Behaviour is considered to be compulsive when it is performed automatically regardless of whether it results in deleterious consequences. Although most prominently associated with obsessive-compulsive disorder, compulsivity is also present in a host of other psychiatric disorders and likely represents a trans-diagnostic trait with shared dysfunctional circuitry (Gillan et al., 2016a). Despite this, no single treatment shows anticompulsive efficacy across disorders, and disorder-specific treatments are not particularly efficacious either (Grant et al., 2016). This may be because different circuitry parameters are disrupted in different disorders, but result in similar behavioural outcomes, therefore a treatment targeting one parameter will not alleviate dysfunction caused by alterations in a different parameter. This thesis investigates the circuitry of compulsivity by administering drugs that differentially target these parameters to rats undergoing associative learning tasks shown to be dependent on this neural circuitry. We found that the acute administration of phencyclidine – a drug which models the psychotic state (by blocking NMDA receptors; Rafter et al., 2016) – promoted compulsive approach towards a formerly rewarded stimulus but not compulsive avoidance to a formerly unrewarded stimulus. We also found that administration of this drug to neonatal pups in combination with adolescent social isolation led to the opposite effect, that is, reduced compulsive approach towards a formerly rewarded stimulus once it became unrewarded. Administration of a serotonin 5-HT2C receptor antagonist (a putative anti-compulsive agent) had no effect on choices but accelerated the speed of responding. Meanwhile intra-orbitofrontal cortex infusion of the dopamine neurotoxin 6-hydroxydopamine or the serotonin neurotoxin 5,7-dihydroxytryptamine failed to reliably induce neurotransmitter depletion, and subsequently had no effect on any behavioural measure. These findings suggest that targeting glutamate systems upstream of dopamine and serotonin systems may result in better treatment outcomes for compulsivity driven by formerly reinforced associations, e.g. in delusions, behavioural addictions, and drug addiction.

The work presented in this thesis aims to increase clinical capacity for magnetoencephalography (MEG) by developing an understanding of how, in healthy participants, individual differences in brain structure, personality, and demographics influence measurements of neural oscillatory responses and functional connectivity. To this end, a large cohort of normative data was acquired using MEG with additional data acquisition using high-field MRI and supplementary individual difference data collected via a psychometric battery and screening questionnaire. MEG data were analysed to elucidate both primary sensory responses to stimulation and functional connectivity within task and task-free acquisitions. Chapters two and three introduce the physiological origins of the MEG signal and the instrumentation required to record it. Chapter four describes data acquisition and preprocessing, from the methods used in the recruitment of participants to the scanning parameters employed for our MEG and MRI acquisitions. Chapters five to seven present three empirical studies. The first investigates the relationship between MEG derived measurements of functional connectivity and cortical myeloarchitecture. We demonstrate that covariation of cortical myelin is significantly predicted by MEG-derived measurements of functional connectivity both within individual frequency bands and by their linear and non-linear combination. Chapter six presents an exploratory analysis into the impact of aging and sex-differences on MEG derived measurements of sensorimotor responses and whole-brain functional connectivity. We find trends indicating increased oscillatory responses with age. Further, we find female volunteers to exhibit greater induced responses than males. Analysis of whole-brain functional connectivity revealed a near-global increase in connectivity in female participants as compared to males. The final empirical chapter assesses the shared neuronal representations between patients diagnosed with schizophrenia and healthy individuals scoring highly on a personality questionnaire measuring schizotypy. We found highly schizotypal individuals to exhibit attenuated sensorimotor responses akin to those previously observed in schizophrenia. Patients displayed reduced functional connectivity within an occipital network, identified in task and task free data. We found this aberrant network connectivity to also be present in healthy subjects scoring highly on a questionnaire assessing schizotypy. The thesis, in sum, presents work demonstrating the significant modulatory effects of individual differences ranging from sex differences to schizotypy. This work highlights the need for consideration of participant demographics and individual differences in both clinical and basic science studies. Further, the thesis presents a newly identified relationship between MEG-derived measurements of functional connectivity and cortical myeloarchitecture. Future work assessing the role of other sources of individual difference in modulating MEG measurements is required. Moreover, the framework for assessing the relationship between functional connectivity and cortical myeloarchitecture is well suited to application in clinical populations where this relationship is hypothesised to break down.

