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Dual-site beta transcranial alternating current stimulation during a bimanual coordination task modulates functional connectivity between motor areas.
BACKGROUND: Communication within brain networks depends on functional connectivity. One promising approach to modulate such connectivity between cortical areas is dual-site transcranial alternating current stimulation (tACS), which non-invasively applies weak alternating currents to two brain areas. OBJECTIVES: /Hypotheses: In the current study, we aimed to modulate inter-regional functional connectivity with dual-site tACS to bilateral primary motor cortices (M1s) during bimanual coordination and, in turn, alter behaviour. METHODS: Using functional magnetic resonance imaging (fMRI), we recorded participants' brain responses during a bimanual coordination task in a concurrent tACS-fMRI design. While performing a slow and fast version of the task, participants received one of three types of beta (20 Hz) dual-site tACS over both M1s: zero-phase, jittered-phase or sham, in a within-participant, repeated measures design. RESULTS: While we did not observe any significant tACS effects on behaviour, the study revealed an attenuation effect of zero-phase tACS on interhemispheric connectivity. Additionally, the two active types of tACS (zero-phase and jittered-phase) differed in the task-related M1 connectivity with other motor cortical regions, such as premotor cortex and supplementary motor area. Furthermore, individual E-field strengths were related to functional connectivity in the zero-phase condition. CONCLUSIONS: Dual-site beta tACS over both M1s altered functional connectivity between motor areas. However, this effect did not translate significantly to the behavioural level in the presence of a restricted sample size. Future studies may thus integrate mechanistic measures, such as measures of interhemispheric inhibition, to strengthen causal interpretations.
AI-based prediction of depression symptomatology in first-episode psychosis patients: insights from the EUFEST and RAISE-ETP clinical trials.
BACKGROUND: Depressive symptoms are highly prevalent in first-episode psychosis (FEP) and worsen clinical outcomes. It is currently difficult to determine which patients will have persistent depressive symptoms based on a clinical assessment. We aimed to determine whether depressive symptoms and post-psychotic depressive episodes can be predicted from baseline clinical data, quality of life, and blood-based biomarkers, and to assess the geographical generalizability of these models. METHODS: Two FEP trials were analyzed: European First-Episode Schizophrenia Trial (EUFEST) (n = 498; 2002-2006) and Recovery After an Initial Schizophrenia Episode Early Treatment Program (RAISE-ETP) (n = 404; 2010-2012). Participants included those aged 15-40 years, meeting Diagnostic and Statistical Manual of Mental Disorders IV criteria for schizophrenia spectrum disorders. We developed support vector regressors and classifiers to predict changes in depressive symptoms at 6 and 12 months and depressive episodes within the first 6 months. These models were trained in one sample and externally validated in another for geographical generalizability. RESULTS: A total of 320 EUFEST and 234 RAISE-ETP participants were included (mean [SD] age: 25.93 [5.60] years, 56.56% male; 23.90 [5.27] years, 73.50% male). Models predicted changes in depressive symptoms at 6 months with balanced accuracy (BAC) of 66.26% (RAISE-ETP) and 75.09% (EUFEST), and at 12 months with BAC of 67.88% (RAISE-ETP) and 77.61% (EUFEST). Depressive episodes were predicted with BAC of 66.67% (RAISE-ETP) and 69.01% (EUFEST), showing fair external predictive performance. CONCLUSIONS: Predictive models using clinical data, quality of life, and biomarkers accurately forecast depressive events in FEP, demonstrating generalization across populations.
Lucid Dreaming: Not Just Awareness, but Agency.
During lucid dreaming (LD), dreamers are aware that they are dreaming and may be able to influence the oneiric content. There has been recent debate about the relative importance of the ability to influence the dream and having agency over the pure awareness of dreaming. To underline this, we examined the associations of lucid dreams without agency (LD-Ag) and lucid dreams with agency (LD + Ag) to sleep and mental health problems and long COVID during the pandemic. We collected data in 16 countries on four continents from May to December 2021 on 10,715 subjects. Logistic regression was performed to predict LD-Ag and LD + Ag, with a sample of 8133 participants. We found that 30% of the participants frequently knew they were dreaming during the pandemic. About half of those (17%) reported that they could influence their dreams. Female gender and anxiety symptoms were negatively associated with LD + Ag. Dream recall, nightmares, insomnia, dream enactment behaviour (DEB), sleep vocalisation, short and long COVID and PTSD were positively associated with LD + Ag. Old age, dream recall, nightmares and anxiety symptoms were positively associated with LD-Ag, while short sleep length, being an evening type, and short COVID were negatively associated with LD-Ag. The different associations for LD-Ag and LD + Ag suggest that they may be distinct sleep states. This is also the first study to show that both COVID-19 and long COVID are associated with LD.
Local adaptation and validation of a transdiagnostic risk calculator for first episode psychosis using mental health patient records.
BACKGROUND: Few at-risk adults are identified by specialized services prior to the development of a first episode of psychosis. A transdiagnostic risk calculator, predicting psychosis using electronic health record (EHR) data, was developed in London, UK to identify patients at risk, using structured data and 14 natural language processing (NLP)-derived symptom and substance use concepts. We report the adaptation and internal validation of this risk calculator in a Southeast England region. METHODS: In a retrospective cohort study using EHR patient notes we identified individuals accessing mental healthcare in Southeast England (Nov-1992 to Jan-2023) who received a primary diagnosis of a non-psychotic or non-organic mental disorder. We developed new machine-learning NLP algorithms for diagnosis, symptom and substance use concepts by fine-tuning existing open-source transformer models. Baseline and outcome coded diagnoses were supplemented with NLP-derived diagnosis data. Cox regression was used to predict psychosis and prior weights were applied; discrimination (Harrell's C) was assessed. RESULTS: Nearly all NLP concepts achieved an F1-measure of accuracy above 0.8 following development. In an analysis sample of 63,922 patients with complete data, the risk calculator had acceptable but lower accuracy in Southeast England (Harrell's C 0.71) compared to the London benchmark (Harrell's C 0.85). CONCLUSIONS: The risk calculator performed similarly in Southeast England to other external validation studies, discriminating acceptably, suggesting that this calculator may be adapted successfully for new patient populations, services and geographic areas. Differences in accuracy may be due to different cultures of data capture, different NLP approaches, or differences in the patient cohort.
Pramipexole augmentation for the acute phase of treatment-resistant, unipolar depression: a placebo-controlled, double-blind, randomised trial in the UK.
BACKGROUND: About 30% of patients with depression treated with antidepressant medication do not respond sufficiently to the first agents used. Pramipexole might usefully augment antidepressant medication in such cases of treatment-resistant depression, but data on its effects and tolerability are scarce. We aimed to assess the efficacy and tolerability of pramipexole augmentation of ongoing antidepressant treatment, over 48 weeks, in patients with treatment-resistant depression. METHODS: We did a multicentre, double-blind, placebo-controlled randomised trial in which adults with resistant major depressive disorder were randomly assigned (1:1; using an online randomisation system) to 48 weeks of pramipexole (titrated to 2·5 mg) or placebo added to their ongoing antidepressant medication. The study was conducted in nine National Health Service Trusts in England. Participants, investigators, and researchers involved in recruitment and assessment were masked to group allocation, and the central pharmacy team dispensing the medication was not masked. The primary outcome was change from baseline to week 12 in the total score of the 16-item Quick Inventory of Depressive Symptomology self-report version (QIDS-SR16). The primary analysis was performed on the intention-to-treat population that included all eligible, randomly assigned participants. People with lived experience were involved in the design, oversight, and interpretation of the study. The trial was registered with ISCTRN (ISRCTN84666271) and EudraCT (2019-001023-13) and is complete. FINDINGS: Between Feb 16 and May 29, 2024, 217 participants attended a screening visit, of whom 66 were excluded due to ineligibility. 151 participants were randomly assigned (75 to the pramipexole group and 75 to the placebo group, after one participant was found to be ineligible after randomisation). 84 (56%) participants were female and 66 (44%) were male and the mean age of participants was 44·9 years (SD 14·0). Ethnicity data were not available. The mean QIDS-SR16 total score at baseline was 16·4 (SD 3·4) in the pramipexole group and 16·2 (3·5) in the placebo group. The mean dose of pramipexole received at week 12 was 2·3 mg (SD 0·45). Adjusted mean decrease from baseline to week 12 of the QIDS-SR16 total score was 6·4 (SD 4·9) for the pramipexole group and 2·4 (4·0) for the placebo group; the mean difference between groups was -3·91 (95% CI -5·37 to -2·45; p<0·0001). Termination of trial treatment due to adverse events was more frequent in the pramipexole group (15 participants [20%]) than in the placebo group (four participants [5%]), with reported adverse events consistent with known side-effects of pramipexole, in particular nausea, headache, and sleep disturbance or somnolence. INTERPRETATION: In this trial involving participants with treatment-resistant depression, pramipexole augmentation of antidepressant treatment, at a target dose of 2·5 mg, demonstrated a reduction in symptoms relative to placebo at 12 weeks but was associated with some adverse effects. These results suggest that pramipexole is a clinically effective option for reducing symptoms in patients with treatment-resistant depression. Future trials directly comparing pramipexole with existing treatments for this disorder are needed. FUNDING: National Institute of Health and Care Research, Efficacy and Mechanism Evaluation Programme.
