Polygenic risk for schizophrenia, transition and cortical gyrification: a high-risk study.

BACKGROUND: Schizophrenia is a highly heritable disorder, linked to several structural abnormalities of the brain. More specifically, previous findings have suggested that increased gyrification in frontal and temporal regions are implicated in the pathogenesis of schizophrenia. METHODS: The current study included participants at high familial risk of schizophrenia who remained well (n = 31), who developed sub-diagnostic symptoms (n = 28) and who developed schizophrenia (n = 9) as well as healthy controls (HC) (n = 16). We first tested whether individuals at high familial risk of schizophrenia carried an increased burden of trait-associated alleles using polygenic risk score analysis. We then assessed the extent to which polygenic risk was associated with gyral folding in the frontal and temporal lobes. RESULTS: We found that individuals at high familial risk of schizophrenia who developed schizophrenia carried a significantly greater burden of risk-conferring variants for the disorder compared to those at high risk (HR) who developed sub-diagnostic symptoms or remained well and HC. Furthermore, within the HR cohort, there was a significant and positive association between schizophrenia polygenic risk score and bilateral frontal gyrification. CONCLUSIONS: These results suggest that polygenic risk for schizophrenia impacts upon early neurodevelopment to confer greater gyral folding in adulthood and an increased risk of developing the disorder.

Childhood adversity and hippocampal and amygdala volumes in a population at familial high risk of schizophrenia.

BACKGROUND: There is an established link between childhood adversity (CA) and schizophrenia. Hippocampus and amygdala abnormalities pre-date onset in those at high familial risk (fHR) of schizophrenia, but it is not clear whether these alterations are associated with CA in those at elevated risk of schizophrenia. METHODS: We examined hippocampal and amygdala volumes in those at fHR who had been referred to a social worker or the Children's Panel compared to those who had not. RESULTS: The right hippocampus and left amygdala were significantly smaller in those that had been referred to social work and Children's Panel. CONCLUSIONS: Our findings suggest that CA can influence structural changes in the brain in a cohort at fHR of schizophrenia. These findings provide further evidence that while genetic factors contribute to the structural changes found in schizophrenia, environmental factors such as CA can have a lasting impact on specific brain regions.

Childhood adversity and cortical thickness and surface area in a population at familial high risk of schizophrenia.

BACKGROUND: There is now a well-established link between childhood adversity (CA) and schizophrenia. Similar structural abnormalities to those found in schizophrenia including alterations in grey-matter volume have also been shown in those who experience CA. METHOD: We examined whether global estimates of cortical thickness or surface area were altered in those familial high-risk subjects who had been referred to a social worker or the Children's Panel compared to those who had not. RESULTS: We found that the cortical surface area of those who were referred to the Children's Panel was significantly smaller than those who had not been referred, but cortical thickness was not significantly altered. There was also an effect of social work referral on cortical surface area but not on thickness. CONCLUSIONS: Cortical surface area increases post-natally more than cortical thickness. Our findings suggest that CA can influence structural changes in the brain and it is likely to have a greater impact on cortical surface area than on cortical thickness.

Tensor-based morphometry of cannabis use on brain structure in individuals at elevated genetic risk of schizophrenia.

BACKGROUND: Schizophrenia is associated with various brain structural abnormalities, including reduced volume of the hippocampi, prefrontal lobes and thalami. Cannabis use increases the risk of schizophrenia but reports of brain structural abnormalities in the cannabis-using population have not been consistent. We used automated image analysis to compare brain structural changes over time in people at elevated risk of schizophrenia for familial reasons who did and did not use cannabis. METHOD: Magnetic resonance imaging (MRI) scans were obtained from subjects at high familial risk of schizophrenia at entry to the Edinburgh High Risk Study (EHRS) and approximately 2 years later. Differential grey matter (GM) loss in those exposed (n=23) and not exposed to cannabis (n=32) in the intervening period was compared using tensor-based morphometry (TBM). RESULTS: Cannabis exposure was associated with significantly greater loss of right anterior hippocampal (pcorrected=0.029, t=3.88) and left superior frontal lobe GM (pcorrected=0.026, t=4.68). The former finding remained significant even after the exclusion of individuals who had used other drugs during the inter-scan interval. CONCLUSIONS: Using an automated analysis of longitudinal data, we demonstrate an association between cannabis use and GM loss in currently well people at familial risk of developing schizophrenia. This observation may be important in understanding the link between cannabis exposure and the subsequent development of schizophrenia.

Orbitofrontal morphology in people at high risk of developing schizophrenia.

BACKGROUND: Abnormalities of orbitofrontal cortex (OFC) sulcogyral patterns have been reported in schizophrenia, but it is not known if these predate psychosis. METHODS: Hundred and forty-six subjects at high genetic risk of schizophrenia, 34 first episode of schizophrenia patients (SZ) and 36 healthy controls were scanned and clinically assessed. Utilising the classification system proposed by Chiavaras, we categorised OFC patterns and compared their distribution between the groups, as well as between those high risk subjects who did, and did not develop schizophrenia. The relationship between OFC pattern and schizotypy was explored in high risk subjects. RESULTS: We refined Chiavaras' classification system, with the identification of a previously unreported variant of OFC surface structure. There were significant differences in distribution of OFC patterns between high risk subjects who did or did not develop schizophrenia as well as between the first episode of schizophrenia group and healthy controls. Within the high risk group, possession of OFC Type III was associated with higher ratings on the Structured Inventory for Schizotypy (SIS) psychotic factor. CONCLUSIONS: Our results suggest that OFC Type III is associated with psychotic features before the development of schizophrenia. Characterisation of OFC morphology may have a role in the identification of those at greatest risk of developing schizophrenia.

Specific cognitive deficits in a group at genetic high risk of schizophrenia.

BACKGROUND: Neuropsychological deficits in schizophrenia patients and their relatives have been thought to represent possible genetic vulnerability markers or endophenotypes of the disorder. The present study describes results from the Edinburgh High Risk Study of computerized testing using the Cambridge Neuropsychological Test Automated Battery (CANTAB) on a group at genetic high risk (HR) of schizophrenia and a control group. METHOD: A total of 97 HR and 25 control participants were assessed on three tests from the CANTAB - spatial span, spatial working memory, and Stockings of Cambridge. Analyses of covariance were used to compare the HR and control groups on the main outcome measures whilst controlling for intelligence quotient (IQ). Subsequent analysis examined the effects of the presence of symptoms on group differences. RESULTS: HR participants had significantly reduced spatial memory capacity [F(1, 118)=4.06, p=0.046] and significantly reduced planning processing speed [F(1, 116)=4.16, p=0.044] compared with controls even after controlling for general intelligence (IQ). Although HR individuals made more errors and showed poorer problem-solving and strategy performance compared with controls, these differences were not significant after controlling for IQ. Subsequent analysis indicated that the presence or absence of psychotic symptoms in the HR group did not influence these specific cognitive deficits. CONCLUSIONS: Spatial memory capacity and planning processing speed may represent cognitive endophenotypes characterising the genetic predisposition to schizophrenia in this HR group.

fMRI changes over time and reproducibility in unmedicated subjects at high genetic risk of schizophrenia.

BACKGROUND: Functional brain abnormalities have been repeatedly demonstrated in schizophrenia but there is little data concerning their progression. For such studies to have credibility it is first important to establish the reproducibility of functional imaging techniques. The current study aimed to examine these factors in healthy controls and in unmedicated subjects at high genetic risk of the disorder: (i) to examine the reproducibility of task-related activation patterns, (ii) to determine if there were any progressive functional changes in high-risk subjects versus controls reflecting inheritance of the schizophrenic trait, and (iii) to examine changes over time in relation to fluctuating positive psychotic symptoms (i.e. state effects). METHOD: Subjects were scanned performing the Hayling sentence completion test on two occasions 18 months apart. Changes in activation were examined in controls and high-risk subjects (n=16, n=63). Reproducibility was assessed for controls and high-risk subjects who remained asymptomatic at both time points (n=16, n=32). RESULTS: Intra-class correlation values indicated good agreement between scanning sessions. No significant differences over time were seen between the high-risk and control group; however, comparison of high-risk subjects who developed symptoms versus those who remained asymptomatic revealed activation increases in the left middle temporal gyrus (p=0.026). CONCLUSIONS: The current results suggest that functional changes over time occur in the lateral temporal cortex as high genetic risk subjects become symptomatic, further, they indicate the usefulness of functional imaging tools for investigating progressive changes associated with state and trait effects in schizophrenia.

fMRI correlates of state and trait effects in subjects at genetically enhanced risk of schizophrenia.

Schizophrenia is a highly heritable disorder that typically develops in early adult life. Structural imaging studies have indicated that patients with the illness, and to some extent their unaffected relatives, have subtle deficits in several brain regions, including prefrontal and temporal lobes. It is, however, not known how this inherited vulnerability leads to psychosis. This study used a covert verbal initiation fMRI task previously shown to elicit frontal and temporal activity (the Hayling sentence completion task) to examine this issue. A large (n = 69) number of young participants at high risk of developing schizophrenia for genetic reasons took part, together with a matched group of healthy controls (n = 21). At the time of investigation, none had any psychotic disorder, but on detailed interview some of the high-risk participants (n = 27) reported isolated psychotic symptoms. The study aimed to determine: (i) whether there were activation differences that occurred in all subjects with a genetic risk of schizophrenia (i.e. 'trait' effects); and (ii) whether there were activation differences that only occurred in those at high risk who had isolated psychotic symptoms ('state' effects). No activation differences were found in regions commonly reported to be abnormal in the established illness, namely the dorsolateral prefrontal cortex or in the temporal lobes, but group differences of apparent genetic cause were evident in medial prefrontal, thalamic and cerebellar regions. In addition, differences in activation in those with symptoms were found in the intraparietal sulcus. No significant differences in performance were found between the groups, and all subjects were antipsychotic naïve. These findings therefore suggest that vulnerability to schizophrenia may be inherited as a disruption in a fronto-thalamic-cerebellar network, and the earliest changes specific to the psychotic state may be related to hyperactivation in the parietal lobe.

Sustained attention in young people at high risk for schizophrenia.

BACKGROUND: Sustained attention has been found to be impaired in individuals suffering from schizophrenia and their close relatives. This has led to the hypothesis that impaired sustained attention is an indicator of vulnerability to schizophrenia. METHODS: The Edinburgh High Risk Study used the Continuous Performance Test-Identical Pairs version (CPT-IP) to assess sustained attention in 127 high risk participants, 30 controls and 15 first-episode schizophrenic patients. A second assessment was completed by 59 high risk and 18 control participants 18 months to 2 years after the first. RESULTS: No differences in attentional capacity were found between the high risk and control groups and there was no association between genetic liability to schizophrenia and poor performance on the CPT-IP. Additionally, no association between occurrence of psychotic symptoms in the high risk group and impaired attentional capacity was found. CONCLUSIONS: The results suggest that deficits in sustained attention are not indicative of a genetic vulnerability to schizophrenia, and are not associated with the occurrence of psychotic symptoms.