NIHRDataInsights/HRCSData huggingface dataset:
Title: Detecting early signs of relapse in psychosis using remote monitoring technology
Funder: Medical Research Council

Abstract: AIM: To investigate the association between disturbances in sleep and circadian rhythm, motor activity, and heart rate variability (predictor variables), and symptomatic deterioration and relapse (outcome variables) in psychosis, using remote monitoring technology (RMT). OBJECTIVES 1) To use RMT to collect predictor and outcome variables in 50 patients with psychosis for up to a year. 2) To evaluate the predictive value and temporal relationship of the bio-signatures for relapse, individually and in combination. 3) To identify evidence for sleep and circadian rhythm disturbance playing a causal role in the development of psychopathology. 4) To gain specific skills in the use and development of RMT in psychiatry, that will allow me to play a role in the future development and evaluation of clinical prediction tools. METHODOLOGY Objective 1: A sample of 50 individuals with psychosis will use the RMT for 12 months. Predictor variables will be gathered using a wrist-worn device and smartphone sensors. Outcome variables are obtained from a twice-weekly, validated smartphone symptom questionnaire, and from fortnightly review of the electronic patient record. Objectives 2 and 3: The strength and temporal association between predictors and outcomes will be modelled using multilevel modelling (continuous symptom fluctuation outcomes) and penalised functional regression (binary relapse outcomes). Additionally, predictive modelling (machine learning) approaches will be used to explore these associations. Objective 4: I will fulfil this training objective through the running of this study, and in visits to project supervisors and collaborators at this and other centres of expertise. SCIENTIFIC AND MEDICAL OPPORTUNITIES Results may have far-reaching implications for the development of a relapse prediction tool for psychosis, and for understanding the relationship between sleep disruption and psychopathology.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Does cannabis use modulate brain glutamate levels in early psychotic illness?
Funder: Medical Research Council

Abstract: Schizophrenia is a devastating disease with around 30-40% of patients using cannabis at presentation. Why cannabis-using patients have worse outcomes is unclear. Dysfunction of glutamatergic pathway may explain this, with demonstrable abnormalities detected on proton magnetic resonance spectroscopy (1H-MRS) in both psychotic patients and cannabis-users. However, no study to date has compared glutamatergic abnormalities in cannabis-using and non- using patients with psychosis. This is important as establishing an alternative biochemical abnormality in cannabis-using patients may suggest alternative pharmacological treatment for this group. Furthermore memory has consistently been noted to be impaired in both cannabis use and psychosis. Yet whether functioning of the critical neural substrate for memory, in particular the medial temporal cortex is altered in cannabis-using patients with psychosis compared to non-users, has never been tested. This study will therefore examine whether differences exist in brain glutamatergic levels and verbal learning between cannabis-using and non-using patients with psychosis. I will study the following three cohorts: cannabis users (n=30); non-cannabis users (n=30); alongside healthy controls (n=20). Participants will be interviewed using SCID to confirm diagnoses, the Cannabis Experiences Questionnaire (CEQ), Severity of Dependence Scale (SDS), and other measures; and interviewed to ascertain duration of illness, history of relapse/ hospitalisation, dose and duration of antipsychotic and other psychotropic drug exposure and severity of psychopathology. Participants will be studied using a combination of 1H-MRS and functional MRI (fMRI). Region of Interest analysis will be undertaken in the left Hippocampus and left Anterior Cingulate Cortex, key regions implicated in psychotic illness.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: MENTAL HEALTH
Title: MICA: Correction of behavioural, circuit and cellular deficits in rat models of ID/ASD
Funder: Medical Research Council

Abstract: Intellectual disabilities (IDs) and autism spectrum disorders (ASDs) are co-occurring neurodevelopmental disorders (NDDs). With a prevalence estimated at 2-3% of the population, between 1-2 million people in the UK alone have an ID/ASD. The urgent unmet need, therefore, is to develop more effective therapeutics to reverse and/or prevent the emergence of the core deficits associated with ID/ASD. Two areas of research have provided a sea change in how we envision potential treatments for NDDs. First, evidence suggests that genetically disparate NDDs converge on relatively few axes of pathophysiology that are susceptible to common therapeutic intervention. Second, at least some forms of these disorders may be treatable throughout the lifespan. The experiments outlined in this proposal take advantage of two recently developed rat models for FXS and SYNGAP haploinsufficiency, two of the most common genetic forms of ID/ASD. It builds on our recent publications and preliminary data to address these key research areas. The experiments outlined in this proposal will test our two hypotheses: 1) FXS and SYNGAP haploinsufficiency converge on common pathophysiology in the hippocampus, prefrontal cortex and amygdala. 2) The cellular and behavioural phenotypes associated with loss of FMRP and SYNGAP can be reversed throughout the lifespan in an age, treatment, and circuit-specific manner. By focusing on two clinically-relevant brain circuits that regulate learning and memory emotion and anxiety/fear we will determine whether deficits associated with these disorders can be prevented and/or reversed as well as whether any beneficial effects are permanent.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH
Title: Reducing the harmful effects of cannabis use: finding the optimal CBD:THC ratio
Funder: Medical Research Council

