Lysosomal storage disorders (LSDs) are rare diseases caused by inherited mutations in genes coding for proteins of the endolysosomal system. The lysosome is an organelle responsible for the degradation of dysfunctional organelles and for the catabolism, and subsequent recycling, of macromolecules within the cell. When this process becomes defective the substrates of lysosomal catabolism accumulate; these can include lipids, proteins, polysaccharides, nucleotides and diverse combinations of all three. The phenotypic spectrum of these diseases in isolation, and even more so as a group, is extremely broad but an almost universal consequence of lysosomal dysfunction is severe, early onset neurodegeneration. Neurodegenerative diseases of ageing such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease represent a major challenge to the provision of human healthcare in light of an ageing global population. Whilst some commonalities exist between these three diseases a myriad of hypotheses for the onset of pathology has been proposed. There is growing evidence for involvement of the lysosome in all three of these diseases. We have been looking at specific lysosomal pathologies such as lipid storage, endocytosis and Ca2+ dysregulation in forms of these three neurodegenerative diseases of ageing whilst using LSDs as models to inform our study. We have found that lysosomal alkalisation in familial models of Alzheimer’s disease results in changes to lipid and Ca2+ homeostasis in this compartment and identified a lysosomal ion channel, transient receptor potential cation channel, mucolipin subfamily, member 1 (TRPML1), as a key constituent of this process. Our study of models of Huntington’s disease have implicated the Niemann-Pick type C1 protein (NPC1) in the pathogenesis of this disease and identified ways in which this could be therapeutically targeted. Finally, we have found evidence of Ca2+ dyshomeostasis throughout the cell in genetic models of Parkinson’s disease which have defects in lysosomal proteins. Taken together, these studies strengthen the evidence for lysosomal involvement in neurodegenerative diseases of ageing, albeit with different mechanisms in each case, whilst expanding on the molecular basis for these processes. Accordingly, our understanding of the mechanisms underlying the pathogenesis of these diseases has improved and new therapeutic targets have been identified by these studies.

This thesis explores parenthood in the context of anxiety. Chapter One presents a systematic literature review exploring parenting behaviours in parents with anxiety disorders. This aims to critically review studies which consider the association between parental anxiety disorder and parenting behaviour towards school-aged children, specifically those that independently observe parent-child interactions. Fifteen such studies of parents diagnosed with anxiety disorders were reviewed. The majority of studies presented comparative data of anxious and non-anxious parents, frequently finding no differences between groups. Inconsistencies in the findings are highlighted and discussed. Methodological and theoretical limitations, implications for clinical practice and theory, and recommendations for future research are discussed. The review concludes that evidence does not consistently demonstrate a relationship between parental anxiety disorder and parenting, which supports findings of other reviews in the area. However, numerous methodological limitations associated with the use of independent observation must be considered. Chapter Two is an empirical paper regarding mothers’ experiences of obsessive-compulsive disorder (OCD). Nine mothers who associated their OCD onset or exacerbation with a pregnancy or child’s birth were interviewed. Interpretative Phenomenological Analysis was used to explore their experiences, with particular consideration to motherhood in the context of OCD. Two superordinate themes of ‘changing identity’ and ‘disconnection’ were interpreted. Consideration is given to how these findings relate to existing research into obsessive-compulsive disorder, maternal mental health and motherhood. Methodological limitations, clinical implications and potential future directions for research are discussed. Chapter Three provides reflections on the research journey. Specifically, the paper considers the researcher’s selection of the research area and explores reflections on areas where the researcher’s experience of the research converged with experiences of the mothers with OCD who participated in the research project.

This study was undertaken with people who have a learning disability and dementia and their carers. The overall aim of this research was to gain insight into the perspective of the person with a learning disability who had developed dementia, alongside that of their carer, with the anticipation that this would influence the development of practice and service delivery accordingly. People with a learning disability are two to three times more likely to develop dementia than the general population, but historically, dementia care policy has rarely made specific reference to this group of people. In order to ensure that the needs of people with a learning disability and dementia are met, their voices need to be heard regarding their views and perceptions on what their needs are and what health and social care support services are required in order to meet those needs. Very few studies relating to this group of people can be found, one of the main reasons appearing to be the ethical and methodological challenges involved in carrying out research with people who have a learning disability. This qualitative study involved 11 people who had a learning disability and dementia, along side a nominated carer participant for each person. Semi-structured interviews were used and the transcriptions were analysed using Interpretative Phenomenological Analysis, whereby themes were identified. The findings illustrated that services experienced difficulties in providing person centred care, particularly the poor communication between service providers working with each individual, and the general lack of person centred approaches to care. The data indicated that people with a learning disability and dementia wanted improved communication between service providers; improved understanding of dementia by those with the illness, and by family, paid and professional carers; to stay as well as possible; continue living in their home; and to have good access to a range of activities, services and support as deemed necessary. In conclusion, this research goes someway to exploring and overcoming the barriers to including people with a learning disability and dementia in research studies. It found ways of listening to and interpreting the views of people with a learning disability and dementia about their lives and circumstances and has made it possible to produce recommendations in relation to practice and policy development. These include ways of ensuring person centred approaches to care, and suggestions on the effective implementation of policy documents key to this group of people.

Cerebral autoregulation is the process by which blood flow to the brain is maintained despite changes in arterial blood pressure. Experiments using transcranial Doppler ultrasonography allow rapid measurements of blood flow velocity in the middle cerebral artery. Measurements of this velocity and a subject's arterial blood pressure are used in the assessment of the dynamic cerebral autoregulatory response. Two mathematical models representing the dynamic cerebral autoregulation response as a feedback mechanism, dependent on pressure and flow respectively, are derived. For each model two parameters are introduced, a rate of restoration and a time delay. Solutions for both flow between fixed plates and flow in a rigid pipe are obtained using Laplace transform methods. In both cases solutions for the velocity are found for a general arterial blood pressure, allowing the model to be applied to any experiment that uses changes in arterial blood pressure to assess dynamic cerebral autoregulation. Velocity profiles are determined for the thigh cuff and vacuum box experiments, modelled as a step change and sinusoidal variation in pressure gradient in the middle cerebral artery respectively. The influence of the underlying heart and breathing cycles on measurements obtained from the vacuum box experiments is assessed, before results derived using the mathematical model with a flow dependent feedback mechanism are compared with data from the two experiments. The comparisons yield similar estimates for the rate of restoration and time delay suggesting that these parameters could be independent of the pressure change stimulus and depend only on the main features of the dynamic cerebral autoregulation process. The modelling also indicates that for imposed oscillatory variations in arterial blood pressure a small phase difference between the pressure and velocity waveforms does not necessarily imply impaired autoregulation. The ratio between the percentage variation in maximum velocity and pressure can be used, along with the phase difference, to indicate more accurately the nature of the autoregulatory response. Finally, the relationship between arterial blood pressure and pressure gradient in the middle cerebral artery is modelled using electrical analogue theory. The influence of this relationship on the autoregulation model for flow in a rigid pipe is investigated.

The cerebellar granule cell layer has inspired numerous theoretical models of neural representations that support learned behaviors, beginning with the work of David Marr and James Albus. In these models, granule cells form a sparse, combinatorial encoding of diverse sensorimotor inputs. Such sparse representations are optimal for learning to discriminate random stimuli. However, recent observations of dense, low-dimensional activity across granule cells have called into question the role of sparse coding in these neurons. In this thesis, I generalize theories of cerebellar learning to determine the optimal granule cell representation for tasks beyond random stimulus discrimination, including continuous input-output transformations as required for smooth motor control. I show that for such tasks, the optimal granule cell representation is substantially denser than predicted by classic theories. The results provide a general theory of learning in cerebellum-like systems and suggest that optimal cerebellar representations are task-dependent.

