Anterior cingulate morphology in people at genetic high-risk of schizophrenia.

BACKGROUND: Morphological abnormalities of the anterior cingulate (AC) occur in patients with schizophrenia and in symptomatic high-risk individuals, and may be predictive of subsequent psychosis. We investigated AC sulcal morphology in the Edinburgh High Risk Study cohort to see if such abnormalities are evident and predict psychosis in patients' relatives. We also investigated the association of the cingulate sulcus (CS) and paracingulate sulcus (PCS) variants with intelligence quotient (IQ). PATIENTS AND METHODS: We compared cingulate and paracingulate sulcal anatomy, using reliable standardised measurements, blind to group membership, in those at high genetic risk (n=146), first episode patients (n=34) and healthy controls (n=36); and compared high-risk subjects who did (n=17) or did not develop schizophrenia. RESULTS: Interruptions of the cingulate sulcus were more common in high-risk individuals and in those with schizophrenia, in both hemispheres, compared to controls. When separated by gender, these results were only present in males in the left hemisphere and only in females in the right hemisphere. A well-formed paracingulate sulcus was less common in high-risk participants and patients with schizophrenia, compared to controls; but this association was only present in males. These morphological variants of the paracingulate sulcus and the continuous cingulate sulcus were also associated with the higher IQ in male high-risk individuals. CONCLUSIONS: An interrupted cingulate sulcus pattern in both males and females and paracingulate morphology in males are associated with increased genetic risk of schizophrenia. Associations between cingulate and paracingulate morphology and premorbid IQ scores provide evidence that intellectual ability could be related to particular cytoarchitectural brain regions. Given that these sulci develop in early fetal life, such findings presumably reflect early neurodevelopmental abnormalities of genetic origin, although environmental effects and interactions cannot be ruled out.

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.

Prefrontal gyral folding and its cognitive correlates in bipolar disorder and schizophrenia.

OBJECTIVE: We sought to address whether dorsal or ventral prefrontal gyrification is abnormal in bipolar disorder and to determine its diagnostic specificity and cognitive associations. METHOD: Forty-two out-patients with bipolar disorder, 28 with schizophrenia and 37 controls underwent magnetic resonance imaging. All subjects also underwent IQ and executive assessments using tasks whose performance has been localized to the ventral or dorsal prefrontal cortex. Cortical folding was quantified using the gyrification index (GI) and related to the cognitive measures. RESULTS: Patients with bipolar disorder showed reduced prefrontal gyrification compared with controls but did not differ from patients with schizophrenia. Neither ventral nor dorsal GI was preferentially affected in either disorder. Current IQ was positively and significantly correlated with GI. CONCLUSION: Patients with bipolar disorder and patients with schizophrenia have reduced prefrontal gyrification affecting both ventral and dorsal subregions. These reductions were significantly associated with cognitive impairments occurring in both disorders.

A diffusion tensor MRI study of white matter integrity in subjects at high genetic risk of schizophrenia.

Diffusion tensor imaging (DTI) has previously shown compromised white matter integrity in frontotemporal white matter fibers in patients with schizophrenia, as indicated by reduced fractional anisotropy (FA). In the present study we investigated whether reduced white matter FA is also present in relatives of individuals with schizophrenia who are at high risk (HR) for genetic reasons. Twenty-two HR subjects, 31 patients with schizophrenia and 51 control subjects underwent DTI. We compared FA between the three groups in the cingulum cingulate gyri, the uncinate and the arcuate fasciculi and the anterior limb of the internal capsules (ALIC). A voxel-based analysis showed lower FA in patients with schizophrenia compared to controls in left and right uncinate (p<0.03), the left arcuate (p<0.03) and left and right ALIC (p<0.01). Using an automatic region-of-interest analysis, less sensitive to potential misregistration errors, produced essentially the same results, as well as reduced FA of the ALIC in the HR group compared to controls (p<0.05). This study replicates previous findings showing lower FA in frontotemporal white matter fibers of schizophrenia patients. We also found reduced FA in the ALIC of both patients and subjects at high risk of schizophrenia when compared to controls. This may be a possible indicator of the higher vulnerability of relatives to develop the disorder.

The effects of a neuregulin 1 variant on white matter density and integrity.

Theories of abnormal anatomical and functional connectivity in schizophrenia and bipolar disorder are supported by evidence from functional magnetic resonance imaging (MRI), structural MRI and diffusion tensor imaging (DTI). The presence of similar abnormalities in unaffected relatives suggests such disconnectivity is genetically mediated, albeit through unspecified loci. Neuregulin 1 (NRG1) is a psychosis susceptibility gene with effects on neuronal migration, axon guidance and myelination that could potentially explain these findings. In the current study, unaffected subjects were genotyped at the NRG1 single nucleotide polymorphism (SNP) rs6994992 (SNP8NRG243177) locus, previously associated with increased risk for psychosis, and the effect of genetic variation at this locus on white matter density (T(1)-weighted MRI) and integrity (DTI) was ascertained. Subjects with the risk-associated TT genotype had reduced white matter density in the anterior limb of the internal capsule and evidence of reduced structural connectivity in the same region using DTI. We therefore provide the first imaging evidence that genetic variation in NRG1 is associated with reduced white matter density and integrity in human subjects. This finding is discussed in the context of NRG1 effects on neuronal migration, axon guidance and myelination.