NIHRDataInsights/HRCSData huggingface dataset:
Title: Zebrafish behavioural assays to identify genetic mechanisms underlying drug seeking and addiction.
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Human studies demonstrate that genetic factors contribute to an individual’s vulnerability to drug dependence but few genetic markers have been identified. Nonetheless, recent evidence suggests that tailoring treatment to individual characteristics based on the small number of available genetic markers improves treatment outcomes. Impulsivity and novelty seeking are risk factors for vulnerability to drug dependence; novelty seeking predicts propensity to initiate drug taking, impulsivity is associated with progression to compulsive drug taking and return to drug taking following abstinence (relapse). These latter aspects are key characteristics of drug addiction with relapse presenting the greatest challenge for treatment. Increasing understanding of the genetic contributions to drug seeking behaviour will aid development of new therapies to improve treatment outcomes. Here we develop assays of impulsivity and novelty seeking in zebrafish and use these to selectively-breed lines to identify genetic mechanisms contributing to drug addiction. We have shown previously that zebrafish have a conserved reward response to drugs of abuse and have developed assays of compulsive drug seeking and relapse in zebrafish. Here we use modifications of the novel object, open field assay and delayed reward tasks used in rodents to relate novelty seeking and impulsivity in zebrafish to drug seeking behaviour. Once assays predictive of drug seeking in zebrafish are developed we will use these to screen adults from families of ENU-mutagenised fish to establish lines that show altered drug seeking behaviour. ENU-mutagenesis introduces single nucleotide variations in the genome that may alter drug seeking behaviour and act as markers for genome association studies. The existence of ENU-mutagenised zebrafish lines is an enormous resource facilitating the identification of linked alleles in zebrafish not available in other vertebrate species. In order to obtain a similar resource in rodents expensive, ethically and technically challenging mutagenesis programmes would be required. As the neurochemical pathways involved in drug seeking are evolutionarily conserved and there is a high degree of sequence and functional homology between zebrafish and mammalian genes, results found in zebrafish have translational relevance. Use of zebrafish for neurobehavioural research represents a great opportunity for reduction of the use of higher order vertebrate species thereby reducing animal suffering. The development of zebrafish lines with heightened sensitivity to drugs of abuse and establishment of suitable assays has the potential to minimise costs, both material and ethical, in drug development programmes.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Imaging sensorimotor interactions during speech communication
Funder: Medical Research Council

Abstract: Spoken language is a powerful communication tool, which is unique to humans. Growing evidence shows that both motor and sensory systems in the human brain are engaged in speech production and perception. Fluent speaking involves coordination of precise movements of articulatory organs and monitoring of both somatosensory and auditory consequences of these movements. Speech comprehension, on the other hand, involves auditory analysis of acoustic speech signals and mapping these signals onto motor articulatory gestures. Viewing a talker‘s speech gestures (i.e., lipreading) is an important component of natural face-to-face communication, which engages the motor system and multiple sensory (visual, auditory, and somatosensory) systems How interactions between motor and sensory systems support fluent speaking and efficient analysis of acoustic and visual speech signals is still poorly understood. The present research project will address these fundamental questions by using a novel method, which combines brain stimulation and imaging. We will use transcranial magnetic stimulation (TMS) to disrupt the regions in the motor cortex that control movements of articulators and functional MRI (fMRI) and magnetoencephalography (MEG) to measure the consequences of these motor disruptions on processing of sensory signals. This method will reveal whether sensory systems are functionally connected with the motor system during processing of speech signals. The project also uses fMRI to examine functional connectivity between motor and sensory systems during speech communication in fluent speakers and in people who stutter. We aim to determine whether in stuttering speakers functional coupling between the motor and sensory systems during speech perception and production is abnormal. We will also examine the effects of TMS-induced motor disruption on the sensorimotor mechanisms supporting fluency of speech. Delayed auditory feedback (DAF) reduces fluency in normal speakers, but improves it in people who stutter. We will test whether a new promising brain stimulation method (direct current stimulation, DCS) could prolong the effects of DAF on fluency in people who stutter. In sum, the research project is expected to provide new knowledge on the interregional connections that support speech perception and production in the healthy brain and in the brain of people who stutter. The findings will lead to better understanding of the neural basis of speech communication and possibly to development of better treatments for speech and language problems


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Investigation of the roles of CMIP and ATP2C2 in Specific Language Impairment (SLI).
Funder: Medical Research Council