Abstract: The legislative landscape of cannabis has been changing recently; all while prevalence and negative cannabis related outcomes have been on the rise. Interventions to prevent or reduce cannabis use have been unsuccessful to date. Therefore, manipulation of CBD levels in cannabis may be a viable way to minimise cannabis related harms, in places where cannabis is regulated. This will be a randomised, double-blind, 4-arm, cross-over, within-subjects design study in healthy volunteers being administered different intra-pulmonary cannabis preparations with varying CBD:THC ratios. Forty five female and male volunteers, aged between 21-50, and who have used cannabis at least once and no more than once per week on average in the last year will be invited for a screening/baseline visit. Participants will be excluded if they have a past history of major mental or physical illness, a first degree family member with psychosis, history of drug or alcohol dependence, current pregnancy or lactation in women, currently taking prescription medication (except oral contraceptives), positive urine drug screen at any study visit, alcohol use within the last 24h hour, and weekly use over recommended limits. At each experimental visit, participants will be administered a vaporised cannabis preparation containing CBD:THC ratios of 0:1, 1:1, 2:1, and 3:1 (CBD: 10-30mg, THC: 10mg, loaded). This will be followed by a social interaction task (purchase item in hospital shop), a comprehensive cognitive test battery and clinical assessment of psychopathology. Blood samples and vital signs will be collected at 5min, 15min and 1h post-inhalation to analyse plasma THC and CBD levels, as well as their relevant metabolites. We predict that CBD will in a dose dependent manner reduce the negative impact of THC on cognition and psychopathology, while not influencing its intoxicating properties. We expect these effects to be due to the CBD:THC ratio and not due to changes in THC plasma levels.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: MENTAL HEALTH
Title: Self-control and motivation in addictions
Funder: Medical Research Council

Abstract: Harmful alcohol use is a major international public health issue. It remains poorly treated emphasizing the need for novel therapeutic approaches. Understanding the interaction of self-control and motivation is crucial to the capacity to regulate behavior and to the risk for and relapse underlying substance use disorders. Impulsivity or self-control is a heterogeneous construct with multiple subtypes. Waiting impulsivity, a subtype of impulsivity, characterized by anticipatory early responses, has a robust preclinical history and association with addictions but is poorly understood in humans. Waiting impulsivity itself is comprised of multiple components. Here I propose a model of waiting impulsivity involving intentional inhibition and motivation mediated by opponent dorsomedial and ventral prefrontal processes. Intentional inhibition is a uniquely human construct involving the inhibition of responding based on internal and voluntary processes which are likely highly relevant to the real world self-control of addictions. I use a novel task developed in my group and multimodal techniques in healthy controls to interrogate the underlying neural architecture of intentional inhibition and motivation. I then uniquely capitalize on patient populations who have undergone deep brain stimulation to allow direct modulation and dissociation of these relevant networks to understand the underlying cognitive neuroanatomy. I then test a mechanistically-informed intervention for alcohol use disorders combining a behavioural intervention to train self-control and non-invasive neuromodulation to enhance network activity. Finally, I seek to contextualize these measures at the population neuroscience level and ask how these factors predict addiction behaviours on a data-driven dimensional population level. Together these studies emphasize a testable theory-driven neurobiologically coherent model of waiting impulsivity with immediate translational treatment for addictions.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH
Title: PRO-YOUTH TRIAL: Protecting Youth from Interpersonal Violence via Implementation of the Strengthening Families Programme 10-14 in Panama
Funder: Medical Research Council