"The purpose of this study was to determine the differences, if any, between seventeen foster families who indicated a financial reason as a factor in offering their service to provide family care to neuropsychiatric patients, and nineteen families who stated non-financial reasons, but who were also providing family care to mentally ill patients. The focus of the analysis of the data collected for these thirty-six foster families was to ascertain which of the twenty-two items significantly differentiated the families when dichotomized by financial reason and cross-tabulated on these selected items"--Introduction. / Typescript. / "January, 1961." / "Submitted to the Graduate School of Florida State University in partial fulfillment of the requirements for the degree of Master of Social Work." / Advisor: Dorothy D. Hayes, Professor Directing Study. / Includes bibliographical references.

One of the consequences of traumatic brain injury is the postconcussion syndrome. The symptoms in this syndrome include headache, dizziness, poor memory, poor concentration, easy fatigue, drowsiness, irritability, sensitivity to light, sensitivity to noise, low alcohol tolerance, visual problems, auditory problems, nausea, vomiting, anxiety, and depression. Several factor analytic studies have shown that these symptoms load onto cognitive and noncognitive factors (Bohnen, Twijnstra, & Jolles, 1992). The aim of this study was to determine whether patients who report different symptoms also evidence differences in cognitive deficits, as indexed by reaction time. For this purpose 106 subjects (mean age 25.92 years; SD=6.05) of both sexes were tested on 8 reaction time tasks adapted from Shum, McFarland, Bain, and Humphreys (1990). There were 54 traumatic brain injury patients (mean age 26.40 years; SD=6.23) drawn from three Pretoria hospitals. They were heterogeneous with respect to diagnosis and severity of injury. For the controls (N=52), the mean age was 25.43 years (SD=5.88). The eight reaction time tasks constituted 4 task variables, each with 21evels. From these tasks, 36 reaction time indexes were derived. The indexes were classified into 4 groups, viz., reaction time (RT), movement time (MT), total reaction time (TT), and subtraction scores (SB, the difference between the 2 levels for each task variable). RT reflects the decision component and MT reflects the response execution component of reaction time. Partial correlation coefficients for all symptoms (p0,01) showed that some symptoms were most frequently associated with RT whilst others were most frequently associated with MT. On factor analysis with varimax rotation, symptoms loaded predominantly with SB scores. Symptoms also loaded with different task variablseuiggesting that they correlated with deficits on different stages of information processing. Taking into account possible methodological constraints that were discussed, these results confirm that different symptoms within the postconcussion syndrome correlate with different cognitive deficits. The correlations between symptoms and indices of reaction time are moderated by the characteristics of the symptoms (frequency & intensity), and the duration since injury. These findings have significance for understanding the aetiology of the postconcussion symptoms and for planning treatment. / Psychology / Ph. D. (Psychology)

The present study aimed at investigating the neuropsychological sequelae of transient ischaemic attacks. Transient ischaemic attacks are defined as those neurological disorders in which there is complete resolution of neurological symptoms within twenty·four hours. Transient ischaemic attacks may or may not reveal evidence of brain infarcts on imaging studies. In the present study, the neuropsychological sequelae of transient ischaemic attacks in the carotid circulation were investigated since, within the perspective of cognitive neuropsychology, it was assumed that localized changes in cognitive functions could be demonstrated.Since several psychological, medical and neurological factors are known to influence scores·on neuropsychological tests, regression analyses were performed to determine which factors contributed significantly to the variance of scores on neuropsychological tests in the transient ischaemic attack and control groups. Two transient ischaemic attack groups, each comprising forty left and forty right hemisphere involvement patients, were then compared with each other and with a control group of forty general medical patients. Stenosis of the carotid artery formed a significant predictor of test scores in the combined transient ischaemic attack group. When the groups were·analyzed independently, in the left transient ischaemic attack group stenosis predicted performance on the same tests reaching significance for the combined group, and for the Wisconsin Card Sorting Test (Perseverative Score). In the right transient ischaemic attack group, stenosis significantly predicted performance on Digits Forward, Backward and Total, the PASAT (2.4 seconds) and Trails B. On the other hand, education formed a significant predictor of performance on Digits Forward, Digits Backward and Digits Total and the PASAT (all levels) in the control group. Multivariate comparisons revealed that the left and right transient ischaemic attack groups performed worse than the controls on tests of attention, concentration and conceptual flexibi1ity. The left transient ischaemic attack group performed worse than the right transient ischaemic attack group on all tests of attention and concentration, but there was a significantly better performance of the former group on the Rey Auditory Verbal Learning Test (Trial 1), Block Designs and Verbal Fluency. The findings on the PASAT that left transient ischaemic attack patients performed significantly worse than the right hemisphere group ·were considered to be relatively unreported previously in the literature on transient ischaemic attacks. The findings obtained are discussed from a neurocognitive perspective of neuropsychological functioning in transient ischaemic attacks. / Psychology / Ph. D. (Psychology)

The lateral reticular nucleus (LRN) is a component of the indirect spino-reticulo-cerebellar pathway that conveys sensorimotor information to the cerebellum. Although extensive work has been done on this pathway using electrophysiological techniques in cat, little is known about its infrastructure or neurochemistry in both cat and rat. Thus defining the morphology of this spinoreticular pathway would provide a better understanding of its intricate connections and the role of various neurotransmitters involved, which in turn would provide insight into the process by which these neurons carry out, for example, reflex modulation. We thus became interested in finding out more about the role of the spinoreticular neurons (SRT) in this pathway, what and how these cells receive inputs, their role within the spinal circuitry and how they modulate sensorimotor output. Thus, in view of these limitations, we formulated a hypothesis: ‘That spinoreticular neurons form a component of a feedback loop which influences activity of medullary descending control systems’. To test this hypothesis we developed four main aims: (1) to find out the distribution pattern of spinoreticular tract (SRT) neurons and their axonal projections to the LRN; (2) to examine the origins of two bulbospinal pathways projecting to the rat lumbar spinal cord via the medial longitudinal fasciculus (MLF) and caudal ventrolateral medulla (CVLM); (3) to determine the origin of excitatory and inhibitory contacts on SRT neurons in rat and cat lumbar spinal cord; and (4) to analyse some of the neurochemical phenotypes of SRT neurons and their response to noxious stimulus. In order to fulfil these aims, we combined tract tracing by retrograde and in some cases anterograde transport of the b subunit of cholera toxin (CTb) and retrograde transport of fluorogold (FG) along with immunohistochemistry in rats. In addition to this, SRT cells in cat were identified electrophysiologically and intracellularly labelled with Neurobiotin (NB), in vivo which were further investigated by using immunohistochemistry. As most of the electrophysiological data available to date is from cat studies so in this study we wanted to see how well this correlated to the anatomical results obtained from both cat and rat experiments. Results from Aim 1 demonstrated that, although there was extensive bilateral labelling of spinoreticular neurons in rat on both sides of the lumbar spinal cord, ~ 70% were contralateral, to the LRN injection site, in the ventromedial Lamina V to VIII. There were also some SRT cells that project ipsilaterally (31-35%) in addition to ~8% projecting bilaterally to both lateral reticular nuclei. Further experiments showed that the majority of SRT axons ascending via the ventrolateral funiculus terminate within the ipsilateral LRN with fewer projections to the contralateral LRN (2.6:1 ratio). These projections are predominantly excitatory (~80% both vesicular glutamate transporter 1 and 2; VGLUT-1, VGLUT-2) in addition to a significant inhibitory component (~15%, vesicular GABA transporter; VGAT), that consists of three subtypes of axons containing GABA, glycine or a mixture of GABA and glycine. LRN pre-cerebellar neurons receive convergent connections from excitatory (~13%) and inhibitory (~2%), SRT axons. Experiments undertaken to meet the second aim of this thesis revealed that, in rat, bulbar cells projecting via the MLF (medial longitudinal fasciculus) or the CVLM (caudal ventrolateral medulla) to the lumbar spinal cord have mostly overlapping spatial distributions. The vast majority of cells in both pathways are located in identical reticular areas of the brainstem. Furthermore, both pathways have a mixture of crossed and uncrossed axonal fibres, as double labelled cells were located both ipsi and contralateral to unilateral spinal injection sites. Bulbospinal (BS) cells that project via CVLM, form predominantly excitatory contacts with spinoreticular cells but there is also an inhibitory component targeting these cells; ~56% and ~45% of the BS contacts, respectively, In investigating the third aim to provide insight into the inputs to spinoreticular cells in two species, rat and cat we observed that; in both species these cells receive predominantly inhibitory inputs (VGAT) in addition to excitatory glutamatergic contacts that are overwhelmingly VGLUT-2 positive (88% to 90%). Thus, it appears that most inputs to these cells are from putative interneuronal populations of cells, for example PV (parvalbumin) and ChAT cells (choline acetyl transferase). SRT neurons in the rat receive a significant proportion of contacts from proprioceptors (~17%) but in the cat these cells do not seem to respond monosynaptically to inputs from somatic nerves. Furthermore, a significant proportion of contacts on rat SRT cells originate from myelinated cutaneous afferents (~68%). Data from the final series of experiments demonstrate the heterogeneity of spinoreticular neurons in terms of immunolabelling by neurochemical markers as well as their varied responses to noxious stimulation. Many SRT neurons express NK-1 receptors (~27%, neurokinin 1) and approximately 20% of SRT neurons were immunoreactive for calcium binding proteins, CB, CR (calretinin) or both CB & CR and hardly any cells labelled for ChAT. While a smaller proportion immunolabelled for neuronal nitric oxide synthase (nNOS). Nine percent of SRT cells responded to mechanical noxious stimulation as demonstrated by phosphorylation of extracellular signal regulated kinase (ERK). The present findings provide a new basis for understanding the organisation and functional connectivity of spinoreticular tract neurons which convey information from peripheral and spinal inputs to the LRN where it is integrated with information from the brain and conveyed to the cerebellum and their role in a spino-bulbo-spinal loop that is responsible for modulating activity of pre-motor networks to ensure co-ordinated motor output.

