Relationship Between Gyrification and Functional Connectivity of the Prefrontal Cortex in Subjects at High Genetic Risk of Schizophrenia

Abstract

Measures of cortical folding ('gyrification') and connectivity are both reported to be disrupted in schizophrenia. There are also reports that increases in prefrontal gyrification may be predictive of subsequent illness in individuals at familial risk of the disorder. Such measures therefore have important potential clinical relevance. The nature of the relationship between cortical morphology and underlying connectivity is however unclear. In the current study we sought to explore the relationship between measures of gyrification and functional connectivity in a cohort of individuals at high genetic risk for the disorder. The theoretical background is based on the hypothesis that increased gyrification index (GI) in the prefrontal cortex may reflect increased short range regional connectivity. The cohort comprised 68 young unaffected relatives of schizophrenia patients and 21 healthy controls. Cortical folding was assessed using an automated Gyrification Index method (A-GI). Participants performed the Hayling sentence completion paradigm in the scanner and measures of functional connectivity were assessed using a correlation based approach. In the high risk subjects significant positive associations were found between prefrontal GI and prefrontal lateral-medial connectivity, while a negative correlation was found between prefrontal GI and prefrontal-thalamic connectivity. These associations indicate that measures describing morphological features of the brain surface relate to measures of underlying functional connectivity in the high risk subjects. Correlations in high risk people were more pronounced than in control subjects. We suggest our previous finding of increased prefrontal gyrification may therefore relate to increased local short range prefrontal connectivity and reduced long range connectivity.

Local Gyrification Index in Probands with Psychotic Disorders and Their First-Degree Relatives

“…The observed patient-control differences were all in the direction of lower patient gyrification. The consistency of this finding of hypogyria is particularly notable amid the mixed findings of hypogyria and hypergyria in previous literature in schizophrenia (Table 1) and in high risk populations (29-31; 75-77). However, this study's findings appear especially robust given its large sample size, which was more than three times the size of the next largest comparable study of which we are aware.…”

“…It has been suggested that cortical connectivity development in the second trimester generates fiber tension, which draws densely connected regions together, forming bulging gyri, whereas more sparsely connected regions drift apart and are separated by inward sulci (16). The case for abnormal gyrification being an endophenotype for schizophrenia is supported by the presumed neurodevelopmental nature of the disorder, demonstrated heritability of gyrification (17) and observations of atypical cortical folding in both schizophrenia probands (16; 18-28) and, to a lesser degree, unaffected relatives (29-31). …”

Common variation inNCAN, a risk factor for bipolar disorder and schizophrenia, influences local cortical folding in schizophrenia

“…In line with this, mechanical models of brain development in primates indicate that folding is driven by the formation of corticocortical connections (Hilgetag & Barbas, 2006), and further animal experiments have demonstrated that early disruption of white matter connections are related to focal hypergyria (Goldman-Rakic, 1980). This view is also supported by a recent study by Dauvermann et al (2012), who analysed prefrontal gyrification together with functional connectivity. Overall, our results, in conjunction with prior knowledge, indicate that increased prefrontal gyrification might be related to increased short-range and reduced long-range connectivity.…”

Evidence for alterations of cortical folding in anorexia nervosa

“…This model is supported by experiments in rodents showing that a disruption of fiber tracts in early brain development leads to local hypergyria [60]. More recent publications using MRI lend further support to this hypothesis by showing a linkage between functional connectivity and local cortical folding [61]. The results of the latter study indicate that a disruption of longrange fiber tracts (e.g., thalamo-prefrontal connections) seem to specifically be associated with locally increased cortical folding.…”