Abstract: Objective: This study assesses implementation of the Strengthening Families Programme for adolescents 10-14 years old (SFP 10-14) in Panama. Design: This is a cluster randomized controlled implementation trial. A total of 28 sites will be randomly allocated to implementation of SFP 10-14 or services as usual. Families (N = 840) will be assessed at baseline, post-intervention, 6 months, and 12 months after baseline. Outcomes will be youth externalizing difficulties as measured by the Child Behaviour Checklist (CBCL). Other outcomes will be youth pro-social competencies (Normative Beliefs Scale), family functioning (Family Relationship Index), parental discipline (Children's Report of Parent Behaviour Inventory & Parenting Scale), parental stress (Depression Anxiety Stress Scale), substance misuse (SFP 10-14 scale), academic performance (school grades), delinquency (Self-report Delinquency Scale), and gang involvement (Jamaica Survey of Gang Involvement). Process Evaluation: Recruitment, attendance, fidelity, and receipt will be measured. Key influences on intervention implementation will be explored, such as interaction between the intervention and local context. Finally, potential sustainability of the intervention beyond the trial will be assessed. Process data will be collected by 1) monitoring recruitment, attendance, group composition, and staff numbers, 2) fidelity ratings of sessions by facilitators and research assistants, 3) and qualitative interviews with facilitators, trainers, families and adolescents to explore barriers/facilitators to implementation, variations across sites and time, and systems/structures needed for sustainability. Economic Evaluation: Costs and consequences associated with implementation of the intervention will be identified. Service use information will be gathered with a 3-month recall period. Within-trial cost-effectiveness analysis will be performed and Incremental Cost Effectiveness ratios will be estimated.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: MENTAL HEALTH
Title: The Friendship Bench for adolescents: evaluating strategies for scaling interventions to treat common mental disorders among adolescents in Zimbabwe
Funder: Medical Research Council

Abstract: We recently completed a cluster randomised trial of a lay health worker (LHW) delivered intervention for common mental disorders (CMD) in Zimbabwe called the Friendship Bench Intervention (FBI); (www.friendshipbenchzimbabwe.org). It was very effective among primary healthcare clinic (PHC) attenders aged 18 or older. The FBI comprises 6-sessions of problem-solving therapy, delivered by a trained LHW, stepped-up to treatment by a nurse for those who do not recover. Scale up of the FBI is funded from April 2016 to 60 clinics in 3 cities in Zimbabwe. Trial data indicate that the FBI was equally effective in those aged 18-22 as in older adults but few young people attend PHCs. We hypothesise that implementation of the FBI as part of a youth friendly package will i) increase the demand for and uptake of the FBI among 16-19 year olds compared to usual care FB delivery; and ii) be an effective, cost-effective, and sustainable model to treat CMD among 16-19 year olds. We will evaluate the uptake, effectiveness and cost-effectiveness of two strategies among 16-19 year olds with CMD. The two strategies are 1) the usual care FBI with delivery extended to include 16-17 year olds; 2) a youth-friendly FBI package. We will randomize 30 clinics to receive the usual care FBI and 30 to the youth friendly FBI package. Individuals aged 16-19 years who screen positive for CMD using the locally validated Shona Symptom Questionnaire (SSQ-14) will be enrolled. A random sample of 500 eligible participants will be recruited to take part in the outcome evaluation after 6 months. This will include a comprehensive mental health assessment using the SSQ-14, Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7) and WHO Disability Assessment Schedule (WHO-DAS). A detailed process evaluation and cost effectiveness study will be conducted. Our aim is that this study will result in a sustainable, effective adolescent component to complement the existing FBI for adults.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: MENTAL HEALTH
Title: MICA: 5-HT4 receptor activation as a novel mechanism of antidepressant action
Funder: Medical Research Council

Abstract: The study will explore the potential antidepressant effect of PF-04995274, a novel 5-HT4 receptor partial agonist originally developed by Pfizer for dementia and cognitive impairment. We will use an experimental medicine model, sensitive to the early effects of antidepessant drug treatment, in depressed patients. This battery of tasks measures different aspects of emotional processing (perception, memory, attention and physiological reactivity) and is affected early in treatment by a range of antidepressant drug treatments. The study will recruit two groups of depressed patients, those currently unmedicated and those who have failed to respond to current SSRI treatment. In study one, unmedicated patients will be randomised to PF-04995274, citalopram (as a positive control) or placebo. In study two, patients not responding to current therapy will be randomised to either the addition of PF-04995274 or placebo while they continue their current treatment. The treatment period in both studies will be seven days. Study design will be parallel group, double-blind, placebo-controlled and with emotional processing measured before and after the seven day treatment period. It is hypothesised that PF-04995274 will show antidepressant-like effects in these models, expressed as an increase in perception and memory for positive vs negative stimuli. A positive screen in these models would provide support for assessment of 5HT4 agonists in the treatment of depression.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH
Title: Real-time fMRI Neurofeedback as a novel neurotherapy for children with ADHD
Funder: Medical Research Council