Abstract: Specific Language Impairment (SLI) is diagnosed in children who experience profound language deficits despite otherwise normal development and in the absence of any obvious explanatory factors. Our previous research has identified association between SNPs in two genes on chromosome 16 (CMIP and ATP2C2) and a quantitative measure of language ability, nonword repetition. This test involves the repetition of nonsensical words and is particularly problematic for individuals with SLI, leading to the postulation that this disorder may be caused by a phonological short-term memory deficit. The primary aim of the proposed project is to identify the specific causal variants that underlie the association on chromosome 16. This will be achieved by a multifaceted approach involving variant cataloguing, bioinformatic analyses, mutation screening, expression (and, if necessary, post-transcriptional) assays and functional characterisation. Initial investigations aim to take advantage of recent advances in sequencing technologies to catalogue variants across the 3Mb region of association. The putative function of identified variants will be investigated in-silico exploiting available information from relevant experiments such as expression-QTL databases, chromatin immunoprecipitation assays and cross-species sequencing. Identified variants will be genotyped in our family-based SLI sample and subjected to quantitative association analyses. Concurrent high-throughput sequencing of proband DNA will enable the identification of causative mutations or allow the detection of an increased mutational load. Complementary expression assays will focus the attention of the study to the modulation of specific transcripts. The amalgamation of the information yielded by these various routes of investigation will allow the generation of a ‘short-list‘ of possible causative variants that will subsequently verified in-vitro. The techniques applied in these stages will be particular to the variants in hand but are likely to involve the generation of luciferase reporter vectors, Electrophoretic Mobility Shift Assays (EMSAs), immunocytochemistry and RNAi. The information arising from this investigation will highlight specific variants and mechanisms which underlie the association between the genetic sequence on chromosome 16 and nonword repetition performance. This, in turn, will allow the formation of functional hypotheses that will direct future studies of SLI and related disorders. Ultimately, the data generated from this project will inform our understanding of the biological basis of language impairment and language acquisition. An understanding of these systems will help the early identification of affected individuals and allow the design of better diagnostic programs and intervention therapies and may have wider implications for the study and treatment of associated developmental disorders.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: MOLECULAR GENETICS OF BIPOLAR AFFECTIVE DISORDER
Funder: Medical Research Council

Abstract: A case control sample of 2,000 bipolar affective disorder cases and 2,000 controls will be used for further research into the genetic variation causing susceptibility to bipolar and genetically related unipolar affective disorders. The aim is to use the genetic information to understand the molecular pathology in the brain and to design better treatment and preventive strategies. We have already identified several susceptibility genes in the UCL sample and have partially sequenced the DNA of the ANKYRIN3, GRM7, SLC1A2, TRPM2, SLYNAR and IGF1 genes. We now wish to carry out further exploration of potential aetiological base pair variants found in these genes by genotyping them in the whole enlarged case control sample. In the case of the SYNE1, ANKYRIN3, GRM7 and SLC1A2 genes we wish to extend this sequencing using high through put methods in a greater number of cases as well as to continue sequencing several further genes which are strongly associated with bipolar disorder in the UCL sample. In addition we now wish to make further use of the family lineality and sex of parent transmission data we have in order to find subgroups of cases showing major gene transmission and susceptibility genes which have methylation patterns that correlate with parental sex of transmission. We also wish to explore the genetic role of afective disorder genes in a case control sample of the alcohol dependence syndrome. Lastly we wish to continue to contribute to international collaborations that are generating large enough sample sizes to fully explore the relationship between genetic effects and clinical variables such as prognosis and response to treatment.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Lifestyle Matters
Funder: Medical Research Council

Abstract: The research being proposed is a population based clinical and cost evaluation of an intervention which aims to assist older people to make positive changes to their lifestyle and by doing so avoid the decline associated with poor mental health and low quality of life. The intervention ?Lifestyle Matters? is recommended in NICE guidance but has not been robustly evaluated. It is delivered weekly to the same group of older people in a local community venue by facilitators who are trained using an existing resource and then supervised throughout. The intervention involves using a range of techniques to enable individuals to learn new activities and/or re-engage with neglected activities in a supportive atmosphere. The group intervention extends over four months and is supplemented by monthly individual sessions for each participant as described in the published manualised programme. The research will involve recruiting people aged 65 years and over to the study from local communities in Bangor and Sheffield. Those who meet the study inclusion criteria will be randomised to either receive the intervention or to participate in data collection for the purposes of the study. The aim is to recruit 268 older people, with 134 being randomised to receive the intervention. All those recruited will be asked to complete a range of measures in questionnaire format at the outset, immediately following cessation of intervention delivery (4 months later) and once more 12 months after baseline measurement. They will all be asked to record their use of health and social care services. The primary study outcome is improved mental health. Secondary outcomes include overall quality of life, resilience and self efficacy, experience of loneliness and depressive symptoms and costs of involvement in the intervention compared with use of other existing services. Data will be analysed to determine whether the intervention has positive effect upon mental well being as well as the other factors mentioned above, and if there is a positive effect, to examine if it is maintained over time. We also wish to explore the possibilities that this intervention might have for others with different needs and at various stages of the life course and will consult locally and nationally to identify the best populations to work with. We will then test the feasibility of Lifestyle Matters with the identified populations in each location by recruiting and delivering the programme and interviewing both facilitators and participants about their experiences.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: MENTAL HEALTH
Title: A monitoring device to objectively assess functional/ psychosocial impairment in older-age adults with major depression
Funder: Medical Research Council

Abstract: Depression is one of the most common psychiatric disorders, with at least one in six adults meeting the criteria for a major depressive episode at some time in their life. In later-life depression has a huge negative impact on quality of life and is directly associated with functional impairment. Although the illness is defined by the occurrence of low mood, over recent years there has been an increasing understanding of the profile and magnitude of neuropsychological impairments in mood disorders. These have been shown to be of greater magnitude in older age individuals. One of the most important consequences of neuropsychological and emotional processing deficits is their impact on social and everyday functioning and disability. To date, most studies in older age individuals have utilised questionnaire-based measures of everyday function which have major problems with accuracy and validity as they either rely on informant accounts or are self-report. Technological advances such as the actigraph have enabled more precise assessment of locomotor activity and circadian rhythms in normal, everyday living, while within the pervasive computing community, social informatics technologies based on auditory signal processing have been developed that can measure aspects of social interaction using situated measures of spoken communication. The aims of this pilot study are to develop a truly novel, sensitive worn monitoring device that integrates direct measures both physical activity and social interaction, to use these measures to examine daily activity and social interaction in older age individuals. The instrument will be piloted in older healthy individuals and then depressed patients and the relationship between the device output and illness features, clinical characteristics and neuropsychological performance explored. These results will be compared to those achieved using current measures of social function and activity.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: MENTAL HEALTH
Title: An investigation of parent-child interactions in anxious adolescents and a pilot evaluation of a novel family treatment
Funder: Medical Research Council

Abstract: Aims Anxiety disorders in adolescents are common and disabling; indeed they are known to be more common, severe and co-morbid than in younger children. However, although cognitive-behaviour therapy (CBT) has been demonstrated to be effective in treating anxiety disorders in young people, treatments have been developed principally for children and the specific needs of adolescents have not been adequately addressed. There is evidence that parents of anxious children are more controlling and model more avoidant behaviour than parents of non-anxious children. Family factors appear also to be a significant factor in relation to adolescent anxiety, however studies are limited in the extent to which causal associations can be concluded. The aims of the proposed research are to (i) clarify the family processes experienced by anxious adolescents, in comparison to anxious children and non-anxious adolescents; (ii) establish experimentally whether family processes have a causal influence on adolescent anxiety; (iii) develop and pilot a novel cognitive-behavioural treatment that targets the key parental processes which maintain adolescent anxiety. Objectives 1. To conduct a systematic cross-sectional observational study to enhance understanding of the family processes associated with adolescent anxiety. 2. To conduct experimental studies to test the causal link between parenting behaviours identified in the observational study and anxiety in adolescents. 3. To conduct a pilot study of a parental-behaviour focused adjunct to standard CBT for adolescent anxiety. Design 1. Three groups will be recruited (i) anxious adolescents, (ii) non-anxious adolescents, and (iii) anxious children. Assessments will be made of anxiety symptoms and diagnoses, common co-morbid disorders and parent-offspring interactions. Observational assessments of interactions between participants and their primary caregiver will be made and rated. 2. Experimental studies will be carried out with non-anxious adolescents and their primary caregiver. This will involve manipulating caregiver behaviour via training and then asking them to support their adolescent perform a challenging task. Adolescent response to the task will be assessed. 3. Clinically anxious adolescents will be randomised to receive either CBT + control family intervention or CBT + parent-focused intervention that targets behaviours identified in the observational and experimental studies. Scientific and medical opportunities The proposed research is of both scientific and clinical importance as it will (i) contribute to a greater understanding of the role of family factors in adolescent anxiety, and (ii) improve clinical interventions for anxious adolescents.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH
Title: Psychobiological sequelae of cumulative exposure to violence: The Environmental Risk Longitudinal Twin Study
Funder: Medical Research Council

