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•We reviewed 33 studies of functional connectivity of emotion in healthy participants.•Our results challenge a hierarchical model of emotion processing.•Causal connectivity analyze identify dynamic modulatory relationships between regions.•We derive a quality tool to make recommendations addressing variability in study design. Existing models of emotion processing are based almost exclusively on brain activation data, yet make assumptions about network connectivity. There is a need to integrate connectivity findings into these models. We systematically reviewed all studies of functional and effective connectivity employing tasks to investigate negative emotion processing and regulation in healthy participants. Thirty-three studies met inclusion criteria. A quality assessment tool was derived from prominent neuroimaging papers. The evidence supports existing models, with primarily limbic regions for salience and identification, and frontal areas important for emotion regulation. There was mixed support for the assumption that regulatory influences on limbic and sensory areas come predominantly from prefrontal areas. Rather, studies quantifying effective connectivity reveal context-dependent dynamic modulatory relationships between occipital, subcortical, and frontal regions, arguing against purely top-down regulatory theoretical models. Our quality assessment tool found considerable variability in study design and tasks employed. The findings support and extend those of previous syntheses focused on activation studies, and provide evidence for a more nuanced view of connectivity in networks of human emotion processing and regulation.

Background Inpatient psychiatric care is a scarce and expensive resource in the National Health Service (NHS), with chronic bed shortages being partly driven by high re-admission rates. Brief inpatient talking therapies for psychosis could help reduce re-admission rates. The primary aim was to assess feasibility and acceptability of a novel, brief, mindfulness-based intervention for inpatients with psychosis. The secondary aim was to collect pilot outcome data on readmission rate, at 6 and 12 months (m) post discharge, and self-report symptom measures at 6 m. Methods The amBITION study (BrIef Talking therapIes ON wards) was a parallel group, feasibility randomised controlled trial (RCT). In addition to treatment as usual (TAU), eligible inpatients with psychotic symptoms were randomly allocated to receive either (Mindfulness-Based Crisis Intervention; MBCI) or a control intervention (Social Activity Therapy; SAT), for 1–5 sessions. Results Fifty participants were recruited (26 MBCI; 24 SAT); all received at least 1 therapy session (mean = 3). Follow-up rates were 98% at 6 m and 96% at 12 m for service use data extracted from clinical notes, and 86% for self-report measures. At 6 m follow-up, re-admission rates were similar across groups (MBCI = 6, SAT = 5; odds ratio = 1.20, 95% CI: 0.312–4.61). At 12 m follow-up, re-admissions were lower in the MBCI group (MBCI = 7, SAT = 11; odds ratio = 0.46, 95% CI: 0.14–1.51). Three participants experienced adverse events; none was related to trial participation. Conclusions Delivering a brief mindfulness-based inpatient intervention for psychosis is feasible and acceptable, and may reduce risk of short-term readmission. These promising findings warrant progression to a larger clinical effectiveness trial. Trial registration ISRCTN37625384 .

Noise stress (NS) is detrimental to many aspects of human health and behavior. Understanding the effect of noise stressors on human cognitive function is a growing area of research and is crucial to helping clinical populations, such as those with schizophrenia, which are particularly sensitive to stressors. A review of electronic databases for studies assessing the effect of acute NS on cognitive functions in healthy adults revealed 31 relevant studies. The review revealed (1) NS exerts a clear negative effect on attention, working memory and episodic recall, and (2) personality characteristics, in particular neuroticism, and sleep influence the impact of noise stressors on performance in interaction with task complexity. Previous findings of consistent impairment in NS-relevant cognitive domains, heightened sensitivity to stressors, elevated neuroticism and sleep disturbances in schizophrenia, taken together with the findings of this review, highlight the need for empirical studies to elucidate whether NS, a common aspect of urban environments, exacerbates cognitive deficits and other symptoms in schizophrenia and related clinical populations.

