Channelopathies are disorders caused by inherited mutations of specific ion channels. Neurological channelopathies in particular offer a window into fundamental physiological functions such as action potential modulation, synaptic function and neurotransmitter release. One such channelopathy Episodic Ataxia type 1 (EA1), is caused by a mutation to the gene that encodes for the potassium channel subunit Kv1.1. This channel is predominantly found in presynaptic terminals and EA1 mutations have previously been shown to result in increased neuronal excitability and neurotransmitter release. A possible reason is that presynaptic action potential waveforms are affected in EA1. Thus far, direct electrophysiological recording of presynaptic terminals has been limited to large specialised synapses e.g. mossy fibre boutons, or axonal blebs, unnatural endings of transected axons. This is not representative of the vast majority of small synapses found in the forebrain. Using a novel technique termed Hopping Probe Ion Conductance Microscopy (HPICM) I have been able to directly record action potentials from micrometer sized boutons in hippocampal neuronal culture. I have shown that in a knockout model of Kv1.1 and in a knockin model of the V408A EA1 mutation, presynaptic action potentials are broader than in wild type; however action potentials are unaffected in the cell body. Finally in some central synapses neurotransmitter release has been shown to depend on not only action potentials received in the presynaptic terminal, but also on slow subthreshold membrane potential fluctuations from the soma, termed analogue digital signalling. Kv1 channels have been implicated in partly mediating this form of signalling. I have shown via dual recordings from the soma and small presynaptic boutons, that analogue-digital signalling occurs in wild type and knockout of Kv1.1, but is abolished in the V408A EA1 mutation. This implies that analogue-digital signalling may not depend on Kv1.1 in particular, rather a change in the stoichiometry of the Kv1 channel.

Relatively little is known about people who self-harm and are not conveyed to the emergency department, or the experiences of ambulance service staff in working with people who self-harm and the conveyance decisions that they make. This research, with two linked studies, was conducted using a sequential mixed methods design. In Study 1, quantitative data was collected about episodes of self-harm that received an ambulance crew decision following a 999 call made in the Yorkshire region. The data collected included details of the episode of self-harm, demographic information, the care provided by ambulance staff, clinical outcomes (including conveyance rates), and explanations for care and conveyance decisions. In the sample there was a proportion of conveyance of 87% and only 13% non-conveyance. Method of self-harm was related to conveyance, with people who had cut themselves significantly less likely to be conveyed than those using other methods. Non-conveyance was associated with a longer duration of ambulance visit. The findings from Study 1 informed Study 2, which was a qualitative interview-based study with staff from the ambulance service. Six ambulance service staff were interviewed about their experiences of working with people who have self-harmed and about the decision-making around non-conveyance. There were six major themes identified using thematic analysis and the themes were presented as if they were clinicians’ thoughts to demonstrate the decision-making process around whether or not to convey the person who has self-harmed: ‘I’ll do my best to help’ but ‘I worry about getting it wrong’ because ‘I’m not sure what I’m doing’ and ‘I’m not supported’ so ‘It’s more than your job’s worth’, which contributes to an overall ‘conveyance culture’. There are a number of recommendations for future research and improving clinical practice, and the results are presented in relation to existing literature.

The activity of neurons is dependent on the manner in which they process synaptic inputs from other cells. In the event of clustered synaptic input, neurons can respond in a nonlinear manner through synaptic and dendritic mechanisms. Such mechanisms are well established in principal excitatory neurons throughout the brain, where they increase neuronal computational ability and information storage capacity. In contrast for parvalbumin-positive (PV+) interneurons, the most common cortical class of in- hibitory interneuron, synaptic integration is thought to be either linear or sub-linear in nature, facilitating their role as mediators of precise and fast inhibition. This thesis addresses situations in which PV+ interneurons integrate synaptic inputs in a nonlinear manner, and explores the functions of this synaptic processing. First, I describe a form of cooperative supralinear synaptic integration by local excitatory inputs onto PV+ interneurons, and I extend these results to show how this augments the computational capability of PV+ cells within spiking neuron networks. I also explore the importance of polyamine-modulation of synaptic receptors in mediating sublinear synaptic integration, and discuss how this expands the array of mechanisms known to perform similar functions in PV+ cells. Finally, I present work manipulating PV+ cells experimentally during epilepsy. I consider these findings together with recent scientific advances and suggest how they account for a number of open questions and previously contradictory theories of PV+ interneuron function.

As epilepsy develops an enormous range of changes occurs in neurons. This process, epileptogenesis, involves complex spatiotemporal alterations of neuronal homeostasis and neural networks. The molecular mechanism of epileptogenesis remains obscure and gene regulation during the epileptogenic process dynamically controls various signalling and functional pathways which play an important role in defining the mechanisms of epilepsy. This thesis explores gene regulation in different in vitro models of seizure like activity, and further focuses on the temporal profiles of molecular changes during an in vivo model of epilepsy. We seek to identify important regulators of epileptogenesis which may be the targets for further study of the mechanism of epilepsy in human. The High-K+, Low-Mg2+, Kainic acid, and Pentylenetetrazole models were used to elicit seizure like activity in cortical neuronal cultures. The tetanus toxin (TeNT) model of focal neocortical epilepsy in rats was utilised to characterise gene regulation in different time points: acute, subacute and chronic stages (48-72 hours, 2 weeks, and 30 days after first spontaneous seizure, respectively). A set of candidate genes relevant to epilepsy was selected to analyse changes in mRNA expression during these in vitro and in vivo models. The mRNA expression of the different candidate genes reveals diverse regulatory behaviours in different models, as well as at different time points during the process of epileptogenesis. The cell culture model treated with Low-Mg2+ for 72 hours displayed the most similar mRNA expression profile to the in vivo model of TeNT neocortical epilepsy during subacute to chronic stages. Furthermore, in the in vivo model, GFAP, mTOR, REST, and SNAP-25 are all temporarily apparently up-regulated during epileptogenesis, while CCL2 is strongly up-regulated later when epilepsy is established. Transient down-regulation of BDNF in the acute stage, and the distinctly lower expression of GABRA5 in late stage suggest that this GABAergic signalling pathway may be down-regulated in the late phase of epileptogenesis. Our work highlights how different candidate genes are differentially regulated during epileptogenesis, and how the regulation of individual genes changes as epileptogenesis progresses.

According to the World Health Organization (WHO), approximately 50 million people in the world have active epilepsy. Epilepsy is the most common neurological disorder after migraine, stroke and Alzheimer’s disease. Epilepsy disorder affects men and women of all ages, races and social classes. There is an extensive neuroimaging literature describing patients with chronic epilepsy. However, few studies have investigated brain structural changes in patients with newly diagnosed epilepsy (NDE) using quantitative magnetic resonance imaging (MRI). The main goal of this thesis was to determine the nature and extent of brain structural and functional differences in patients with NDE using different MRI techniques compared with healthy controls. The first study was to determine the morphometric changes in patients with NDE compared to healthy controls using quantitative MRI analysis. The second study was to identify functional connectivity differences (in the whole brain and regions of interest) in patients with NDE and healthy controls using resting state functional magnetic resonance imaging (RS-fMRI). All study participants were recruited from the Walton Centre NHS Foundation Trust, Liverpool. All had been diagnosed with focal epilepsy by a consultant neurologist and recruited for MRI scanning within 12 months of diagnosis. Twenty-seven patients with NDE were recruited (14 male, 13 female, with mean age (M)=33.2) and 32 healthy matched controls (14 male, 18 female, M=33.07).Control and NDE study participants were matched for age, handedness and gender. All participants were scanned using a Siemens 3T Trio whole-body scanner (Siemens, Erlangen, Germany) with eight-channel radiofrequency (RF) head coil together with foam padding to comfortably restrict head motion at the Magnetic Resonance and Image Analysis Research Centre (MARIARC), University of Liverpool. Various MRI sequences were conducted including: 3D MPRAGE T1-weighted anatomical data, and RS-fMRI In the first study, shape, surface based, and voxel based morphometry analysis were applied, and the results suggested differences to the morphology of the brain stem and both the right and left thalami in patients with NDE. The independent component analysis of RS-fMRI showed abnormal different functional connectivity in visual and attention networks in patients with NDE relative to healthy controls while ROI-ROI demonstrated increased functional connectivity between the subcallosal cortex and both thalami in NDE patients. This is the first extensive programme of research to employ various analysis techniques and advanced MRI sequences to study structural and functional differences in patients with NDE compared to healthy controls. The results of this thesis show that structural and functional differences occur in both thalami in patients with NDE. These findings suggest that the thalamus plays a very important role in epilepsy pathophysiology. The results of this thesis offer further understanding regarding the role of structural and functional differences in NDE. They highlight the need for future quantitative MRI analysis studies of NDE to help patients avoid the chronic stage of the disorder and improve their quality of life.

Eating disorders are mostly prevalent in young females, with rates of disordered eating up to five times higher than diagnosable cases. There is evidence to suggest females from a South Asian background have higher rates of eating disorder symptomatology than their White counterparts. Culture plays a role in susceptibility to eating disorders, and factors such as parental control, stigma and ethnic stereotyping by health professionals can be additional barriers to seeking and receiving appropriate help. This thesis was concerned with the clinical decision-making processes of UK mental health practitioners and whether the ethnicity of clients affected this. Three vignettes were devised, one including clinical features indicative of a restrictive eating pattern, one of a binge eating pattern and one with depression and anxiety symptoms. Each vignette was presented with a picture of either a young Asian female or a White female. One hundred and fifty six participants, all clinical staff in IAPT services, filled in an online survey comprising of one vignette and a questionnaire exploring factors involved in clinical decision-making and potential barriers to engagement. Mental health practitioners were less likely to rate the vignette as showing symptoms of anorexia nervosa when the picture presented was that of an Asian female as opposed to a White female, and more likely to rate the Asian version with bulimia nervosa. There were no significant differences between ethnic groups in terms of treatment recommendations. Social and cultural factors were identified as areas of concern in the White vignette version, an unexpected finding. These findings indicate there may be ethnic bias present in decision-making regarding eating disorders and disordered eating patterns. It is recommended training in both identifying eating disorder symptomatology and cultural competency is emphasised more in training courses and beyond. Further research into decision-making by mental health providers is also needed.

Psychological therapists working with service users presenting with trauma can be negatively and positively affected by their work. Client factors, therapist factors and work factors are thought to contribute to therapists’ reactions however there are gaps in the research. To address this, the present study investigated the well-being of psychological therapists to test whether i) when working with complex Post-traumatic Stress Disorder (PTSD), perceived personal resilience and the supervisory relationship were associated with compassion satisfaction, burnout and secondary traumatic stress, and ii) perceived personal resilience and the supervisory relationship moderated the relationship between working with complex PTSD and compassion satisfaction, burnout and secondary traumatic stress. Data from 298 psychological therapists was collected via an online questionnaire. Participants completed measures of resilience (Brief Resilience Scale), the supervisory relationship (safe base subscale of the Short-Supervisory Relationship Questionnaire), compassion satisfaction, burnout and secondary traumatic stress (Professional Quality of Life Scale). Demographic and background information was also collected. Multiple regression and analysis of variance were used to explore the associations between the variables and interaction effects. Results showed a trend towards working with complex PTSD being associated with higher burnout and a significant association between working with complex PTSD and secondary traumatic stress. Perceived personal resilience was significantly positively associated with compassion satisfaction and significantly negatively associated with burnout and secondary traumatic stress once complex PTSD was controlled for. The quality of the supervisory relationship was significantly positively associated with compassion satisfaction and significantly negatively associated with burnout once complex PTSD was controlled for. There was a trend towards the supervisory relationship being associated with lower levels of secondary traumatic stress. The supervisory relationship also significantly interacted with the relationship between working with complex PTSD and compassion satisfaction. There was a trend towards an interaction effect between complex PTSD and the supervisory relationship on secondary traumatic stress. These findings suggest that client factors, clinician factors and work factors may affect psychological therapists’ responses to their work.

Autism spectrum disorder (ASD) is characterised by impairment in the social domain and is often comorbid with depression and social anxiety. Several neuronal systems have been implicated in the neuropathology of ASD, yet the underlining neurobiology remains unclear, with no effective treatment being identified. Therefore, we utilised a well-validated mouse neurobiological candidate systems and we detected dysregulation of opioid, oxytocin, vasopressin, glutamate and dopamine in this model. Current ASD pharmacotherapy is only symptomatic and does not target core symptomatology. Intranasal oxytocin is a promising target for the treatment of ASD with known acute effects on related ASD-like symptomatology, but little currently is known about the effect of chronic exposure to the drug. Therefore, we performed a battery of behavioural experiments to assess the efficacy and neurobiological consequences of chronic oxytocin administration in the Fmr1 KO and wild-type mice. We observed restoration of sociability but not stereotypy upon acute and chronic oxytocin treatment in the mutants and prevention of comorbid anxiety following chronic oxytocin administration. Opposingly, detrimental effects in sociability, stereotypy and emotionality following chronic oxytocin treatment were detected in wild-type mice. Differential regulation of several transcripts was detected in Fmr1 KO and wild-type mice. Lastly, we investigated the effect of chronic exposure to social-defeat stress (CSS), a common psychopathology characterised by impairment in sociability and depression on central nicotinic acetylcholine receptor (nAchR) subtype and D2 dopamine receptor density. While CSS did not affect 07* and CI4P2* nAChR binding, it downregulated D2. These findings offer better understanding of the neurobiology underpinning psychopathologies characterised by social deficit and highlight chronic OXT as an effective pharmacotherapy for their treatment. Nonetheless, our findings reveal potential safety concerns of its chronic use in healthy subjects with intact oxytocinergic system.

Quality of life (QoL) is impaired in clients with Borderline Personality Disorder (BPD). The recovery literature considers QoL an important outcome and in particular this diagnostic group value it. Yet few studies measure QoL following treatment. As a result, it is unclear how treatments work. Treatments often target symptom improvement with the assumption that QoL will also improve. Whilst this may be partially correct, the literature implicates other factors as potential mechanisms of change. This thesis aimed to explore the impact of treatment on QoL outcomes and investigate predictors of QoL. Part one presents a literature review examining QoL outcomes following BPD treatment. The findings extended a previous literature review and confirmed that QoL does improve following treatment. Different domains of QoL may improve at different rates which may be as a function of treatment targets. Part two is an empirical paper investigating symptomatic, service usage and QoL outcomes following Systems Training for Emotional Predictability and Problem-Solving (STEPPS) and also investigated the following predictors of QoL: symptom change, change in cognitive schema (filters) and group cohesion. The findings suggested that QoL and symptomatic outcomes improved following STEPPS; yet service usage did not and remained consistently low. Symptom change and change in cognitive filters predicted QoL outcomes but group cohesion did not.

Background: Individuals with OCD tend to delay help seeking due to fear of stigma, particularly individuals who experience sexual intrusive thoughts. Few studies have examined sexual intrusive thoughts about children (sometimes called pedophile-OCD). The current study assessed the effectiveness of a brief education intervention in reducing stigma towards a person experiencing such thoughts. Method: 120 participants took part in an online survey. Participants were shown a vignette describing a target individual who experienced sexual intrusive thoughts about a child. Participants completed stigma measures (perceived dangerousness, perceived unpredictability, and desired social distance), and assigned a diagnostic label before and after being shown educational information about OCD and Pedophilic Disorder. Participants also completed six open-ended questions about their decision making. Results: Ninety participants (75%) assigned an initial diagnosis of pedophilia. Following the education, more than half of these changed their diagnosis from pedophilia. A McNemar’s test demonstrated that a significant number of individuals moved away from a pedophilia diagnosis post education. Paired comparison tests demonstrated that perceived dangerousness and desired social distance from the target decreased significantly following the intervention. Repeated measures ANOVA demonstrated that the group of participants who moved away from an initial pedophilia diagnosis showed a greater decrease in stigma ratings than those who did not. Discussion: Based on the mere presence of a sexual thought about a child, most individuals assigned a label of pedophilia. However, initial judgments and level of stigma were amenable to significant change following a brief education intervention. Future research may benefit from examining the experiences of people with pedophile-OCD directly as well as ascertaining the most effective style of psycho-education materials to promote anti-stigma messages.