Reducing the Delay in the Diagnosis of Bipolar Disorder: A Qualitative Study
ABSTRACTIntroductionPatients living with bipolar disorder in the UK face, on average, a delay of 9.5 years from initial presentation of symptoms to confirmation of diagnosis. The aim of this qualitative study was to understand the challenges and facilitators involved in diagnosing individuals with BD from the perspectives of GPs and psychiatrists and how the delay in diagnosis of BD from the first presentation might be reduced.MethodsSemi‐structured interviews with clinicians (GPs and psychiatrists) were used to explore attitudes and perspectives towards diagnosing, managing, and accessing or delivering specialist opinion for BD within the current NHS systems and pathways. Thematic analysis was conducted.ResultsGPs report a lack of confidence in identifying BD due to limited understanding of the condition, resources, and lack of continuity of care. Both primary and secondary care clinicians expressed frustrations with the referral pathway in relation to high thresholds for secondary care acceptance and long waiting times for assessments.Clinicians suggest that further education and training in primary care supported by psychometric tools and mood diaries to improve identification of BD. Clinicians also advocated for enhanced communication and collaboration between primary and secondary care to streamline and reduce delays in the diagnostic process.ConclusionWe suggest a number of strategies which could reduce the harmful delay in diagnosis of bipolar.Patient or Public ContributionA Lived Experience Advisory Panel (LEAP) was convened with the support of the McPin Foundation. LEAP members have contributed towards the development of public‐facing documents, including the topic guides, qualitative data analysis and dissemination of findings.
The dynamic interplay between mental health difficulties and the family environment in early adolescence
Background: Adolescents experiencing mental health problems have an elevated risk of persisting difficulties as they transition into adulthood, stressing the importance of identifying modifiable factors impacting mental health during adolescence. The family environment is recognised as a key influence on adolescent mental health in theory and interventions. Notably, few studies have disentangled within-person and between-person effects in relating adolescent mental health and the family environment. Methods: We analysed data from 1067 adolescents across three waves using panel graphical vector autoregressive modelling, separating contemporaneous and temporal within-person and between-person associations in relationships between mental health difficulties (i.e., emotional, hyperactivity/inattention, conduct problems) and family-related factors (i.e., aspects of the general family environment, parent-child relationships, and sibling dynamics). We also assessed how the different mental health difficulties and family environment factors were themselves interrelated over time. The mean age (in years) was 10.51 at Wave 1, 12.49 at Wave 2, and 14.49 at Wave 3. Results: Emotional symptoms predicted increases in hyperactivity/inattention and more sibling problems over time. Lack of family support and negative feelings towards family were reciprocally related, indicative of a reinforcing loop. Both mental health difficulties and family environment factors exhibited considerable stability. In contemporaneous within-person associations, mental health difficulties were strongly interrelated, as were aspects of the family environment. Furthermore, conduct problems were linked to externalising behaviours (e.g., fighting with parents, bothering siblings) and emotional symptoms to internalising experiences of family dynamics (e.g., feeling negative towards family, being bothered by siblings). Negative feelings towards family and hyperactivity/inattention were strongly predicted by included variables, while emotional symptoms, fighting with parents, and lacking family support were predictive of other variables. Conclusions: Our findings point to the importance of emotional problems in adolescence, which may contribute to worsened hyperactivity/inattention and more problems with siblings over time, and the interrelatedness of mental health and the family environment. Alleviating internalising problems in affected adolescents may help mitigate development of other mental health difficulties and negative sibling dynamics.
Navigating Discharge From Early Intervention in Psychosis Services: A Qualitative Exploration of the Experiences of Service Users and Carers.
INTRODUCTION: Early Intervention in Psychosis (EIP) services in England offer up to 3 years' time-limited support to people experiencing early psychosis. Service users (SUs) are discharged to primary care, a community mental health team (CMHT), or other specialist mental health service. The aim of this study is to explore the SU and carer journey through discharge from EIP and into the early post-discharge period. METHODS: Qualitative longitudinal study comprising semi-structured interviews with SUs and carers at, or shortly after, discharge from EIP, and follow-up interviews with SUs 6-11 months later. Data collection conducted between January 2023-September 2024 and informed by information power. Data were thematically analysed by a multidisciplinary team. RESULTS: SUs and carers expressed their desire to be actively involved in EIP discharge planning and decision-making. They contrasted close relationships with EIP practitioners with inaccessibility of care and difficulties navigating healthcare systems after discharge. Some SUs described feelings of abandonment and expressed a wish for transitional support, and proactive, relationship-based care post-discharge. Carers played an important role as patient advocates but were rarely offered support themselves. CONCLUSION: Improved collaboration is needed between SUs, carers and primary care/CMHT practitioners in the build-up to EIP discharge. There should be proactive contact from primary care at the point of discharge and in the early post-discharge period. Carer needs are often overlooked; primary care could utilise the 'carers register' and proactively offer support. PATIENT OR PUBLIC CONTRIBUTION: Patient and carer involvement and engagement was key to all stages of this study. The research team met regularly with our two co-investigators with lived experience (as a service user and a carer), who contributed to data analysis and writing this paper. We worked closely with our patient and carer advisory group, EXTEND-ing, throughout the research process. They helped formulate research questions, co-designed topic guides and participant information sheets, and contributed to data analysis and interpretation.
Supporting people in Early Intervention in Psychosis services: the role of primary care.
BACKGROUND: Early Intervention in Psychosis (EIP) services offer treatment to people experiencing a first episode of psychosis. Service users may be referred from primary care and discharged directly back at the end of their time in an EIP service. AIM: To explore the role of primary care in supporting EIP service users (SUs) and to understand how to improve collaboration between primary and specialist care. METHOD: Qualitative study comprising semi-structured interviews with SUs, carers, healthcare professionals (HCPs), managers, and commissioners. Interviews were conducted either online or by telephone. Thematic analysis was carried out using principles of constant comparison. Patient and public involvement were key to all stages, including data analysis. RESULTS: In total, 55 interviews were conducted with SUs (n = 13), carers (n = 10), and GPs, EIP HCPs, managers, and commissioners (n = 33). GPs reported difficulties in referring people into EIP services and little contact with SUs while in EIP services, even about physical health. GPs suggested they were not included in planning discharge from EIP to primary care. SUs and carers reported that transition from EIP can lead to uncertainty, distress, and exacerbation of symptoms. GPs reported only being made aware of patients on or after discharge, with no contact for 3 years. GPs described difficulty managing complex medication regimes, and barriers to re-referral to mental health services. CONCLUSION: GPs have a key role in supporting people within EIP services, specifically monitoring and managing physical health. Inclusion of GPs in planning discharge from EIP services is vital.
Research-ready data: the C-Surv data model.
Research-ready data (data curated to a defined standard) increase scientific opportunity and rigour by integrating the data environment. The development of research platforms has highlighted the value of research-ready data, particularly for multi-cohort analyses. Following stakeholder consultation, a standard data model (C-Surv) optimised for data discovery, was developed using data from 5 population and clinical cohort studies. The model uses a four-tier nested structure based on 18 data themes selected according to user behaviour or technology. Standard variable naming conventions are applied to uniquely identify variables within the context of longitudinal studies. The data model was used to develop a harmonised dataset for 11 cohorts. This dataset populated the Cohort Explorer data discovery tool for assessing the feasibility of an analysis prior to making a data access request. Data preparation times were compared between cohort specific data models and C-Surv.It was concluded that adopting a common data model as a data standard for the discovery and analysis of research cohort data offers multiple benefits.
Research-ready data for multi-cohort analyses: The Dementias Platform UK (DPUK) C-Surv data model
Abstract Research-ready data (that curated to a defined standard) increases scientific opportunity and rigour by integrating the data environment. The development of research platforms has highlighted the value of research-ready data, particularly for multi-cohort analyses. Following user consultation, a standard data model (C-Surv), optimised for data discovery, was developed using data from 12 Dementias Platform UK (DPUK) population and clinical cohort studies. The model uses a four-tier nested structure based on 18 data themes selected according to user behaviour or technology. Standard variable naming conventions are applied to uniquely identify variables within the context of longitudinal studies. The data model was used to develop a harmonised dataset for 11 cohorts. This dataset populated the Cohort Explorer data discovery tool for assessing the feasibility of an analysis prior to making a data access request. It was concluded that developing and applying a standard data model (C-Surv) for research cohort data is feasible and useful.
Risk and protective factors of healthy cognitive ageing across diverse global cohorts and causal effect of education
The global rise in cognitive impairment calls for preventive strategies through early identification of risk and protective factors in the community, healthy elderly, that take into account cultural and geographic diversity. This study investigates how risk and protective factors influence cognitive functioning and depressive symptoms of older adults across six diverse cohorts (n=1,636) from Europe, Asia, and Australia. We found that younger age at baseline and longer education covary with better baseline cognitive function, with a marginal average effect of education beyond individual, geographical, and birth cohort differences. Harnessing multimodal brain MRI, we nd that this relationship is mediated by normalised grey matter, with a statistically significant pooled effect across cohorts. Using a natural experiment, we then establish the causal effect of education on cognition six decades later. By including underrepresented populations and by generalising findings, this research extends the evidence base beyond dominant Western-focused research norms, underscoring a call for inclusive and equitable access to education to enhance lifelong cognitive trajectories