reproduced.Male reproductive health has deteriorated in many countries during the last few decades. In the 1990s, declining semen quality has been reported from Belgium, Denmark, France, and Great Britain. The incidence of testicular cancer has increased during the same time incidences of hypospadias and cryptorchidism also appear to be increasing. Similar reproductive problems occur in many wildlife species. There are marked geographic differences in the prevalence of male reproductive disorders. While the reasons for these differences are currently unknown, both clinical and laboratory research suggest that the adverse changes may be inter-related and have a common origin in fetal life or childhood. Exposure of the male fetus to supranormal levels of estrogens, such as diethlylstilbestrol, can result in the above-mentioned reproductive defects. The growing number of reports demonstrating that common environmental contaminants and natural factors possess estrogenic activity presents the working hypothesis that the adverse trends in male reproductive health may be, at least in part, associated with exposure to estrogenic or other hormonally active (e.g., antiandrogenic) environmental chemicals during fetal and childhood development. An extensive research program is needed to understand the extent of the problem, its underlying etiology, and the development of a strategy for prevention and intervention.Supported by EU Contract BMH4-CT96-0314

Brane-World Gravity

The observable universe could be a 1+3-surface (the "brane") embedded in a 1+3+\textit{d}-dimensional spacetime (the "bulk"), with Standard Model particles and fields trapped on the brane while gravity is free to access the bulk. At least one of the \textit{d} extra spatial dimensions could be very large relative to the Planck scale, which lowers the fundamental gravity scale, possibly even down to the electroweak ($\sim$ TeV) level. This revolutionary picture arises in the framework of recent developments in M theory. The 1+10-dimensional M theory encompasses the known 1+9-dimensional superstring theories, and is widely considered to be a promising potential route to quantum gravity. At low energies, gravity is localized at the brane and general relativity is recovered, but at high energies gravity "leaks" into the bulk, behaving in a truly higher-dimensional way. This introduces significant changes to gravitational dynamics and perturbations, with interesting and potentially testable implications for high-energy astrophysics, black holes, and cosmology. Brane-world models offer a phenomenological way to test some of the novel predictions and corrections to general relativity that are implied by M theory. This review analyzes the geometry, dynamics and perturbations of simple brane-world models for cosmology and astrophysics, mainly focusing on warped 5-dimensional brane-worlds based on the Randall--Sundrum models. We also cover the simplest brane-world models in which 4-dimensional gravity on the brane is modified at \emph{low} energies -- the 5-dimensional Dvali--Gabadadze--Porrati models. Then we discuss co-dimension two branes in 6-dimensional models.Comment: A major update of Living Reviews in Relativity 7:7 (2004) "Brane-World Gravity", 119 pages, 28 figures, the update contains new material on RS perturbations, including full numerical solutions of gravitational waves and scalar perturbations, on DGP models, and also on 6D models. A published version in Living Reviews in Relativit