Introduction: Schizotypy is a personality trait that shares some of the characteristics of clinical disorders such as schizophrenia. Similarities are found in expression of psychotic-like experiences and presence of attenuated negative signs. Furthermore, schizotypal samples are associated with impairments in cognitive tasks, albeit in a less comprised form. For these reasons and others, schizotypy is considered a part of the extended-phenotype of schizophrenia and as such can be utilised as an analogue sample without some of theconfounds associated with illness. Objective: The aim of the PhD is to examine the relationship of schizotypal features and brain function and structure in a sample of adolescents and young adults (age 16-25 years). This will attempt to provide further evidence for the placement of schizotypy on the continuum, along with insights into pathophysiological mechanisms involved in schizophrenia and related disorders. Methods: The study involved three main phases: recruitment via an online survey, further neuropsychological testing and brain imaging on selected high schizotypes and controls. The thesis comprises 5 papers/experiments. Paper 1 utilises confirmatory factor analysis (CFA) to examine the factorial structure of the schizotypal personality questionnaire (SPQ) in a community sample aged 16-25 years. It also examined the effects of demographics on schizotypal levels. Paper 2 examined the association between schizotypy and measures of sustained attention and spatial working memory both in a total sample, and in samples split by age and by sex. Paper 3 further examined the association between schizotypy and cognition laboratory tests of attention, executive function and verbal learning/memory. Paper 4 tested the same participants on measures of functional brain asymmetry. Paper 5 used diffusion tensor imaging (DTI) to examine white matter structures in a sample of high schizotypes and controls. Results: Paper 1 confirmed that the SPQ is most appropriately modelled by a four-factor structure in an adolescent and young adult sample. Demographic effects on SPQ subscales scores mirrored those seen in clinical samples. Paper 2 found that where small associations between schizotypy and sustained attention/spatial working memory function occurred, these were in relation to either age of sex. Paper 3 demonstrated an association between increased schizotypal features and a slight reduction in performance on verbal learning/memory, but no association with tasks of executive function or attention. In Paper 4, schizotypy was associated with a left-hemifield bias on a computerised line bisection task. Paper 5 found that a group of high schizotypes had an increase in tract coherence in the uncinate fasciculus compared to controls. Furthermore, increasing subclinical hallucinatory experiences were associated with increased tract coherence in the right hemisphere arcuate fasciculus. Conclusions: Schizotypy was associated with changes in brain function and structure similar to that demonstrated in more serious mental illness, although to a lesser degree. The current studies suggested that schizotypy is associated with relatively intact prefrontal function, but slight performance bias on measures of medial temporal lobe function. There was also evidence for structural brain changes in schizotypes, with these being indicative of either a protective factor, or a marker of a pathological process. Correlations between hallucinatory experiences and white matter tracts between language regions support theories implicating hyperconnectivity and presentation of symptoms in clinical groups. The functional and structural data collected from this study suggests that the ‘schizotypal’ brain may represent an ‘early’ stage of pathology, but which is likely to be compensated enough such that transition to serious mental illness is unlikely. Further studies could examine similarities and differences between the schizotypal profile and clinical conditions, which would provide further insights into aetiological mechanisms in schizophrenia/psychosis.

Paediatric posterior fossa tumors are often effectively controlled with a combination of radiation, chemotherapy and surgery. However, therapeutic craniospinal radiation has been associated with widespread cognitive late effects. Working memory is one such cognitive ability that has yet to be fully examined in this clinical population. Bilateral tracts connecting the cerebellum with the DLPFC were delineated using DTI tractography in all participants, replicating the cerebrocerebellar pathway outlined in an animal model. There were observable differences in white matter integrity (quantified by DTI measures of anisotropy, and mean, axial, and radial diffusivity) of the cerebellum-DLPFC pathway in patients versus controls. Additionally, working memory deficits that were found in patients were correlated with DTI indices pertaining to the cerebellum-DLPFC pathway. Therefore, this thesis is the first to explore the possible relations between white matter integrity of this pathway following treatment for paediatric posterior fossa tumors and working memory function.

Paediatric posterior fossa tumors are often effectively controlled with a combination of radiation, chemotherapy and surgery. However, therapeutic craniospinal radiation has been associated with widespread cognitive late effects. Working memory is one such cognitive ability that has yet to be fully examined in this clinical population. Bilateral tracts connecting the cerebellum with the DLPFC were delineated using DTI tractography in all participants, replicating the cerebrocerebellar pathway outlined in an animal model. There were observable differences in white matter integrity (quantified by DTI measures of anisotropy, and mean, axial, and radial diffusivity) of the cerebellum-DLPFC pathway in patients versus controls. Additionally, working memory deficits that were found in patients were correlated with DTI indices pertaining to the cerebellum-DLPFC pathway. Therefore, this thesis is the first to explore the possible relations between white matter integrity of this pathway following treatment for paediatric posterior fossa tumors and working memory function.