Abstract: The aim is to test the efficacy of a novel, non-pharmacological, neural-correlate focussed therapy for ADHD with no side-effects, expected to be welcomed by patients, parents and professionals. Attention Deficit Hyperactivity Disorder (ADHD) is one of the most prevalent childhood disorders, typified by poor attention and self-control. One of the most consistent and disorder-specific neurofunctional biomarkers is the underactivation of right inferior prefrontal cortex (rIFC), which is upregulated with psychostimulants, the benchmark treatment for ADHD. However, longer-term efficacy of stimulant medication has not been shown, it is associated with side effects and is not indicated for all patients. Non-pharmacological treatments are preferred, but have modest efficacy. We hypothesise that Neurofeedback (NF) that teaches patients to achieve volitional self-control over the key rIFC dysfunction region is likely to be successful. NF using electrophysiology has shown moderate but relatively long-term efficacy in improving ADHD symptoms. Real-time functional magnetic resonance imaging neurofeedback (rtfMRI-NF) effects are significantly faster and can target deep (sub)cortical regions that are impaired in ADHD such as rIFC. rtfMRI-NF has been promising in other disorders in remediating key neurofunctional substrates and associated behaviours. Our pilot feasibility rtfMRI-NF study showed that ADHD children can learn to self-regulate rIFC within 11 sessions of 8.5min each with significant transfer effects which is associated with improved clinical symptoms and inhibitory rIFC activation. However, placebo effects cannot be ruled out as we did not include a sham control condition. We therefore plan a larger and more definite data-driven proof of concept study to test the efficacy of a novel neurotherapy for ADHD consisting of rtfMRI-NF of rIFC in 100 children with ADHD, randomised into active and sham control groups, on improving ADHD behaviour, brain function and cognition.


Research activity codes: 5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH
Title: How does cannabis use affect teenagers' brains, cognitive functions and psychological well-being? (CANN-TEEN)
Funder: Medical Research Council

Abstract: In line with preclinical research on adolescent rats and monkeys, and the known importance of the endocannabinoid system in adolescent neurodevelopment, we recently found that teenage humans (16-17 year olds) show a markedly different response profile from adults to acute cannabis: more impulsivity, less satiety (wanting more cannabis) whilst also experiencing significantly fewer negative effects than adults. This project aims to address the following questions: how does cannabis use over a 12 month period affect the brain, cognitive function, symptoms of addiction and of psychosis in 16-17 year olds compared with adults? And can CBD lessen the harms induced by THC in teenagers as it has been found to in adults? Study 1 recruits 360 individuals aged - 16-17 and 26-27 who do and do not use cannabis frequently - and assesses them every 3 months for a year, taking objective measures of cannabis (THC, CBD), alcohol & other drug use in hair, urine and saliva, serum anandamide, and cognitive function & psychological well-being. Study 2 uses s/fMRI to compare a sub-set of the same groups at baseline and +12 months. Study 3 uses pharmacological fMRI to compare teenagers and adults who use cannabis in their acute response to different cannabis strains (THC+CBD, THC-CBD, matched placebo). Motivations to use cannabis and beliefs about the drug/strains will be explored in interviews, and analyses will examine why some individuals are vulnerable and others resilient to its harmful effects. If we show differential effects in teenagers and adults then this would be a clear evidence-base for prevention messages (e.g. avoid or delay initiation of cannabis use to adulthood; only use strains with significant CBD content or take CBD supplements). This could lead to a new era of safer cannabis use. Importantly, it could significantly reduce the numbers of young people in the UK currently in treatment for addiction or psychosis who may not have become ill had they not used this drug.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH
Title: Dopaminergic and glutamatergic contribution to the formation of decision variables in fronto-parietal brain circuits
Funder: Medical Research Council

Abstract: Decision making requires accumulation of evidence, evaluation of its quality, and setting a bound to terminate the accumulation once sufficient evidence is available. Neural correlates of perceptual decision making have been delineated in different cortical and subcortical areas, in particular in areas LIP (and less so) FEF/DLPFC. Specifically, neuronal activity in LIP follows predictions from bounded drift diffusion models, where momentary noisy evidence is integrated loss less until it reaches a threshold, thereby triggering the decision. To date we do not understand the mechanisms involved. Theoretical work suggests that the process of evidence accumulation is achieved through slow recurrent excitation, signalled by NMDA receptors, in conjunction with feedback inhibition in local networks. At the same time, Parkinson patient data suggest that evidence accumulation depends on dopaminergic signalling. Given the close interaction of dopaminergic and NMDA receptors, it is likely that both systems are critical for adequate decision making and normal cognitive operations. We will determine which aspect of decision making are supported by D1, D2 and different NMDA (NR2A, NR2B) receptors, by recording single unit activity in area LIP, FEF and DLPFC under control conditions and when D1, D2, and NMDAR agonists and antagonists are applied in the vicinity of the recorded neurons while animals perform a reaction time stochastic motion task or a sequential symbol sampling task. The rich theoretical and analytical framework, generated by previous studies, will help determine which aspects of decision making are affected by our drug manipulations. We predict that the quality of the integrator will depend on NMDAR availability, the speed of accumulation will be controlled by D1 receptors, and the conversion to a categorical decision by D2 receptors. These hypotheses will be tested by systematically varying specific stimulus parameters and speed-accuracy trade-offs.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH