Schizophrenia is often a debilitating psychiatric disorder, characterised by both positive and negative symptoms, and cognitive and psychosocial impairments. The established disorder has been associated with a number of brain abnormalities, however it is at present unknown whether these brain changes occur prior to onset of schizophrenia, or in unaffected relatives with a familial vulnerability to develop the disorder, or only in those at high risk that go on to develop the disorder. Furthermore, most studies have been conducted cross-sectionally, which may have obscured subtle longitudinal changes in familial high risk individuals, and these studies tend to have focused on localized cortical gray matter , and thus it is unclear whether they affect different cortical parameters differentially. Prospective familial high risk studies utilizing surface based MRI programmes provide a good method to investigate this. In the Edinburgh High Risk Study, structural magnetic resonance imaging (MRI) scans of 150 young individuals at familial high risk of schizophrenia, 34 patients with first-episode schizophrenia and 36 matched controls were obtained. Of the high risk participants with scans suitable for analysis, 17 developed schizophrenia after the scans were taken, whilst 57 experienced isolated or sub-clinical psychotic symptoms, and 70 remained well. We used Freesurfer to extract volumetric and surface-based measurements of several cortical and localized sub-cortical regions with the aim of assessing whether any alterations found were present in all those at high risk, or selectively in the high risk cohort based on future clinical outcome, or only in those experiencing their first-episode of psychosis. It was found that those experiencing their first episode of schizophrenia exhibited significantly more widespread brain alterations compared to those at high risk or controls, both on a more global cortical level and in more localized regions of the cortex, with cortical thickness being generally thinner than in the other groups, and cortical surface area and gyrification increased compared to the other groups. An increased global surface area was also shared with the HR[ill] group, suggesting that this could be a marker that is predictive of future transition to psychosis. Within the high risk cohort, some brain alterations seemed to present as general vulnerability markers, specifically in the temporal lobe at baseline, whilst longitudinally both localized and global cortical alterations distinguished the high risk cohort from the control group, and a different developmental trajectory of the hippocampus was also found. These findings show that some brain alterations may be more accurately characterized as general vulnerability markers of the disorder, whilst some are specifically present in patients who have experienced their first episode of schizophrenia, whilst some also occur before disorder onset in those at high risk that go on to develop schizophrenia. The findings have some clinical implications, as they suggest that it is possible to assess who at high risk will go on to develop schizophrenia based on brain structural alterations. This may provide clinicians with an early window of opportunity for intervention, as it has been found that early intervention may improve patient's prognosis. The findings also have important implications for the understanding of the underlying eitology of schizophrenia, as they suggest that some of these alterations are present before illness onset, and not associated with medication effects, thus potentially lying on the causal path of developing schizophrenia.

<p>The aim of this research study was to examine the clinical, behavioural and neurobiological characteristics of children who are considered to be at increased risk for developing anxiety disorders. The study population included high-risk children who have at least one parent with social phobia and normal-risk control subjects. The first objective of the study was to examine the prevalence of anxiety disorders in high-risk children. We determined the proportion of high-risk children who met criteria for a psychiatric disorder using structured clinical interviews and assessed symptom severity using measures of anxiety and depression. We found the prevalence of anxiety disorders to be elevated in high-risk children with 77% meeting criteria for a lifetime psychiatric disorder. High-risk subjects also had significantly higher levels of anxiety symptoms relative to normal-risk subjects. The second objective of the study was to examine threat-related attention processing in high-risk and normal-risk children using the dot-probe attention orienting task. We compared probe detection reaction times of high-risk children and normal-risk control children when they were exposed to emotional facial stimuli. We did not find any significant within-group or between-group differences in reaction times in our high-risk and normal-risk subjects. However, we did observe a trend towards longer reaction times in high-risk subjects for all trial types relative to normal-risk subjects, which could indicate general processing deficits in the high-risk group. The third objective of this study was to examine the activity of emotion processing brain regions using functional magnetic resonance imaging (<em>f</em>MRI) in children who are at increased risk for developing anxiety disorders. We compared the blood oxygenation level dependant (BOLD) response while high-risk and normal-risk subjects were engaged in the dot probe attention orienting task. Using <em>f</em>MRI, the BOLD response was measured while subjects were exposed to masked emotional (angry, happy or neutral) facial stimuli. We found increased activation of several frontal, temporal and limbic regions in high-risk subjects relative to normal-risk subjects during the presentation of emotional facial stimuli. These regions included the prefrontal cortex, anterior cingulate, hippocampus, insula, basal ganglia and temporal regions. To our knowledge this is the first study to characterize a sample of children at-risk for anxiety disorders using clinical, behavioural and neuroimaging data. The findings from this study demonstrate that high-risk children experience heightened anxiety symptoms and that they also present with functional abnormalities of brain regions involved in emotion processing. These results highlight the need for early identification and intervention for children at-risk for anxiety disorders. Future studies should aim for longitudinal study designs combined with neuroimaging techniques to examine changes in anxiety symptoms over time and to study the effects of treatment on the function of limbic and prefrontal structures in children at-risk for anxiety disorders.</p> / Doctor of Philosophy (PhD)

Abstract Both genetic and biological and psychosocial environmental risk factors contribute to the aetiology of schizophrenia spectrum disorders. Among the much studied environmental risk indicators are parental Communication Deviance (CD) and the winter or spring birth of a child. Genetic and environmental risk factors do not function in isolation from each other, but gene-environment interactions play a major role in the aetiology of psychotic disorders. The aim of this doctoral thesis is to investigate the role of parental CD as a risk factor (together with other risk indicators) for thought disorders and schizophrenia spectrum disorders in an adoptive child. A systematised review was performed concerning the association between parental Communication Deviance and schizophrenia spectrum and thought disorders in offspring. A meta-analysis could only be performed for the association of parental CD with schizophrenia spectrum disorders in offspring. A large overall effect size was found (0.79, 95%CI 0.21–1.37). The studies included in the systematised review suggest that frequent parental CD and thought disorders in the offspring are connected with each other. The two original studies are based on the data derived from the total sample of the Finnish Adoptive Family Study (n=382). First, the association between parental Communication Deviance scored from individual and family Rorschach protocols and the characteristics of the adoptive child and the parents themselves was investigated. The variability of CD in the adoptive parents in individual and family Rorschach situations was most closely associated with the characteristics of the parents themselves. The association of an adoptive child’s thought and schizophrenia spectrum disorders with the child’s genetic risk for schizophrenia spectrum disorders, winter or spring birth, and parental Communication Deviance, and their interactions was also explored. The adoptive child’s thought disorders were associated only with parental CD. None of the risk indicators or their interactions predicted the adoptee’s schizophrenia spectrum diagnosis. In conclusion, the results indicate that the amount of Communication Deviance is a stable trait of an individual. It may be considered as a risk indicator for schizophrenia spectrum disorders in offspring and, with a lower level of confidence, also for thought disorders in offspring. / Tiivistelmä Skitsofreniaspektrin sairauksien varsinaisia syytekijöitä ei tunneta, mutta niillä on lukuisia sekä perimään että biologiseen ja psykososiaaliseen ympäristöön liittyviä riskitekijöitä. Nykytietämyksen mukaan riskitekijät eivät vaikuta sairauden syntyyn itsenäisesti, vaan perimän ja ympäristön vuorovaikutuksella on merkittävä osuus. Paljon tutkittuja ympäristöön liittyviä riskitekijöitä ovat lapsen talvi- tai kevätsyntymä ja vanhempien hajanainen kommunikaatio. Tässä väitöskirjassa tutkitaan vanhempien hajanaista kommunikaatiota adoptiolapsen ajatushäiriöiden ja skitsofreniaspektrin sairauksien riskitekijänä. Vanhempien hajanaisen kommunikaation ja lapsen skitsofreniaspektrin sairauksien ja ajatushäiriöiden yhteydestä laadittiin systemaattinen katsaus. Meta-analyysi voitiin tehdä vain skitsofreniaspektrin sairauksiin liittyen. Vanhempien hajanaisen kommunikaation ja lapsen skitsofreniaspektrin sairauksien välisellä yhteydellä havaittiin olevan suuri efektikoko (0,79, 95 % luottamusväli 0,21–1,37). Katsaukseen sisällytetyt tutkimukset viittaavat siihen, että vanhempien hajanaisella kommunikaatiolla ja lapsen ajatushäiriöillä on myös yhteys. Väitöskirjan alkuperäistutkimukset perustuvat Suomalaisen adoptiolapsiperhetutkimuksen aineistoon (n= 382). Aluksi tutkittiin vanhempien yksilö- ja perhe-Rorschach-tilanteissa mitatun hajanaisen kommunikaation määrän ja lapsen ja vanhempien ominaisuuksien välistä yhteyttä. Hajanaisen kommunikaation määrän vaihtelu selittyi pääosin vanhempien ominaisuuksilla. Seuraavaksi tutkittiin adoptiolapsen ajatushäiriöiden ja skitsofreniaspektrin sairauksien yhteyttä lapsen skitsofreniaspektrin sairauksille altistavan perimän, talvi- tai kevätsyntymän ja vanhempien hajanaisen kommunikaation kanssa. Huomioon otettiin myös riskitekijöiden yhteisvaikutukset. Mikään riskitekijä tai niiden yhteisvaikutus ei ollut yhteydessä lapsen skitsofreniaspektrin sairauteen. Lapsen ajatushäiriöt olivat yhteydessä ainoastaan vanhempien hajanaiseen kommunikaatioon. Tutkimuksen tulokset osoittavat, että vanhempien hajanainen kommunikaatio on kohtalaisen muuttumaton piirre, joka on lapsen skitsofreniaspektrin sairauksien riskitekijä. Tulokset viittaavat myös siihen, että vanhempien hajanainen kommunikaatio voi olla lapsen ajatushäiriöiden riskitekijä.