Abstract: BACKGROUND: We propose to test the hypothesis that a history of violence exposure in early life increases individuals? risk of compromised psychobiological health, thereby mediating the pathway from stress in childhood to physical and mental illnesses in adulthood. Using innovative approaches, we will test whether young people who suffer violence exposure will show already by age 18 psychiatric symptoms, mild neuropsychological deficits and abnormal status of biomarkers that are considered to be prognostic for adult diseases. METHOD: We will test this hypothesis in the Environmental Risk (E-Risk) Longitudinal Twin Study, a longitudinal study from birth to age 18 of a cohort of twin children growing up in Britain (N=2232 children). We propose to assess the cohort at age 18, for new data collection. Each cohort member?s history of violence exposure will be defined using prospectively-collected data from repeated home-visit assessments of exposure to physical maltreatment, sexual abuse, bullying, parents? domestic violence, dating violence and assault victimisation across multiple years. We will assess the twins? perceptions of their violence exposure and sensitive outcome measures of psychobiological status that are known predictors of diseases in later life: a) psychiatric syndromes, b) neuropsychological tests of working memory, executive functions and reaction times, c) telomere erosion, d) obesity and inflammation biomarkers, e) DNA methylation profiles and f) expression of selected genes. We will compare exposed children to non-exposed controls on psychobiological outcomes, and we will also test for dimensional associations between the frequency/severity of violence exposure and psychobiological outcomes. A unique design feature of the E-Risk Study is that baseline assessments of psychobiological status were carried out from birth to age 12, which can be used to test whether such status has changed in individuals exposed to violence in the interim years. Furthermore, our twin study offers a special design advantage, because twin siblings discordant for violence exposure can be compared to rule out other effects on psychobiological outcomes. INNOVATION AND SIGNIFICANCE: The hope of preventing diseases and of increasing health expectancy requires research to identify candidate risk targets that can be tackled successfully, in early life. If the hypothesis that stress has psychobiological sequelae in early adult life was shown to be true by our proposed research, this would imply that the burden of adult disease could be reduced by successfully treating early, at a pre-clinical stage, psychobiological conditions in children exposed to stress early in life.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Effects of antipsychotics: linking brain structural imaging changes to cellular alterations and evaluating mitigation st
Funder: Medical Research Council

Abstract: Since the 1990?s there has been nearly a doubling in the use of antipsychotics leading to over 50 million prescriptions per year globally and an almost five-fold increase in non-psychotic conditions and younger patients. This proliferating use assumes that antipsychotics have few long-term adverse effects. However, emerging clinical, primate, and rodent data (from our lab) show that antipsychotics lead to a loss of grey matter - a matter of substantial relevance and clinical concern. Since antipsychotics are administered to patients with pre-existing brain abnormalities it has been difficult to differentiate the effects of illness from effect of the drugs in standard clinical studies. We have developed an animal model that provides a way to separate the effects of illness from that of drug and provides an opportunity to link MRI-observed changes to the mechanisms at the cellular level. Using this model we have demonstrated that antipsychotics cause a decrease in grey matter on MRI which is confirmed with ex-vivo MRI and histopathology, and there is early indication that Lithium administration may help overcome the deficit. In this proposal we would like to confirm these initial findings and then address the following questions: (i) Are the structural effects of antipsychotics seen in normal rats also seen in a model thought to reflect the pathology of schizophrenia (MAM model)?; ii) Are these effects of antipsychotics dose and duration dependent, and if so are they reversible on stopping the medication?; (iii) What are the underlying cellular bases and how do these relate to the MRI findings?; and (iv) What can be done to mitigate these adverse effects? If we can confirm the adverse effects of antipsychotics on the brain ? this would have significant clinical relevance. It should provide an impetus and an imperative for more rigorous and large-scale clinical studies to confirm/reject the preclinical findings. Our pilot positive data on lithium, if confirmed further in this project, could provide a testable clinical strategy. Finally, the cellular and mechanistic findings from our studies would point to potential solutions and the model can be used to identify and develop new antipsychotics that do not show this deficit in the first place.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH