NIHRDataInsights/HRCSData huggingface dataset:
Title: Novel approaches to the investigation of psychobiological mechanisms in functional neurological disorder
Funder: Medical Research Council

Abstract: Functional (dissociative) neurological disorder is a neuropsychiatric disorder defined by the presence of motor, sensory and/or seizure symptoms that are not caused by neuropathology (DSM-5; ICD-11). The mechanisms underlying FND symptoms are poorly understood. Psychological risk factors (e.g., trauma, emotional dysregulation), comorbidities (e.g., dissociative, affective disorders) and distress are common, yet the ways in which these factors contribute to FND symptoms is unclear. The aim of this research is to investigate further the psychobiological mechanisms underlying FND with robust, innovative methods. I recently proposed that aberrant emotional processing of salient stimuli results in elevated autonomic arousal, thereby triggering or exacerbating FND symptoms (Pick et al., 2019). I have also proposed a key role for dissociation (Pick et al., 2017; 2020), which potentially mediates the relationship between abnormal emotional responses and FND symptoms. Hyperactivity in limbic regions (e.g., amygdala) and abnormal interactions between limbic neurocircuits and those involved in awareness of self/body (e.g., insula, anterior cingulate), executive (e.g., dorsolateral prefrontal cortex) and motor control (e.g., supplementary motor area) are predicted (Pick et al., 2019). Laboratory-based experimental tasks, neuroimaging and remote measurement technology (RMT) will be used to rigorously test these hypotheses. Patients with FND (seizure or motor) will be compared to clinical and healthy control groups. Experimental tasks and functional neuroimaging will probe subjective and physiological responses to affective stimuli, alongside measuring the impact on FND symptoms. RMT will allow real-time capture of affectively salient triggers, autonomic arousal, dissociation and FND symptoms in daily life. The results will have considerable translational value and will inform the further development of integrative explanatory models.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Psychological, pharmacological and developmental insights into the prefrontal circuits underlying threat regulation and negative bias in marmosets
Funder: Medical Research Council

Abstract: Dysregulation of negative emotions is a prominent symptom of neuropsychiatric disorders. Unfortunately, the range of treatments is restricted and the level of treatment success highly variable; due in part to the diverse set of cognitive control processes and underlying brain circuits that regulate responses to negative events and when dysregulated, induce clinical anxiety. Clinical anxiety is associated with altered activity across prefrontal and cingulate cortex but a fundamental understanding of these regions' distinct contributions is lacking. We have shown that heightened threat reactivity is induced by both ventromedial prefrontal overactivation or orbitofrontal inactivation. By focussing on the negative biases in decision making that are a common symptom of anxiety disorders we will differentiate these regions' unique cognitive contributions to such biases; applying computational modelling to identify the distinct underlying psychological constructs. We will also determine the contribution of dorsolateral prefrontal cortex which has been little studied with respect to threat reactivity and negative biases. These studies will provide insight into the multi-determined nature of clinical anxiety and inform diagnoses. By differentiating the effectiveness of different classes of anxiolytics to ameliorate the anxiety-like phenotypes induced by distinct prefrontal manipulations, we will provide insight into the variable success of current anxiolytics and guide future individualised treatment strategies. Since clinical anxiety emerges during adolescence, neuroimaging of prefronto-cingulate cortex across development will identify the discrete developmental stages in which the different regions integrate into structural and resting state networks. This will reveal those stages likely to be most vulnerable to environmental stress, a risk factor for clinical anxiety and how individual differences in developmental trajectories relate to anxiety-like traits in adulthood.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Prosocial behaviour in children with conduct problems: Investigating putative cognitive-affective mechanisms and their malleability
Funder: Medical Research Council

Abstract: Children with conduct problems (CP) are at risk of developing persistent antisocial behaviour, which costs society £60 billion annually. There is an urgent need to improve our ability to help and support these children. There remain significant gaps in our understanding of potential information processing mechanisms underlying CP. To date the field has predominantly focused on how children with CP process negative affect and how this may influence their risk of aggression. There has been surprisingly little work focusing on how children with CP process positive affect, particularly given the role that positive affect is thought to play in promoting prosocial engagement and behaviour. The primary aims of the current study are to investigate: (i) how positive affect signals are processed by children with CP; (ii) the degree to which such processing is malleable following affective perception training; and (iii) whether training reduces aggressive and increases prosocial behaviour. Children with CP are a heterogeneous group with varied presentations and needs. Those with high levels of callous-unemotional (CU) traits have been distinguished at cognitive and behavioural levels from their peers with low levels of CU traits and there is tentative evidence that these groups may also differ in their processing of positive affect. The proposed research will compare these groups with matched typically developing controls. It will inform a genuinely mechanistic cognitive model of CP subtypes and test a potential translational application by addressing the following key questions: 1) Do children with CP display atypical processing of positive affect signals, indexed by measures of perception, attention and motivation? 2) Can training impact perception, attention and motivation of positive affect in children with CP? 3) Does training: a) reduce antisocial behaviour; b) promote prosocial behaviour in children with CP?


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES;5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Dysregulation of Ca2+-activated K+ channel signalling by reduced dosage of the psychiatric risk gene CACNA1C
Funder: Medical Research Council

Abstract: In this project we aim to understand the role of large- (BK) and small-(SK) conductance Ca2+-activated potassium (KCa) channels in the neurophysiological alterations associated with reduced dosage of the psychiatric risk gene CACNA1C encoding the pore-forming CaV1.2 subunit of L-type voltage-gated calcium channels (L-VGCCs). Our hypotheses are: 1) CACNA1C hemizygosity results in distinct alterations of somatic and dendritic KCa channels functions, which contribute to circuit-selective loss of synaptic plasticity in the dorsal hippocampus and subsequent deficit in hippocampal-dependent associative learning. 2) Targeting KCa channels directly or via modulatory cholinergic muscarinic receptors rescues the deficits in hippocampal synaptic plasticity and hippocampal-dependent associative learning associated with reduced CACNA1C dosage. To address these problems, we will conduct studies in animals hemizygous for the rodent gene homolog Cacna1c (Cacan1c+/- rats) with the following aims: 1) Demonstrate dysregulated L-VGCC - KCa signalling as principal cause for altered somato-dendritic excitability of pyramidal neurons in the CA1 area of the dorsal hippocampus (dCA1) in Cacna1c+/- rats, using electrophysiology, two-photon imaging, and molecular methods. 2) Demonstrate a link between reduced Cav1.2 dosage, dysregulated L-VGCC-KCA signalling, and synaptic plasticity deficits in Cacna1c+/- dCA1 pyramidal neurons. 3) Investigate the potential of KCa channels and their modulation by cholinergic muscarinic receptors, as potential drug targets for rescuing the synaptic plasticity deficits and behavioural phenotype in Cacna1c+/- animals. In achieving these aims we will define a causal link between genetic variation in the cross-disorders risk gene CACNA1C, synaptic dysfunction and cognitive deficits in psychoses and identify alternative therapeutic strategies to compensate the functional consequences of altered L-VGCC signalling.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: MRC Transition Support Award CSF Sanjay Manohar
Funder: Medical Research Council

Abstract: The fellowship aimed to answer four main questions: 1. Do dopamine agonists affect different types of motivation differentially? 2. Can anticholinergic drugs modulate motivation in healthy volunteers? 3. Are motivational changes following ventromedial prefrontal damage explainable as reduced context-sensitivity? Question 1 constituted 3 experiments, which were completed and published. We established that - dynamic effects of motivation can be captured by online corrective feedback during a movement (Manohar et al. Neuropsychologia 2018), - dopamine has opposing effects on two types of motivation (Grogan, Sandhu, Hu & Manohar, eLife 2020), - we can predict impulse control disorders using pupillometry (Drew, Muhammed, Baig, ... Manohar*, Husain* et al. Brain 2020), - dopamine improved cognitive fluency (Ang*, Manohar* et al. Curr Biol 2018) - dopamine also has opposing effects on different aspects of working memory (Fallon, Kienast, ... Manohar & Husain , J. Psychopharmacol. 2019), - the effect on working memory influences control over actions (Fallon, Drew, Muhammed, Manohar & Husain, Cortex 2018), and - I developed the first physiological model of working memory that also accounts for action control (Manohar et al. Neurosci Biobeh Rev. 2019) that formed the basis for my Leverhulme grant. This work has led to my being awarded the Thomas Willis Intermediate Career Researcher award. The second two questions are left unanswered by this data: 1. Acetylcholine is a critical regulator of striatal dopamine release. Can cholinergic drugs modulate disorders of motivation? 2. Dopamine release may be controlled by medial prefrontal cortex. Do apathy and impulsivity arise after lesions to different subregions within this area? The transition award will permit me to answer these questions. Data collection and recruitment have already begun. I aim to have these two key publications out by the time of applying for a Senior Fellowship in 2022.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES;5.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Cortical feedback circuits for sensory integration and control of synaptic plasticity
Funder: Medical Research Council