Attachment theory describes the importance of the child’s early relationship with the caregiver and insecure attachment has been identified as a risk factor for adolescent self-harm. Research presented in this thesis aims to further our understanding of this relationship by firstly exploring whether attachment impacts on self-harm via its effect on coping, secondly examining how peer attachment styles relate to self-harm and finally establishing what role attachment has in the repetition of self-harm and other related outcomes. Study 1, an online survey of 314 undergraduate students,revealed that attachment has an indirect effect onself-harm through coping. Higher quality of attachment was association with greater reliance on problem-focused (adaptive) coping, which in turn was associated with a decreased risk of having self-harmed. Furthermore, poorer paternal attachmentwas associated withlower appraisal of problem-solving skills, which in turn was associated with an increased risk of having self-harmed. Study 2 prospectively examined self-reported peer attachment as a risk factor for self-harm over 6-months amongst adolescents (n= 4508) in school years 8-11. Findings indicated that insecure attachment at baseline significantly predicted self-harm at follow-up, even after adjusting for baseline covariates (school year, gender, previous self-harm and levels of anxiety and depression). Lastly, study 3 hypothesised that insecure attachment would be associated with poorer outcomes over 6-months amongst adolescents aged 12-17 years who had self-harmed and been referred to Specialist CAMHS. Attachment styles were classified using the Child Attachment Interview: a validated assessment for young people. Compared to secure adolescents, those with insecure maternal attachment were more likely to repeat self-harm and showed less improvement in problem-solving. There were no differences between the groups in concordance with therapy. These findings provide novel insights into the relationship between attachment and self-harm and highlight the importance of considering attachment when planning treatment and assessing the risk of future self-harm.