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A major UK research study - PHOSP-COVID, will investigate the long-term health impacts of COVID-19 on hospitalised patients. The new study has been awarded £8.4 million jointly by UK Research and Innovation (UKRI) and the National Institute for Health Research (NIHR).
Real-world effectiveness of antidepressants, antipsychotics and their combinations in the maintenance treatment of psychotic depression. Evidence from within-subject analyses of two nationwide cohorts.
Psychotic depression (PD) is a severe mental disorder leading to functional disability and high risk of suicide, but very little is known about the comparative effectiveness of medications used in its maintenance treatment. The objective of this study was to investigate the comparative effectiveness of specific antipsychotics and antidepressants, and their combinations, on the risk of psychiatric hospitalization among persons with PD in routine care. Persons aged 16-65 years with a first-time diagnosis of PD were identified from Finnish (years 2000-2018) and Swedish (years 2006-2021) nationwide registers of inpatient care, specialized outpatient care, sickness absence, and disability pension. The main exposures were specific antipsychotics and antidepressants, and the main outcome measure was psychiatric hospitalization as a marker of severe relapse. The risk of hospitalization associated with periods of use vs. non-use of medications (expressed as adjusted hazard ratio, aHR) was assessed by a within-individual design, using each individual as his/her own control, and analyzed with stratified Cox models. The two national cohorts were first analyzed separately, and then combined using a fixed-effect meta-analysis. The Finnish cohort included 19,330 persons (mean age: 39.8±14.7 years; 57.9% women) and the Swedish cohort 13,684 persons (mean age: 41.3±14.0 years; 53.5% women). Individual antidepressants associated with a decreased risk of relapse vs. non-use of antidepressants were bupropion (aHR=0.73, 95% CI: 0.63-0.85), vortioxetine (aHR=0.78, 95% CI: 0.63-0.96) and venlafaxine (aHR=0.92, 95% CI: 0.86-0.98). Any long-acting injectable antipsychotic (LAI) (aHR=0.60, 95% CI: 0.45-0.80) and clozapine (aHR=0.72, 95% CI: 0.57-0.91) were associated with a decreased risk of relapse vs. non-use of antipsychotics. Among monotherapies, only vortioxetine (aHR=0.67, 95% CI: 0.47-0.95) and bupropion (aHR=0.71, 95% CI: 0.56-0.89) were associated with a significantly decreased risk of relapse vs. non-use of both antidepressants and antipsychotics. In an exploratory analysis of antidepressant-antipsychotic combinations, a decreased relapse risk was found for amitriptyline-olanzapine (aHR=0.45, 95% CI: 0.28-0.71), sertraline-quetiapine (aHR=0.79, 95% CI: 0.67-0.93) and venlafaxine-quetiapine (aHR=0.82, 95% CI: 0.73-0.91) vs. non-use of antidepressants and antipsychotics. Benzodiazepines and related drugs (aHR=1.29, 95% CI: 1.24-1.34) and mirtazapine (aHR=1.17, 95% CI: 1.07-1.29) were associated with an increased risk of relapse. These data indicate that, in the maintenance treatment of PD, bupropion, vortioxetine, venlafaxine, any LAI, clozapine, and only few specific antidepressant-antipsychotic combinations are associated with a decreased risk of relapse. These findings challenge the current recommendation by treatment guidelines to combine an antipsychotic with an antidepressant (without further specification) as standard treatment in PD.
Exploring causal mechanisms of psychosis risk.
Robust epidemiological evidence of risk and protective factors for psychosis is essential to inform preventive interventions. Previous evidence syntheses have classified these risk and protective factors according to their strength of association with psychosis. In this critical review we appraise the distinct and overlapping mechanisms of 25 key environmental risk factors for psychosis, and link these to mechanistic pathways that may contribute to neurochemical alterations hypothesised to underlie psychotic symptoms. We then discuss the implications of our findings for future research, specifically considering interactions between factors, exploring universal and subgroup-specific factors, improving understanding of temporality and risk dynamics, standardising operationalisation and measurement of risk and protective factors, and developing preventive interventions targeting risk and protective factors.
Investigating the brain's neurochemical profile at midlife in relation to dementia risk factors.
Changes in the brain's physiology in Alzheimer's disease are thought to occur early in the disease's trajectory. In this study our aim was to investigate the brain's neurochemical profile in a midlife cohort in relation to risk factors for future dementia using single voxel proton magnetic resonance spectroscopy. Participants in the multi-site PREVENT-Dementia study (age range 40-59 year old) underwent 3T magnetic resonance spectroscopy with the spectroscopy voxel placed in the posterior cingulate/precuneus region. Using LCModel, we quantified the absolute concentrations of myo-inositol, total N-acetylaspartate, total creatine, choline, glutathione and glutamate-glutamine for 406 participants (mean age 51.1; 65.3% female). Underlying partial volume effects were accounted for by applying a correction for the presence of cerebrospinal fluid in the magnetic resonance spectroscopy voxel. We investigated how metabolite concentrations related to apolipoprotein ɛ4 genotype, dementia family history, a risk score (Cardiovascular Risk Factors, Aging and Incidence of Dementia -CAIDE) for future dementia including non-modifiable and potentially-modifiable factors and dietary patterns (adherence to Mediterranean diet). Dementia family history was associated with decreased total N-acetylaspartate and no differences were found between apolipoprotein ɛ4 carriers and non-carriers. A higher Cardiovascular Risk Factors, Aging, and Incidence of Dementia score related to higher myo-inositol, choline, total creatine and glutamate-glutamine, an effect which was mainly driven by older age and a higher body mass index. Greater adherence to the Mediterranean diet was associated with lower choline, myo-inositol and total creatine; these effects did not survive correction for multiple comparisons. The observed associations suggest that at midlife the brain demonstrates subtle neurochemical changes in relation to both inherited and potentially modifiable risk factors for future dementia.
Predictive Intelligence for Learning and Optimization: Multidisciplinary Perspectives from Social, Cognitive, and Affective Neuroscience
Many different definitions of intelligence exist but, in the end, they all converge on the brain. In this chapter, we explore the implications of the simple idea that, ultimately, intelligence must help optimize the survival of the individual and of the species. Central to this evolutionary argument, intelligence must offer superior abilities to learn and flexibly adapt to new challenges in the environment. To enhance the possibility of survival, the brain must thus learn to make accurate predictions that optimize the amount of time and energy spent on choosing appropriate actions in a given situation. Such predictive models have a number of parameters, like speed, complexity, and flexibility, that ensure the correct balance and usefulness to solve a given problem (Deary, Penke, & Johnson, 2010; Friedman et al., 2008; Fuster, 2005; Houde, 2010; Johnson-Laird, 2001; Kringelbach & Rolls, 2004; Roth & Dicke, 2005). These parameters come from a variety of cognitive, affective, and social factors, but a main requirement is one of motivation to initiate and sustain the learning process. Finally, one thing is to survive, another is to flourish, and so we discuss whether the intelligent brain is also optimal in terms of wellbeing given that spending too much time predicting something that may never come to pass could be counterproductive to flourishing. Thus, in this perspective, intelligence can be thought of as the process of balancing and optimizing the parameters that allow animals to survive as individuals and as a species, while still maintaining the motivation to do so. Improving the predictive, intelligent brain is a lifelong process where there are important shifts throughout the lifespan in how different aspects and parameters are prioritized.
Passive exercise provides a simultaneous and postexercise executive function benefit
IntroductionPassive exercise involves limb movement via an external force and is an intervention providing an immediate postexercise executive function (EF) benefit. It is, however, unknown whether EF is improved simultaneous with passive exercise—a salient question given the advent of passive (and active) exercise workstations designed to enhance productivity and wellbeing for individuals engaged in sedentary occupations.MethodsHere, participants (N = 23) completed separate 20-min conditions involving active (i.e., via volitional muscle activation) and passive (i.e., via mechanically driven cycle ergometer) cycle ergometry and a non-exercise control condition. EF was assessed prior to (i.e., preintervention), simultaneous with, and immediately after (post-intervention) each condition via the antipointing task. Antipointing involves a goal-directed limb movement mirror-symmetrical to a target and is an ideal tool for the current investigation given that the task is mediated via EF inhibitory control networks that show response-dependent changes following a single bout of exercise.Results and discussionResults showed that passive exercise produced a simultaneous and post-intervention reduction in antipointing reaction time (RT), whereas active exercise selectively produced a post-intervention—but not simultaneous—RT reduction. Thus, passive and active exercise elicited a postexercise EF benefit; however, only passive exercise produced a simultaneous benefit. That passive—but not active—exercise produced a simultaneous benefit may reflect that the intervention provides the necessary physiological or psychological changes to elicit improved EF efficiency without the associated dual-task cost(s) of volitional muscle activity.
Pupil dilation reflects effortful action invigoration in overcoming aversive Pavlovian biases
Abstract“Pavlovian” or “motivational” biases describe the phenomenon that the valence of prospective outcomes modulates action invigoration: Reward prospect invigorates action, whereas punishment prospect suppresses it. The adaptive role of these biases in decision-making is still unclear. One idea is that they constitute a fast-and-frugal decision strategy in situations characterized by high arousal, e.g., in presence of a predator, which demand a quick response. In this pre-registered study (N = 35), we tested whether such a situation—induced via subliminally presented angry versus neutral faces—leads to increased reliance on Pavlovian biases. We measured trial-by-trial arousal by tracking pupil diameter while participants performed an orthogonalized Motivational Go/NoGo Task. Pavlovian biases were present in responses, reaction times, and even gaze, with lower gaze dispersion under aversive cues reflecting “freezing of gaze.” The subliminally presented faces did not affect responses, reaction times, or pupil diameter, suggesting that the arousal manipulation was ineffective. However, pupil dilations reflected facets of bias suppression, specifically the physical (but not cognitive) effort needed to overcome aversive inhibition: Particularly strong and sustained dilations occurred when participants managed to perform Go responses to aversive cues. Conversely, no such dilations occurred when they managed to inhibit responses to Win cues. These results suggest that pupil diameter does not reflect response conflict per se nor the inhibition of prepotent responses, but specifically effortful action invigoration as needed to overcome aversive inhibition. We discuss our results in the context of the “value of work” theory of striatal dopamine.
A Phase I trial of Non-invasive Ventilation and seizure prophylaxis with levetiracetam In Children with Cerebral Malaria Trial (NOVICE-M Trial)
Background African children with cerebral malaria and seizures caused Plasmodium falciparum are at greater risk of poor outcomes including death and neurological sequelae. The agonal events are severe hypoventilation and respiratory arrest often triggered by seizures. We hypothesised that prophylactic anti-seizure medication (ASM) could avert ‘spikes’ of intracranial pressure during or following seizures and that adequate ventilation could be supported by biphasic Cuirass Ventilation (BCV) which requires no intubation. Methods A Phase I trial conducted in Kilifi, Kenya designed to provide data on safety, feasibility and preliminary data on seizure control using prophylactic ASM (levetiracetam) and BCV as non-invasive ventilatory support in children with cerebral malaria. Children aged 3 months to 12-years hospitalised with P falciparum malaria (positive rapid diagnostic test or a malaria slide), a Blantyre Coma Score ≤2 and a history of acute seizures in this illness are eligible for the trial. In a phased evaluation we will study i) BCV alone for respiratory support (n=10); ii) prophylactic LVT: 40mg/kg loading dose then 30mg/kg every 12 hours given via nasogastric tube for 72 hours (or until fully conscious) plus BCV support (n=10) and; iii) prophylactic LVT: 60mg/kg loading dose then 45mg/kg every 12 hours given via nasogastric tube for 72 hours (or until fully conscious) plus BCV support (n=10). Primary outcome measure: cumulative time with a clinically detected seizures or number of observed seizures over 36 hours. Secondary outcomes will be assessed by feasibility or ability to implement BCV, and recovery from coma within 36 hours. Safety endpoints include: aspiration during admission; death at 28 days and 180 days; and de-novo neurological impairments at 180 days. Conclusions This is a Phase I trial largely designed to test the feasibility, tolerability and safety of using non-invasive ventilatory support and LVT prophylaxis in cerebral malaria. Registration ISRCTN76942974 (5.02.2019); PACTR202112749708968 (20.12.2021).
Feasibility of multiorgan risk prediction with routinely collected diagnostics: a prospective cohort study in the UK Biobank.
OBJECTIVES: Despite rising rates of multimorbidity, existing risk assessment tools are mostly limited to a single outcome of interest. This study tests the feasibility of producing multiple disease risk estimates with at least 70% discrimination (area under the receiver operating curve, AUROC) within the time and information constraints of the existing primary care health check framework. DESIGN: Observational prospective cohort study SETTING: UK Biobank. PARTICIPANTS: 228 240 adults from the UK population. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Myocardial infarction, atrial fibrillation, heart failure, stroke, all-cause dementia, chronic kidney disease, fatty liver disease, alcoholic liver disease, liver cirrhosis and liver failure. RESULTS: Using a set of predictors easily gathered at the standard primary care health check (such as the National Health Service Health Check), we demonstrate that it is feasible to simultaneously produce risk estimates for multiple disease outcomes with AUROC of 70% or greater. These predictors can be entered once into a single form and produce risk scores for stroke (AUROC 0.727, 95% CI 0.713 to 0.740), all-cause dementia (0.823, 95% CI 0.810 to 0.836), myocardial infarction (0.785, 95% CI 0.775 to 0.795), atrial fibrillation (0.777, 95% CI 0.768 to 0.785), heart failure (0.828, 95% CI 0.818 to 0.838), chronic kidney disease (0.774, 95% CI 0.765 to 0.783), fatty liver disease (0.766, 95% CI 0.753 to 0.779), alcoholic liver disease (0.864, 95% CI 0.835 to 0.894), liver cirrhosis (0.763, 95% CI 0.734 to 0.793) and liver failure (0.746, 95% CI 0.695 to 0.796). CONCLUSIONS: Easily collected diagnostics can be used to assess 10-year risk across multiple disease outcomes, without the need for specialist computing or invasive biomarkers. Such an approach could increase the utility of existing data and place multiorgan risk information at the fingertips of primary care providers, thus creating opportunities for longer-term multimorbidity prevention. Additional work is needed to validate whether these findings would hold in a larger, more representative cohort outside the UK Biobank.
Spatiotemporal brain hierarchies of auditory memory recognition and predictive coding
AbstractOur brain is constantly extracting, predicting, and recognising key spatiotemporal features of the physical world in order to survive. While neural processing of visuospatial patterns has been extensively studied, the hierarchical brain mechanisms underlying conscious recognition of auditory sequences and the associated prediction errors remain elusive. Using magnetoencephalography (MEG), we describe the brain functioning of 83 participants during recognition of previously memorised musical sequences and systematic variations. The results show feedforward connections originating from auditory cortices, and extending to the hippocampus, anterior cingulate gyrus, and medial cingulate gyrus. Simultaneously, we observe backward connections operating in the opposite direction. Throughout the sequences, the hippocampus and cingulate gyrus maintain the same hierarchical level, except for the final tone, where the cingulate gyrus assumes the top position within the hierarchy. The evoked responses of memorised sequences and variations engage the same hierarchical brain network but systematically differ in terms of temporal dynamics, strength, and polarity. Furthermore, induced-response analysis shows that alpha and beta power is stronger for the variations, while gamma power is enhanced for the memorised sequences. This study expands on the predictive coding theory by providing quantitative evidence of hierarchical brain mechanisms during conscious memory and predictive processing of auditory sequences.
The circulating proteome and brain health: Mendelian randomisation and cross-sectional analyses.
Decline in cognitive function is the most feared aspect of ageing. Poorer midlife cognitive function is associated with increased dementia and stroke risk. The mechanisms underlying variation in cognitive function are uncertain. Here, we assessed associations between 1160 proteins' plasma levels and two measures of cognitive function, the digit symbol substitution test (DSST) and the Montreal Cognitive Assessment in 1198 PURE-MIND participants. We identified five DSST performance-associated proteins (NCAN, BCAN, CA14, MOG, CDCP1), with NCAN and CDCP1 showing replicated association in an independent cohort, GS (N = 1053). MRI-assessed structural brain phenotypes partially mediated (8-19%) associations between NCAN, BCAN, and MOG, and DSST performance. Mendelian randomisation analyses suggested higher CA14 levels might cause larger hippocampal volume and increased stroke risk, whilst higher CDCP1 levels might increase intracranial aneurysm risk. Our findings highlight candidates for further study and the potential for drug repurposing to reduce the risk of stroke and cognitive decline.
Genetic structure correlates with ethnolinguistic diversity in eastern and southern Africa.
African populations are the most diverse in the world yet are sorely underrepresented in medical genetics research. Here, we examine the structure of African populations using genetic and comprehensive multi-generational ethnolinguistic data from the Neuropsychiatric Genetics of African Populations-Psychosis study (NeuroGAP-Psychosis) consisting of 900 individuals from Ethiopia, Kenya, South Africa, and Uganda. We find that self-reported language classifications meaningfully tag underlying genetic variation that would be missed with consideration of geography alone, highlighting the importance of culture in shaping genetic diversity. Leveraging our uniquely rich multi-generational ethnolinguistic metadata, we track language transmission through the pedigree, observing the disappearance of several languages in our cohort as well as notable shifts in frequency over three generations. We find suggestive evidence for the rate of language transmission in matrilineal groups having been higher than that for patrilineal ones. We highlight both the diversity of variation within Africa as well as how within-Africa variation can be informative for broader variant interpretation; many variants that are rare elsewhere are common in parts of Africa. The work presented here improves the understanding of the spectrum of genetic variation in African populations and highlights the enormous and complex genetic and ethnolinguistic diversity across Africa.
Methods and associations of suicidality in Kenyan high school students: clinical and public health implications.
BACKGROUND: Most evidence on suicidal thoughts, plans and attempts comes from Western countries; prevalence rates may differ in other parts of the world. AIMS: This study determined the prevalence of suicidal thoughts, plans and attempts in high school students in three different regional settings in Kenya. METHOD: This was a cross-sectional study of 2652 high school students. We asked structured questions to determine the prevalence of various types of suicidality, the methods planned or effected, and participants' gender, age and form (grade level). We provided descriptive statistics, testing significant differences by chi-squared and Fisher's exact tests, and used logistic regression to identify relationships among different variables and their associations with suicidality. RESULTS: The prevalence rates of suicidal thoughts, plans and attempts were 26.8, 14.9 and 15.7%, respectively. These rates are higher than those reported for Western countries. Some 6.7% of suicide attempts were not associated with plans. The most common method used in suicide attempts was drinking chemicals/poison (18.8%). Rates of suicidal thoughts and plans were higher for older students and students in urban rather than rural locations, and attempts were associated with female gender and higher grade level - especially the final year of high school, when exam performance affects future education and career prospects. CONCLUSION: Suicidal thoughts, plans and attempts are prevalent in Kenyan high school students. There is a need for future studies to determine the different starting points to suicidal attempts, particularly for the significant number whose attempts are not preceded by thoughts and plans.
Autistic Women’s Experiences of the Perinatal Period: A Systematic Mixed Methods Review
The perinatal period has challenges for autistic women. This review synthesises evidence on the experiences of autistic women during the perinatal period. This mixed methods evidence synthesis followed JBI guidance for mixed methods systematic reviews. The Mixed Methods Appraisal Tool assessed study quality. Thematic analysis was used to synthesise findings. Thirteen studies were included. Themes identified included sensory demands of the perinatal period are frequently overwhelming; experiencing healthcare as an autistic person is challenging; parenting as an autistic mother has difficulties but also rewards; predictability and control are important in labour and birth. Individualised care with reasonable adjustments can make a difference to the perinatal experiences of autistic women. Despite challenges, autistic women also have many strengths as mothers.
Association of ideal cardiovascular health at age 50 with incidence of dementia: 25 year follow-up of Whitehall II cohort study.
OBJECTIVES: To examine the association between the Life Simple 7 cardiovascular health score at age 50 and incidence of dementia. DESIGN: Prospective cohort study. SETTING: Civil service departments in London (Whitehall II study; study inception 1985-88). PARTICIPANTS: 7899 participants with data on the cardiovascular health score at age 50. EXPOSURES: The cardiovascular health score included four behavioural (smoking, diet, physical activity, body mass index) and three biological (fasting glucose, blood cholesterol, blood pressure) metrics, coded on a three point scale (0, 1, 2). The cardiovascular health score was the sum of seven metrics (score range 0-14) and was categorised into poor (scores 0-6), intermediate (7-11), and optimal (12-14) cardiovascular health. MAIN OUTCOME MEASURE: Incident dementia, identified through linkage to hospital, mental health services, and mortality registers until 2017. RESULTS: 347 incident cases of dementia were recorded over a median follow-up of 24.7 years. Compared with an incidence rate of dementia of 3.2 (95% confidence interval 2.5 to 4.0) per 1000 person years among the group with poor cardiovascular health, the absolute rate differences per 1000 person years were -1.5 (95% confidence interval -2.3 to -0.7) for the group with intermediate cardiovascular health and -1.9 (-2.8 to -1.1) for the group with optimal cardiovascular health. Higher cardiovascular health score was associated with a lower risk of dementia (hazard ratio 0.89 (0.85 to 0.95) per 1 point increment in the cardiovascular health score). Similar associations with dementia were observed for the behavioural and biological subscales (hazard ratios per 1 point increment in the subscores 0.87 (0.81 to 0.93) and 0.91 (0.83 to 1.00), respectively). The association between cardiovascular health at age 50 and dementia was also seen in people who remained free of cardiovascular disease over the follow-up (hazard ratio 0.89 (0.84 to 0.95) per 1 point increment in the cardiovascular health score). CONCLUSION: Adherence to the Life Simple 7 ideal cardiovascular health recommendations in midlife was associated with a lower risk of dementia later in life.