Depression is a heterogeneous condition characterised by low mood and a lack of motivation and enjoyment of regular activities. The response rate to current treatments coupled with adverse side effect profiles requires new avenues of investigation into the development of novel therapeutics to treat the condition. Rearing rats in isolation from weaning causes behavioural, cognitive and neurochemical changes which persist into adulthood; some of the symptoms produced have relevance to depression. In the current thesis, rats raised in social isolation from weaning consistently developed a hyperactive phenotype compared to group-housed littermates when placed into a novel environment. They also developed deficits in associative learning assessed by the conditioned fear response task. They displayed some anxiety-like behaviours in the open field and novelty-suppressed feeding task and deficits in visual memory in the novel object discrimination task, although these were not reliable across cohorts. There was a reduction in levels of hippocampal neurogenesis in a number of cohorts and for the first time it was demonstrated that rats reared in isolation exhibited changes in gut bacteria, opening up a potential new avenue of investigation into potential treatments. The efficacy of novel versus established antidepressant treatments was evaluated in isolated rats. Chronic fluoxetine had some anxiolytic effects in the open field, attenuated isolation induced changes in associative memory and increased neurogenesis but also had inconsistent effects on activity. Treatment with acute ketamine increased freezing time in the conditioned freezing response task, indicating an improvement in associative memory. The final study examined, for the first time, the effect of treatment with the JNK-1 inhibitor DJNKI in isolation reared rats. DJNKI had some positive cognitive effects in both the novel object discrimination task and the conditioned freezing response task. In conclusion, the isolation rearing model induced varying levels of depression-like deficits, which were responsive to some treatments. The model is a useful tool for investigating the symptoms of depression and evaluating novel treatment options.

Many cognitive theories point to key factors underlying the development and maintenance of eating disorders, such as: unhealthy food-related cognitive biases, negative body attitude, and perfectionism. The present research utilised eye-tracking during reading as a novel implicit measure of how these factors may relate to eating disorder tendencies in females and males, followed by the development of two new male body dissatisfaction scales. In four experiments female and male (N = 360) participants’ eye movements were monitored while they read third- and second-person perspective texts in which the characters’ emotional responses to food-, body image-, and perfectionism-related scenarios were described. Overall, results from these studies suggest that on-line processing of characters’ emotional responses to perfectionism-, and to a lesser extent, body image-related information is predictive of participants’ disordered eating tendencies, thus supporting theories in which these two underlying factors are key to developing and maintaining eating disorders. Interestingly, the on-line processing of characters’ emotional responses to food-related scenarios did not predict eating disorder tendencies, as participants read food-related scenarios similarly, regardless of having a higher eating disorder level. In Chapter V, two new male body dissatisfaction scales: The Male Body Scale (MBS; consisting of emaciated to obese figures) and the Male Fit Body Scale (MFBS; consisting of emaciated to muscular figures) were developed, tested, and re-tested. Male participants (N = 103) rated which of nine body figures on each scale most represented their current- and ideal- body figure, followed by the Drive for Muscularity Scale (DMS), the Eating Disorder Examination Questionnaire (EDE-Q 6.0), and the calculation of their actual body mass index (BMI), fat-, and muscularity-percentage. This was followed by a re-test and manipulation check two to six weeks later. Results found both new scales were consistently valid and reliable between test and re-test, and importantly, each scale was sensitive to different types of body dissatisfaction within males. Specifically, the MBS revealed that males’ desire for the thin-ideal significantly corresponded to higher eating disorder tendencies as shown by EDE-Q 6.0 scores, whilst the MFBS revealed much higher body dissatisfaction toward the larger, muscularity-ideal, predicting higher drive for muscularity as shown by DMS scores. Altogether, the present research findings provide novel insights into cognitive processes underlying disordered eating behaviour, demonstrate the utility of eye-tracking as a more natural implicit measure, provide tools to assess and predict eating disorder tendencies in females and males, and inform eating disorder related research.

Schizophrenia is a complex mental disorder characterised by various symptoms which fall into three categories of positive, negative and cognitive. In particular, negative symptoms are poorly treated by current medications although several adjunctive therapies are under investigation including Glycine Transporter (GlyT1) inhibitors and neuropeptides such as oxytocin. Despite accumulating preclinical and clinical evidence that such compounds can influence social behaviour and improve negative symptoms in patients, there is little information as to the precise mechanisms by which they work. Therefore, the aims of this thesis were to ultimately determine some of the key regions and potential signalling pathways activated following administration of these compounds in Lister-hooded rats. Firstly, a functional map of GlyT1 inhibitor RO4993850, an analogue to Bitopertin, identified the selective activation of neurons within the rostral and caudal prefrontal cortex (PFC), suggesting potential NMDA receptor activation in brain areas involved in motivation and goal-directed behaviour. This was further assessed in a novel ‘dual-hit’ neonatal-PCP isolation-rearing rodent model for schizophrenia which was shown herein to induce locomotor hyperactivity and social deficits including reduced social interaction (an index for negative symptoms) and increased communication (as assessed by ultrasonic vocalisations (USVs)). Interestingly neonatal-PCP isolation-reared rats emitted more pro-social 50 kHz USVs which were also longer in duration and had a greater change in call bandwidth compared to controls. Neonatal-PCP isolation-rearing was also shown to selectively decrease parvalbumin expression (a calcium binding protein present in GABAergic interneurons) in the hippocampus but not in the rostral PFC sub-regions assessed, producing similar changes to other rodent models. Microdialysis studies however revealed no change to basal PFC and striatal dopamine levels in these rats. Chronic treatment with the GlyT1 inhibitor RO4993850 improved social deficits in the social interaction test and altered both USV emissions and call characteristics but showed no effect on locomotor hyperactivity, parvalbumin expression in either the PFC or hippocampus, nor dopamine overflow in the PFC or striatum. Finally, an established dose of the neuropeptide oxytocin which did not influence core body temperature, was shown to attenuate PCP-induced hyperactivity, increase pro-social behaviour and selectively enhance dopamine release in the nucleus accumbens (NAc) in group-housed Lister-hooded rats. Thereby providing supporting evidence for regionally-specific oxytocin-dopaminergic interactions within the mesocorticolimbic circuits responsible for regulating associative and rewarding behaviour. There are therefore several potential mechanisms by which both GlyT1 inhibitors and oxytocin can influence social behaviour, most likely via activation of key brain loci involved in motivation. Although further work is required, results herein indicate the potential of GlyT1 inhibitors and oxytocin as adjunctive therapies to treat predominant negative symptoms in schizophrenia.

Tourette syndrome (TS) is a neurodevelopmental disorder characterised by vocal and motor tics. It is associated with cortical–striatal–thalamic–cortical (CSTC) circuit dysfunction and hyper-excitability of cortical motor regions. TS follows a developmental time course, in which tics often become increasingly more controlled during adolescence. Importantly, however, a substantial minority of patients continue to have debilitating tics into adulthood. This indicates that there may be important differences between adult TS patients and children and adolescents with the disorder. The first aim of my thesis was to explore the excitability of the primary motor cortex (PMC) at rest, during motor preparation, motor execution and the inhibition of action. In Chapters 3 and 4 I demonstrate that, in contrast to studies of adult patients, resting motor threshold (RMT) and the variability of motor-evoked potential (MEP) responses are increased in young people with TS, while the gain of motor excitability in reduced. Furthermore, these differences normalise with age over adolescence. I conclude that these effects are likely due to a developmental delay in the maturation of key brain networks in TS, consistent with recent brain imaging studies of structural and functional brain connectivity. Importantly, these findings suggest that the alterations in brain network structure and function associated with TS may be quite different in children and adult patients with the condition. In Chapter 4, I demonstrate that whilst there is evidence of reduced gain during motor execution in young people with TS relative to controls (Chapter 3), the reduction is likely driven by baseline differences and when corrected to baseline patients with TS show an increased ramping of motor excitability during motor execution. In fact, patients’ tic severity was inversely related to the modulation of motor excitability whereby those with the most severe tics were least able to increase excitability. Patients showed largely the same patterns of change in excitability during motor preparation and response inhibition. However, the extent to which patients could modulate excitability during motor preparation was related to phonic tic severity whereby those with the least severe tics had higher excitability change from baseline. In addition, those that were able to suppress motor excitability to a greater extent whilst inhibiting action had the least severe tics, likely engaging inhibitory mechanisms to a greater extent with the consequence of slower response times during the task. I conclude that the ability to modulate motor excitability is both related to pathology and adaptive compensatory mechanisms that may help in tic suppression. The second aim of this thesis was to explore effective connectivity, excitatory and inhibitory physiological mechanisms and the neurochemistry of PMC in young healthy adults. Subsequent experiments in Chapters 5 and 6 used various transcranial magnetic stimulation (TMS) techniques and proton magnetic resonance spectroscopy (1H-MRS) to investigate these issues. Chapter 5 explored interhemispheric facilitation and inhibition (IHI and IHF) in two directions between bilateral PMC. The results provided evidence for an asymmetry of interhemispheric interactions using dual site TMS (ds-TMS) whereby the left-to-right direction is more inhibitory than right-to-left. Furthermore, females appeared to show greater interhemispheric modulation than males and whilst there was robust evidence for IHI (in the left-to-right direction) IHF appeared to not be robust. Finally, Chapter 6 explored how TMS-induced measures of excitation and inhibition related to 1H-MRS measures of neurochemicals γ-aminobutyric acid (GABA), glutamate (Glu) and glutamine (Gln). GABA is the primary inhibitory neurotransmitter in the human brain and is critical for the regulation of neuronal excitability and the orchestration of neuronal networks and is critically important in neurodevelopmental disorders such as TS. GABA was not found to be related to measures of synaptic neurotransmission as assessed by TMS and neither was Gln. In contrast, Glu was found to be related to a hub of TMS measures, in particular, Glu was positively related to both intracortical facilitation (ICF) and long intracortical inhibition (LICI). Chapters 5 and 6 further uncovered relationships between ds-TMS, pp-TMS and 1H-MRS showing that these various measures likely have overlapping mechanisms. The final chapters extend our knowledge about the PMC and the methodologies used to assess its state. Chapter 5 extends our understanding of the communication between right and left PMC and highlights a normal asymmetry in communication. This is important for understanding neurodevelopmental disorders such as TS of which asymmetry in effective connectivity and brain volume have been implicated. Chapter 6 importantly shows that 1H-MRS measured GABA is likely irrelevant for assessing synaptic neurotransmission and thus its interpretations should be limited to non-synaptic levels of GABA. This is particularly important for TS research in which both changes in GABAA receptor activity is present in the PMC and abnormalities in GABA concentration have been shown.

This thesis examines auditory selective attention as a possible cause of Auditory Processing Disorder (APD). APD is a diagnosis based on the clinical needs of the 5% of children who present with listening difficulties but demonstrate normal hearing. This thesis will focus on developmental APD, which affects children with no known infection, trauma or primary cause inducing their listening difficulties. It will seek to address the current lack of understanding of the root causes of APD, which leads to significant variation in clinical referral routes, resulting in inconsistent methods of diagnosis and treatment. APD has historically been approached via a bottom-up route of assessing auditory processing skills, such as temporal-spatial abilities. The inconsistent results of bottom-up studies has led to debate regarding the diagnosis and treatment of APD, resulting in extensive batteries of tests being conducted on children. However, recent evidence suggests that studies on the causality of APD should be refocused on top-down processes such as auditory attention and memory – hence the focus of this thesis on auditory selective attention. The thesis begins by assessing a new test of auditory selective attention, the Test of Attention in Listening (TAiL), to ensure that it measures auditory rather than supramodal attention. Having established the modality-specificity of TAiL, the thesis examines the development of auditory selective attention to both spatial and non-spatial auditory stimulus features, across tasks of varying levels of perceptual demand. Finally, the thesis assesses the selective attention ability of children with listening difficulties. Specifically, listeners’ selective attention is assessed in both the auditory and visual domains, using both spatially- and non-spatially-based tasks. If auditory selective attention deficits are found in those with listening difficulties, this will provide a basis for the diagnosis and treatment of APD to be constructed and managed from a psychological viewpoint rather than an audiological one.

The human brain can be divided into multiple areas, each responsible for different aspects of behaviour. For a century we have been developing techniques to non-invasively map these areas and their associated functions, a discipline now known as neuroimaging. In recent years the field has undergone a paradigm shift to investigate how the brain communicates with itself; it is widely regarded that healthy brain function relies upon efficient connectivity between different functional areas, and the neuroimaging field has been revolutionised by our ability to estimate this connectivity. Studies into communication between spatially separate locations in the brain have revealed a series of robust functional networks which govern mental processes. However these studies have been based on the temporal averaging of minutes or even hours of data to give us a generalised ’snapshot’ of connectivity. Increasing evidence shows us that these connections are dynamic in space, time and frequency and so the next generation of of neuroimaging methods, which capture this 5-dimensional connectivity will prove to be key tools in the investigation of brain networks and ultimately their breakdown in disease. In this thesis we introduce novel methods to capture non-stationarity using magnetoencephalography (MEG), an imaging modality which measures the changes in extracranial magnetic fields associated with neuronal current flow. MEG is a direct measurement of neural activity and has an excellent temporal resolution, which makes it attractive for non-invasively tracking dynamic functional connections. However there are many technical limitations which can confound assessment of functional connectivity which have to be addressed. In Chapters 2 and 3 we introduce the theory behind MEG; specifically how it is possible to measure the femtoTelsa changes in magnetic field generated by the brain and how to project these data to generate a 3-dimensional picture of current in the brain. Chapter 4 reviews some of popular methods of assessing functional connectivity and how to control for the influence of artefactual functional connections erroneously produced during source projection. Chapter 5 introduces a pipeline to assess functional connections across time, space and frequency and in Chapter 6 we apply this pipeline to show that resting state networks, measured using ’static’ metrics are in fact comprised of a series of rapidly forming and dissolving subnetwork connections. Finally, Chapter 7 introduces a pipeline to track dynamic network behaviour simultaneously across the entire brain volume and shows that networks can be characterised by their temporal signatures of connectivity.

Tourette Syndrome (TS) is a developmental neurological disorder characterised by vocal and motor tics and is associated with cortical-striatal-thalamic-cortical circuit dysfunction and hyper-excitability within cortical motor areas. TS symptoms often become more controlled throughout adolescence until the individual is largely tic-free by early adulthood. It is likely that adaptive changes occur in the development of brain structure and function throughout the critical developmental period of adolescence in people with TS, which leads to tic remission in some individuals. To investigate this I used multiple brain-imaging approaches including diffusion tensor imaging to look at white matter microstructure, T1-weighted anatomical MR imaging to measure cortical grey matter thickness and MR-Spectroscopy (MRS) to measure neurotransmitters of interest (GABA and glutamate) in a group of young people with TS and a typically developing matched control group. Brain function (measures of excitation and inhibition in M1) was also considered by using transcranial magnetic stimulation. A significant positive relationship was found between white matter structural integrity (FA) measured from the body of the corpus callosum that contained projections to M1 or the SMA and motor tic severity. The TS group had increased levels of GABA in the SMA, as measured by MRS, compared to the control group. SMA- GABA levels had a significant positive relationship with FA from the SMA ROI but a negative relationship with TMS measures of cortical excitability during movement preparation. This suggests that those individuals with the least severe tic symptoms also have reduced callosal white matter from the SMA (an area implicated in the production and suppression of tics) in adolescents with TS, which relates to a reduction in task based cortical excitability and a reduction in SMA-GABA compared to those with more severe tics. The results from this thesis suggest that tic-suppression may occur through decreasing excitatory inputs to M1, either through increasing the inhibition (GABA levels) of the SMA, or by decreasing the number of excitatory interhemispheric inputs to sensorimotor regions.

The thesis solves the design of the technology of manufacturing the furniture wheel holder from a sheet thickness of 11 321 with a thickness of 2 mm. On the basis of the variant cutting and bending solution, a production solution was chosen in a process proggressive die. As a blank, a sheet metal strip is selected from a 64.1 mm roll. After the technology evaluation, the distances of the openings from the edge of the part and the bend were adjusted and the technological calculations determined the necessary total forces, work and other parameters. On the basis of the previous calculations, the S 160 E eccentric press of Šmeral was chosen as the most suitable machine. The designed tool works in six steps and includes nine cutting and one bending section together with two viewers and one spring retainer. Economic recovery has shown profitable production of the given series where the total profit is CZK 999 310,61 and the reversal point occurs after production 58 382 pieces.