Abstract: Our long-term aim is to understand learning and memory in the cortex. To this end, we aim to understand the operation of a cortical sub-circuit in layer 2/3 (L2/3) that gates plasticity at basal dendrites through excitatory interactions with apical dendritic inputs. We will test how the apical/basal interaction may be controlled through dendrite targeting somatostatin inhibitory interneurons. Further, we aim to understand the consequences for plasticity of mutations associated with mental health conditions such as schizophrenia (human DISC1 t(1;11) mutation), where we have found the basal dendrites remain underdeveloped causing remapping of feedforward connections onto more apical locations. To do so we will: 1. Probe the cortical circuit and its plasticity in slices of barrel cortex where the feedback connections express virally delivered ChR2 and can be activated optically. Preliminary studies show that S2 can gate LTP of L4 input to L2/3 cells. 2. Observe when feedback activity naturally occurs from S2 to S1 during a tactile texture discrimination (head-fixed) task using GCaMP and 2 photon imaging. In a related cohort, asses the effect of mistimed optical stimulation of feedback connections on texture learning. 3. In freely moving mice, test the effect of learning the texture discrimination on basal dendritic structural plasticity by imaging dendritic spines with in vivo 2 photon microscopy. 4. Interrogate the ability of dendritic targeting somatostatin inhibitory interneurones to control the apically gated LTP in vitro and the texture discrimination task learning in vivo. Conversely, test the role of VIP interneurones in facilitating such learning and plasticity. 5. Map feedforward, feedback and inhibitory interneurone connections to L2/3 cells in DISC1 mutants using laser scanning point stimulation of afferents expressing ChR2 (in TTX). We will test the mutation's effect on apically gated LTP and using the mapping results test how plasticity can be rescued.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Striatal astrocytic mechanisms underlying the development of compulsive drug seeking habits
Funder: Medical Research Council

Abstract: This project aims (i) to determine the spatiotemporal profile of the functional recruitment of the striatal astrocytic syncytium across functional domains of the striatum over the course of the development of compulsive heroin seeking habits and identify molecular correlates of this functional recruitment (ii) to causally establish the role of the dorsal striatal astrocytes in the expression of habitual, dorsolateral striatum dopamine-dependent heroin seeking and (iii) to causally establish the role of the ventral striatal astrocytes in the functional recruitment of dorsolateral striatum dopamine-dependent mechanisms over the course of the development of compulsive heroin seeking habits. This original and innovative research project relies on our refined models of persistent cue-controlled heroin seeking deployed that we will deploy in (i) cross-sectional studies in combination with spatiotemporal mapping of the functional recruitment of striatal astrocyte syncytium using cell-specific RNAscope multiplex in situ transcriptomics against GFAP or neuronal markers, and markers of cellular activity/plasticity (e.g., c-fos/zif268/arc) and/or candidate genes such as the glutamate and dopamine transporter, adenosine and dopamine receptors. (ii) longitudinal studies, in combination with our well established causal interrogations of the reliance of cue-controlled drug-seeking on aDLS dopamine-dependent mechanisms together with direct activation or inhibition or dorsal vs ventral striatal astrocyte function, mediated by the GFAP-promoter dependent expression of commercially available hM4Di DREAADs, calcium extruders or empty controls delivered by AAVS infused into different striatal domains. While the combination of these approaches is novel, they are all routinely used in the laboratory, thereby greatly minimizing the overall technical risk of the project.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Brain sulcal folding and mental illness: investigating causal associations and stratification approaches for psychosis
Funder: Medical Research Council