Background AVATAR therapy is a novel intervention targeting distressing auditory verbal hallucinations (henceforth ‘voices’). A digital simulation (avatar) of the voice is created and used in a three-way dialogue between participant, avatar and therapist. To date, therapy has been delivered over 6 sessions, comprising an initial phase, focusing on standing up to a hostile avatar, and a second phase in which the avatar concedes and focus shifts to individualised treatment targets, including beliefs about voices. The first fully powered randomised trial found AVATAR therapy resulted in a rapid and substantial fall in voice frequency and associated distress that was superior to supportive counselling at 12 weeks. The main objective of this AVATAR2 trial is to test the efficacy of two forms of AVATAR therapy in reducing voice-related distress: AVATAR-brief (standardised focus on exposure, assertiveness and self-esteem) and AVATAR-extended (phase 1 mirroring AVATAR-brief augmented by a formulation-driven phase 2). Secondary objectives include the examination of additional voice, wellbeing and mood outcomes, the exploration of mediators and moderators of therapy response, and examining cost-effectiveness of both forms of therapy compared with usual treatment (TAU). Methods This multi-site parallel group randomised controlled trial will independently randomise 345 individuals to receive AVATAR-brief (6 sessions) plus TAU or AVATAR-extended (12 sessions) plus TAU or TAU alone (1:1:1 allocation). Participants will be people with a diagnosis of schizophrenia spectrum and other psychotic disorders who have heard distressing voices for more than 6 months. The primary outcome is the PSYRATS Auditory Hallucinations Distress dimension score at 16 and 28 weeks, conducted by blinded assessors. Statistical analysis will follow the intention-to-treat principle and data will be analysed using linear mixed models. Mediation and moderation analyses using contemporary causal inference methods will be conducted as secondary analyses. Service costs will be calculated, and cost-effectiveness assessed in terms of quality-adjusted life years accrued. Discussion This study will clarify optimal therapy delivery, test efficacy in a multi-site study and enable the testing of the AVATAR software platform, therapy training and provision in NHS settings. Trial registration ISRCTN registry ISRCTN55682735 . Registered on 22 January 2020. The trial is funded by the Wellcome Trust (WT).

Environmental noise causes cognitive impairment, particularly in executive function and episodic memory domains, in healthy populations. However, the possible moderating influences on this relationship are less clear. This study assessed 54 healthy participants (24 men) on a cognitive battery (measuring psychomotor speed, attention, executive function, working memory, and verbal learning and memory) under three (quiet, urban, and social) noise conditions. IQ, subjective noise sensitivity, sleep, personality, paranoia, depression, anxiety, stress, and schizotypy were assessed on a single occasion. We found significantly slower psychomotor speed (urban), reduced working memory and episodic memory (urban and social), and more cautious decision-making (executive function, urban) under noise conditions. There was no effect of sex. Variance in urban noise-induced changes in psychomotor speed, attention, Trail Making B-A (executive function), and immediate recall and social noise-induced changes in verbal fluency (executive function) and immediate recall were explained by a combination of baseline cognition and paranoia, noise sensitivity, sleep, or cognitive disorganization. Higher baseline cognition (but not IQ) predicted greater impairment under urban and social noise for most cognitive variables. Paranoia predicted psychomotor speed, attention, and executive function impairment. Subjective noise sensitivity predicted executive function and memory impairment. Poor sleep quality predicted less memory impairment. Finally, lower levels of cognitive disorganization predicted slower psychomotor speed and greater memory impairment. The identified moderators should be considered in studies aiming to reduce the detrimental effects of occupational and residential noise. These results highlight the importance of studying noise effects in clinical populations characterized by high levels of the paranoia, sleep disturbances, noise sensitivity, and cognitive disorganization.

Background People with psychosis have high rates of trauma, with a post-traumatic stress disorder (PTSD) prevalence rate of approximately 15%, which exacerbates psychotic symptoms such as delusions and hallucinations. Pilot studies have shown that trauma-focused (TF) psychological therapies can be safe and effective in such individuals. This trial, the largest to date, will evaluate the clinical effectiveness of a TF therapy integrated with cognitive behaviour therapy for psychosis (TF-CBTp) on post-traumatic stress symptoms in people with psychosis. The secondary aims are to compare groups on cost-effectiveness; ascertain whether TF-CBTp impacts on a range of other meaningful outcomes; determine whether therapy effects endure; and determine acceptability of the therapy in participants and therapists. Methods Rater-blind, parallel arm, pragmatic randomised controlled trial comparing TF-CBTp + treatment as usual (TAU) to TAU only. Adults ( N = 300) with distressing post-traumatic stress and psychosis symptoms from five mental health Trusts (60 per site) will be randomised to the two groups. Therapy will be manualised, lasting 9 months (m) with trained therapists. We will assess PTSD symptom severity (primary outcome); percentage who show loss of PTSD diagnosis and clinically significant change; psychosis symptoms; emotional well-being; substance use; suicidal ideation; psychological recovery; social functioning; health-related quality of life; service use, a total of four times: before randomisation; 4 m (mid-therapy); 9 m (end of therapy; primary end point); 24 m (15 m after end of therapy) post-randomisation. Four 3-monthly phone calls will be made between 9 m and 24 m assessment points, to collect service use over the previous 3 months. Therapy acceptability will be assessed through qualitative interviews with participants ( N = 35) and therapists ( N = 5–10). An internal pilot will ensure integrity of trial recruitment and outcome data, as well as therapy protocol safety and adherence. Data will be analysed following intention-to-treat principles using generalised linear mixed models and reported according to Consolidated Standards of Reporting Trials-Social and Psychological Interventions Statement. Discussion The proposed intervention has the potential to provide significant patient benefit in terms of reductions in distressing symptoms of post-traumatic stress, psychosis, and emotional problems; enable clinicians to implement trauma-focused therapy confidently in this population; and be cost-effective compared to TAU through reduced service use. Trial registration ISRCTN93382525 (03/08/20)

Background Paranoia, the belief that you are at risk of significant physical or emotional harm from others, is a common difficulty, which causes significant distress and impairment to daily functioning, including in psychosis-spectrum disorders. According to cognitive models of psychosis, paranoia may be partly maintained by cognitive processes, including interpretation biases. Cognitive bias modification for paranoia (CBM-pa) is an intervention targeting the bias towards interpreting ambiguous social scenarios in a way that is personally threatening. This study aims to test the efficacy and safety of a mobile app version of CBM-pa, called STOP (successful treatment of paranoia). Methods The STOP study is a double-blind, superiority, three-arm randomised controlled trial (RCT). People are eligible for the trial if they experience persistent, distressing paranoia, as assessed by the Positive and Negative Syndrome Scales, and show evidence of an interpretation bias towards threat on standardised assessments. Participants are randomised to either STOP (two groups: 6- or 12-session dose) or text-reading control (12 sessions). Treatment as usual will continue for all participants. Sessions are completed weekly and last around 40 min. STOP is completely self-administered with no therapist assistance. STOP involves reading ambiguous social scenarios, all of which could be interpreted in a paranoid way. In each scenario, participants are prompted to consider more helpful alternatives by completing a word and answering a question. Participants are assessed at baseline, after each session, and at 6, 12, 18 and 24 weeks post-randomisation. The primary outcome is the self-reported severity of paranoid symptoms at 24 weeks, measured using the Paranoia Scale. The target sample size is 273 which is powered to detect a 15% symptom reduction on the primary outcome. The secondary outcomes are standardized measures of depression, anxiety and recovery and measures of interpretation bias. Safety is a primary outcome and measured by the Negative Effects Questionnaire and a checklist of adverse events completed fortnightly with researchers. The trial is conducted with the help of a Lived Experience Advisory Panel. Discussion This study will assess STOP’s efficacy and safety. STOP has the potential to be an accessible intervention to complement other treatments for any conditions that involve significant paranoia. Trial registration ISRCTN registry, ISRCTN17754650. Registered on 03/08/2021.  https://doi.org/10.1186/ISRCTN17754650 .

Background The field of digital mental health has followed an exponential growth trajectory in recent years. While the evidence base has increased significantly, its adoption within health and care services has been slowed by several challenges, including a lack of knowledge from researchers regarding how to navigate the pathway for mandatory regulatory approval. This paper details the steps that a team must take to achieve the required approvals to carry out a research study using a novel digital mental health intervention. We used a randomised controlled trial of a digital mental health intervention called STOP (Successful Treatment of Paranoia) as a worked example. Methods The methods section explains the two main objectives that are required to achieve regulatory approval (MHRA Notification of No Objection) and the detailed steps involved within each, as carried out for the STOP trial. First, the existing safety of digital mental health interventions must be demonstrated. This can refer to literature reviews, any feasibility/pilot safety data, and requires a risk management plan. Second, a detailed plan to further evaluate the safety of the digital mental health intervention is needed. As part of this we describe the STOP study’s development of a framework for categorising adverse events and based on this framework, a tool to collect adverse event data. Results We present literature review results, safety-related feasibility study findings and the full risk management plan for STOP, which addressed 26 possible hazards, and included the 6-point scales developed to quantify the probability and severity of typical risks involved when a psychiatric population receives a digital intervention without the direct support of a therapist. We also present an Adverse Event Category Framework for Digital Therapeutic Devices and the Adverse Events Checklist—which assesses 15 different categories of adverse events—that was constructed from this and used in the STOP trial. Conclusions The example shared in this paper serves as a guide for academics and professionals working in the field of digital mental health. It provides insights into the safety assessment requirements of regulatory bodies when a clinical investigation of a digital mental health intervention is proposed. Methods, scales and tools that could easily be adapted for use in other similar research are presented, with the expectation that these will assist other researchers in the field seeking regulatory approval for digital mental health products.