Fluoxetine prevents development of an early stress-related molecular signature in the rat infralimbic medial prefrontal cortex : implications for depression?

Background: Psychological stress, particularly in chronic form, can lead to mood and cognitive dysfunction and is a major risk factor in the development of depressive states. How stress affects the brain to cause psychopathologies is incompletely understood. We sought to characterise potential depression related mechanisms by analysing gene expression and molecular pathways in the infralimbic medial prefrontal cortex (ILmPFC), following a repeated psychological stress paradigm. The ILmPFC is thought to be involved in the processing of emotionally contextual information and in orchestrating the related autonomic responses, and it is one of the brain regions implicated in both stress responses and depression. Results: Genome-wide microarray analysis of gene expression showed sub-chronic restraint stress resulted predominantly in a reduction in transcripts 24 hours after the last stress episode, with 239 genes significantly decreased, while just 24 genes had increased transcript abundance. Molecular pathway analysis using DAVID identified 8 pathways that were significantly enriched in the differentially expressed gene list, with genes belonging to the brain-derived neurotrophic factor – neurotrophin receptor tyrosine kinase 2 (BDNF-Ntrk2) pathway most enriched. Of the three intracellular signalling pathways that are downstream of Ntrk2, real-time quantitative PCR confirmed that only the PI3K-AKT-GSK3B and MAPK/ERK pathways were affected by sub-chronic stress, with the PLCγ pathway unaffected. Interestingly, chronic antidepressant treatment with the selective serotonin reuptake inhibitor, fluoxetine, prevented the stress-induced Ntrk2 and PI3K pathway changes, but it had no effect on the MAPK/ERK pathway. Conclusions: These findings indicate that abnormal BDNF-Ntrk2 signalling may manifest at a relatively early time point, and is consistent with a molecular signature of depression developing well before depression-like behaviours occur. Targeting this pathway prophylactically, particularly in depression-susceptible individuals, may be of therapeutic benefit

Small RNA regulation of neural gene expression in response to environmental exposure associated with neuropsychiatric syndromes

Postmortem molecular analysis of the human brain during development and aging suggests there are epigenetic changes reflecting early life experiences. This includes changes in the expression of non-coding RNAs such as microRNA. These molecules alter the regulation of gene expression and can interact with underlying genetic risk factors, contributing to neurological and neuropsychiatric syndromes such as schizophrenia. Recent evidence suggests that these dynamic and influential molecules play an important role in both brain development and the cellular response to stress. In our recent studies, we investigate the role of microRNA in the brains’ response to maternal immune activation and adolescent cannabinoid exposure, alone and in combination, as both have been identified as environmental risk factors for this disorder. We found that combined exposure to significantly altered microRNA expression in the left hemisphere of the entorhinal cortex as compared to the right. These changes were dominated by a large subgroup of microRNA transcribed from a single imprinted locus on chromosome 6q32 that is associated with schizophrenia. These changes correlated with altered gene expression in the combined treatment group, with microRNA-gene interactions predicted to regulate neuronal growth and differentiation; development of specific cortical layers; synaptic plasticity and transmission; axonogenesis; gamma-aminobutyric acid neurotransmitter system; and learning and memory formation. These findings suggested that the interaction of both an early and late environmental insult enhances changes in offspring microRNA expression in the brain with possible outcomes relevant to neurological disorders in adulthood

Impact assessment of the Centre for Research Excellence in Stroke Rehabilitation and Brain Recovery

Background: Research impact is an emerging measure of research achievement alongside traditional academic outputs such as publications. We present the results of applying the Framework to Assess the Impact from Translational health research (FAIT) to the Centre for Research Excellence (CRE) in Stroke Rehabilitation and Brain Recovery (CRE-Stroke, 2014–2019) and report on the feasibility and lessons from the application of FAIT to a CRE rather than a discrete research project. Methods: Data were gathered via online surveys, in-depth interviews, document analysis and review of relevant websites/databases to report on the three major FAIT methods: the modified Payback Framework, an assessment of costs against monetized consequences, and a narrative account of the impact generated from CRE-Stroke activities. FAIT was applied during the last 4 years of CRE-Stroke operation. Results: With an economic investment of AU$3.9 million over 5 years, CRE-Stroke delivered a return on investment that included AU$ 18.8 million in leveraged grants, fellowships and consultancies. Collectively, CRE-Stroke members produced 354 publications that were accessed 470,000 times and cited over 7220 times. CRE-Stroke supported 26 PhDs, 39 postdocs and seven novice clinician researchers. There were 59 capacity-building events benefiting 744 individuals including policy-makers and consumers. CRE-Stroke created research infrastructure (including a research register of stroke survivors and a brain biobank), and its global leadership produced international consensus recommendations to influence the stroke research landscape worldwide. Members contributed to the Australian Living Stroke Guidelines: four researchers’ outputs were directly referenced. Based only on the consequences that could be monetized, CRE-Stroke returned AU$ 4.82 for every dollar invested in the CRE. Conclusion: This case example in the developing field of impact assessment illustrates how researchers can use evidence to demonstrate and report the impact of and returns on research investment. The prospective application of FAIT by a dedicated research impact team demonstrated impact in broad categories of knowledge-gain, capacity-building, new infrastructure, input to policy and economic benefits. The methods can be used by other research teams to provide comprehensive evidence to governments and other research funders about what has been generated from their research investment but requires dedicated resources to complete

Direct comparison of virtual reality and 2D delivery on sense of presence, emotional and physiological outcome measures

Introduction: Virtual-reality (VR) technology has, over the last decade, quickly expanded from gaming into other sectors including training, education, and wellness. One of the most popular justifications for the use of VR over 2D is increased immersion and engagement. However, very little fundamental research has been produced evaluating the comparative impact of immersive VR on the user’s cognitive, physiological, and emotional state.Methods: A within-subject cross-over study design was used to directly compare VR and 2D screen delivery of different subject matter content. Both physiological and self-report data were collected for scenes containing calming nature environments, aggressive social confrontations, and neutral content.Results: Compared to 2D, the VR delivery resulted in a higher sense of presence, higher ratings of engagement, fun, and privacy. Confrontational scenes were rated as more tense whilst calming scenes were rated as more relaxing when presented in VR compared to 2D. Physiological data indicated that the scenes promoted overall states of arousal and relaxation in accordance with the scene subject matter (both VR and 2D). However, heart rate (HR) and galvanic skin response (GSR) were consistently higher throughout the VR delivery condition compared to 2D, including responses during scenes of neutral and calming subject matter.Discussion: This discrepancy between emotional and physiological responses for calming and neutral content in VR suggest an elevated arousal response driven by VR immersion that is independent of the emotional and physiological responses to the subject matter itself. These findings have important implications for those looking to develop and utilize VR technology as a training and educational tool as they provide insights into the impact of immersion on the user

Opposing associations of stress and resilience with functional outcomes in stroke survivors in the chronic phase of stroke: A cross-sectional study

Stroke survivors report significant levels of psychological distress post stroke. To date, most studies conducted have focused on the relationship between psychological stress and functional outcomes in the acute phase of stroke. However, no studies had considered the role of stress over the chronic phase, where stress may continue to exert negative effects on cognitive and psychological processes. Further, the role of potentially modulatory variables, such as psychological resilience, on stroke outcomes has been understudied. The purpose of this study was to consider the relationships between stress and resilience with functional outcomes in long-term survivors of stroke. People (N = 70) who had experienced a stroke between 5 months and 28 years ago were included in the cross-sectional study, along with age-matched controls (N = 70). We measured stress using both the Perceived Stress Scale and biological markers, and resilience using both the Brief Resilience Scale and the Connor-Davidson Resilience Scale. Stroke outcomes were assessed using the Stroke Impact Scale. We found that, compared with age-matched controls, stroke survivors reported greater levels of perceived stress, and lower levels of resilience. In stroke survivors, both perceived stress and resilience were independently associated with stroke outcomes in linear regression models. In particular, these relationships were observed for cognitive outcomes including mood, memory, and communication. The association between stress and stroke outcome did not differ across time post stroke. Given that resilience is a modifiable psychological construct, future research may consider whether strategies directed at enhancing resilience may improve recovery from stroke

Impact of the COVID-19 Pandemic on the Welfare of Animals in Australia

We report on the various responses in Australia during 2020 to minimize negative impacts of the COVID-19 pandemic on the welfare of animals. Most organizations and individuals with animals under their care had emergency preparedness plans in place for various scenarios; however, the restrictions on human movement to contain the spread of COVID-19, coupled with the economic impact and the health effects of COVID-19 on the skilled workforce, constituted a new threat to animal welfare for which there was no blueprint. The spontaneous formation of a national, multisectoral response group on animal welfare, consisting of more than 34 organizations with animals under their care, facilitated information flow during the crisis, which helped to mitigate some of the shocks to different organizations and to ensure continuity of care for animals during the pandemic. We conclude that animal welfare is a shared responsibility, and accordingly, a multisectoral approach to animal welfare during a crisis is required. Our experience demonstrates that to safeguard animal welfare during crises, nations should consider the following: a national risk assessment, clear communication channels, contingency plans for animal welfare, a crisis response group, and support systems for animal care providers. Our findings and recommendations from the Australian context may inform other countries to ensure that animal welfare is not compromised during the course of unpredictable events

Growth Hormone Deficiency Is Frequent After Recent Stroke

Introduction: The incidence of pituitary dysfunction after severe ischemic stroke is unknown, however given the increasing attention to pituitary dysfunction after neurological injuries such as traumatic brain injury, this may represent a novel area of research in stroke.Methods: We perform an arginine and human growth hormone releasing hormone challenge on ischemic stroke patients within a week of symptom onset.Results: Over the study period, 13 patients were successfully tested within a week of stroke (baseline NIHSS 10, range 7–16). Overall, 9(69%) patients had a poor response, with 7(54%) of these patients meeting the criteria for had human growth hormone deficiency. Other measures of pituitary function were within normal ranges.Conclusion: After major ischemic stroke, low GH levels are common and may play a role in stroke recovery

Rollout of a statewide Australian telestroke network including virtual reality training is associated with improved hyperacute stroke workflow metrics and thrombolysis rate

BackgroundTelestroke networks aim to address variability in both quality and access to stroke care in rural areas, by providing remote access to expert stroke neurologists. Implementation of telestroke requires adaptation of workflow processes and education. We previously developed virtual reality (VR) workflow training and documented acceptability, utility and feasibility. The effects on acute stroke treatment metrics have not been previously described.AimsThe overall aim was to improve hyperacute stroke metrics and shorten the time-to-reperfusion therapy administration in rural settings.MethodsThis study applies a natural experiment approach, collecting stroke metric data during transition from a pre-existing pilot to a statewide telestroke service at five rural hospitals. Pre- and post-intervention data included baseline patient demographics and assessment, diagnosis, and treatment delivery metrics. The primary study outcome was door-to-decision time (thrombolysis and endovascular thrombectomy). Secondary outcomes included door-to-computerized tomography time, door-to-thrombolysis time and proportion of patients receiving thrombolysis or thrombectomy treatment. Usage data relating to the VR stroke workflow training of interprofessional healthcare professionals was automatically captured via Wi-Fi. Statistical comparisons of clinical metrics between the pre- and post-intervention time periods, defined as the timeframes before and after VR deployment, were performed.ResultsA total of 2,683 patients were included (April 2013–December 2022); 1910 pre- and 773 post-intervention. All acute stroke time metrics significantly improved post-intervention. The primary outcome, door-to-decision time, decreased from 80 min [56–118] to 54 min [40–76; P < 0.001]. Secondary outcomes also improved, including door-to-thrombolysis time (90 min [68–114] vs. 68.5 min [54–90]; P < 0.001) and proportion of patients thrombolysed (11 vs. 16%; P < 0.001). The proportion of patients transferred for thrombectomy was unchanged (6 vs. 7%; P = 0.69). Seventy VR sessions totaling 15 h 39 min of training time were logged. VR training usage varied across sites (3–31 sessions per site).ConclusionsDelivery of a multi-factorial intervention including infrastructure, funding, education and training (with VR workflow training) as part of a state-wide telestroke rollout was associated with improved acute stroke treatment metrics. Additional work is required to identify the contribution of each intervention component on clinical outcomes and to increase training uptake and sustainment

COVID-19 trajectories among 57 million adults in England: a cohort study using electronic health records

BACKGROUND: Updatable estimates of COVID-19 onset, progression, and trajectories underpin pandemic mitigation efforts. To identify and characterise disease trajectories, we aimed to define and validate ten COVID-19 phenotypes from nationwide linked electronic health records (EHR) using an extensible framework. METHODS: In this cohort study, we used eight linked National Health Service (NHS) datasets for people in England alive on Jan 23, 2020. Data on COVID-19 testing, vaccination, primary and secondary care records, and death registrations were collected until Nov 30, 2021. We defined ten COVID-19 phenotypes reflecting clinically relevant stages of disease severity and encompassing five categories: positive SARS-CoV-2 test, primary care diagnosis, hospital admission, ventilation modality (four phenotypes), and death (three phenotypes). We constructed patient trajectories illustrating transition frequency and duration between phenotypes. Analyses were stratified by pandemic waves and vaccination status. FINDINGS: Among 57 032 174 individuals included in the cohort, 13 990 423 COVID-19 events were identified in 7 244 925 individuals, equating to an infection rate of 12·7% during the study period. Of 7 244 925 individuals, 460 737 (6·4%) were admitted to hospital and 158 020 (2·2%) died. Of 460 737 individuals who were admitted to hospital, 48 847 (10·6%) were admitted to the intensive care unit (ICU), 69 090 (15·0%) received non-invasive ventilation, and 25 928 (5·6%) received invasive ventilation. Among 384 135 patients who were admitted to hospital but did not require ventilation, mortality was higher in wave 1 (23 485 [30·4%] of 77 202 patients) than wave 2 (44 220 [23·1%] of 191 528 patients), but remained unchanged for patients admitted to the ICU. Mortality was highest among patients who received ventilatory support outside of the ICU in wave 1 (2569 [50·7%] of 5063 patients). 15 486 (9·8%) of 158 020 COVID-19-related deaths occurred within 28 days of the first COVID-19 event without a COVID-19 diagnoses on the death certificate. 10 884 (6·9%) of 158 020 deaths were identified exclusively from mortality data with no previous COVID-19 phenotype recorded. We observed longer patient trajectories in wave 2 than wave 1. INTERPRETATION: Our analyses illustrate the wide spectrum of disease trajectories as shown by differences in incidence, survival, and clinical pathways. We have provided a modular analytical framework that can be used to monitor the impact of the pandemic and generate evidence of clinical and policy relevance using multiple EHR sources. FUNDING: British Heart Foundation Data Science Centre, led by Health Data Research UK