Abstract: The cingulate gyrus presents as a single fold in some people (about 10%) and a double fold in others. About 50% of people have a prominent double fold (a neurodevelopmental feature, seen only in humans and chimpanzees). Individual variation in the degree of folding is linked to liability to specific forms of psychopathology, indicating a potential use of quantitative measures of cingulate folding to be used as clinical biomarkers. We will probe the role of brain folding variation (focussed on the cingulate but also considering other regions) in health and illness. Folding variation is poorly handled by existing automated neuroimaging workflows. The gold standard of measurement is currently laborious manual tracing, greatly restricting the pace of discovery in this field. We have developed a deep learning method to measure the degree of cingulate folding accurately in an automated manner using standard MRI structural data. We will refine and extend this and produce a freely available software tool to easily implement this. We will examine the genetic causes of cingulate folding in much greater detail than has been done before, and assess the consequences of variation in sulcal folding for treatment response, psychopathology, brain connectivity and cognition. In particular, we will examine if brain folding, especially in the cingulate, associates with liability to hallucinations in >1000 patients with schizophrenia, and/or predicts treatment resistance. We will use large scale, high quality datasets where MRI data, psychopathology and cognitive function are already available. This research will clarify the neural and psychological underpinnings of psychopathology (potentially helping treatment development), and lead to sulcal folding biomarkers that (1) can be used in large scale future basic science studies (eg to investigate the genetic and environmental basis of sulcal folding), and (2) can be further developed for clinical utility.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Ventral hippocampal control of behavioural flexibility, and its disruption by adolescent social isolation
Funder: Medical Research Council

Abstract: The aim of this project is to understand how adolescent isolation induced circuit alterations in the ventral hippocampus directly contribute to deficits in behavioural flexibility. Our overarching hypotheses are: i) Isolation-induced behavioural inflexibility results from a combination of alterations affecting different reinforcement learning processes; ii) Each of these processes is impaired by changes to a unique population of projection neurons in the ventral hippocampus. To address these questions we aim to: 1) Apply detailed computational models of behaviour developed through human research, based on state-of-the-art reinforcement learning techniques, to identify the precise cognitive processes that drive the observed alterations to flexible behaviour induced by social isolation, and investigate how these are supported by unique populations of projection neurons in the ventral hippocampus; 2) Use intersectional anatomical, genetic and viral techniques to investigate how chronic social isolation alters the intrinsic electrophysiological properties, synaptic function and genetic makeup of each unique neuronal population in the ventral hippocampus; 3) Combine the findings from these two aims and use optogenetic and molecular manipulations of each projection population to ask whether restoring specific adolescent isolation induced circuit alterations can rescue maladaptive changes in behavioural flexibility. Achieving these aims will provide a quantitative, computationally-informed understanding of how hippocampal circuitry is altered by chronic adolescent social isolation, as well as detailed mechanistic insight into why dysfunction in this circuitry results in cognitive inflexibility: a hallmark of the progression to mental illness.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Biomarkers to investigate Genetics, Environment and Mechanisms in Schizophrenia (Bio-GEMS).
Funder: Medical Research Council

Abstract: BIO-GEMS Recent studies have identified 270 common loci associated with schizophrenia (SWGPGC et al, 2020) as well as copy number and single nucleotide genetic variants (CNVs/SNVs) with large odds ratios for schizophrenia (Marshall et al, 2017; Singh et al, in press). However, we have limited understanding of their mechanisms. AIMS 1. Characterise the effects of high-risk (CNVs/SNVs) and other genetic variants on biomarkers of brain function and structure. 2. Investigate high-risk and other variant influences on clinical outcomes. 3. Investigate associations between high-risk variants and environmental risk factors for schizophrenia. 4. Conduct joint analyses and independent replications. METHODS OUR EXISTING SAMPLE: 14,000 people with psychosis and controls genotyped with SNP-microarrays. Whole genome/exome sequencing are available for 6,700 of them. Most participants are characterised for cognitive, neuroimaging and EEG biomarkers. NEW DATA COLLECTION: Array genotyping for 3,000 participants, clinical assessments, and whole exome sequencing for 2,000 of them. A subgroup of 600 will undergo deep phenotyping with cognitive, EEG testing and biobanking. 1. Biomarker outcomes: Model the effects of CNVs/SNVs and polygenic scores on EEG, cognitive and MRI biomarkers. 2. Clinical outcomes: Model the effects of CNVs/SNVs and polygenic scores on clinical outcomes. 3. Environmental outcomes: Models to test if high-risk variants are associated with subsequent exposure to schizophrenia environmental risk factors (obstetric complications, cannabis use, Maudsley environmental risk score). 4. Replication/joint analyses in collaboration with compatible studies: UK Biobank (500,000 people), The 100,000 Genomes Project (UK clinical sample), iPSYCH (130,000 Danes with/without mental disorders), ALSPAC (14,000 Welsh cohort), and deCODE (Icelandic population). UNDERSTANDING BIOLOGICAL MECHANISMS IS KEY TO DEVELOP NEW TREATMENTS FOR PSYCHOSIS.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL