Altered asymmetry of the anterior cingulate cortex in subjects at genetic high risk for psychosis

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Abstract

Objective

Many studies have reported that patients with schizophrenia often have structural abnormalities of the anterior cingulate cortex (ACC) and that some of these seem to be of genetic origin, therefore predating the onset of illness. The present study aimed to investigate whether these alterations in the ACC are genetic in origin by comparing the morphological patterns of three groups: normal controls, subjects at genetic high risk (GHR) for psychosis, and patients with schizophrenia. The relationships between morphological variations and executive function were also investigated.

Methods

This study examined the magnetic resonance images of cingulate sulcus/paracingulate sulcus (CS/PCS) folding patterns in 222 subjects (103 normal subjects, 30 individuals at GHR, and 89 patients with schizophrenia) and evaluated differences in the morphological and asymmetrical patterns of the ACC among groups. Neurocognitive tests were then performed and differences in cognitive performance were analyzed according to morphological variation.

Results

Differences in PCS folding were detected; the control group was significantly more likely than were other groups to show a well-developed left PCS (p = 0.009) and leftward asymmetry of the PCS (p < 0.001). However, neither GHR subjects (p = 0.346) nor patients (p = 0.784) showed this leftward asymmetry. No statistically significant differences in CS continuity were observed. A more prominent left PCS (p = 0.031) and leftward PCS asymmetry (p = 0.030) were both associated with higher scores on the working memory task.

Conclusion

The results suggest that GHR subjects have distinct neurodevelopmental anomalies that resemble those of patients with schizophrenia even though they do not display any psychotic symptoms. Certain developmental alterations in the ACC, such as the loss of leftward sulcal asymmetry in patients with schizophrenia, might be related to genetic factors. Additionally, this morphological alteration might partly account for the impaired executive function in schizophrenia.

Introduction

Emerging evidence from genetics, neuroimaging, and neuropathology has reinforced the link between abnormal neurodevelopment and the presentation of schizophrenia (Keshavan, 1999, Pantelis et al., 2005, Fatemi and Folsom, 2009). According to the neurodevelopmental hypothesis, the etiopathological processes of schizophrenia, which involve both genetic and environmental factors, start before the maturation of the brain (Rapoport et al., 2005). One approach to the in vivo study of neurodevelopmental abnormalities involves examining cortical folding patterns. These are formed primarily during the second and third trimesters of gestation and remain relatively constant thereafter. Sulcal/gyral patterns and resulting asymmetries respond robustly to factors that can confound analyses of volumetric imaging methods (Magnotta et al., 1999).

The anterior cingulate cortex (ACC) is involved in brain executive functions such as emotion, motor behaviors, memory or learning (Vogt et al., 1992). Recent neuroimaging research has identified structural abnormalities in the ACC that are correlated with the neuropathology (Fornito et al., 2009) and cognitive deficits observed in schizophrenia (Szeszko et al., 2000, G.M. Clark et al., 2010). A similar study using functional magnetic resonance imaging (fMRI) also revealed that activation patterns in the ACC differed according to sulcal/gyral patterns (Artiges et al., 2006). These findings have a parallel in a previous post-mortem study (Ide et al., 1999) and support the notion that anatomical abnormalities are related to ACC dysfunction in schizophrenia. The paracingulate sulcus (PCS), which belongs to the ACC region, is more commonly found in the left cerebral hemisphere and also seems to be more extensive in the left than the right hemisphere (Paus et al., 1996). Consequently, it was reported that healthy subjects tended to have leftward ACC asymmetry (Yücel et al., 2001). Contrastingly, the patients with schizophrenia were apt to have lacked leftward asymmetry (Yücel et al., 2002). It has been proposed that leftward asymmetry in the paracingulate cortex evolved with left hemispheric dominance for language in humans (Paus et al., 1996). The results of imaging studies showing PCS involvement in verbal ability (Fu et al., 2002, G.M. Clark et al., 2010) which might be perceived as a component of executive control (Fornito et al., 2006) support this proposal. Given that cerebral anatomical asymmetries associated with neurodevelopmental processes appear during gestation (Chi et al., 1977), the asymmetries that are characteristic of schizophrenia may reflect a disruption in early neurodevelopment. This is in line with postulates that the genetic mechanism involved in the neurodevelopmental variation of cerebral asymmetry is related to the specific language function of humans and that schizophrenia originates as a “disorder of language disturbance” (Crow, 2008, G.M. Clark et al., 2010). However, structural studies investigating neuroanatomical changes in the ACC have produced inconsistent results due to confounders such as sex and handedness, poorly defined boundaries, and diverse methodologies (Goldstein et al., 1999, Yücel et al., 2001, Fornito et al., 2008a).

Schizophrenia can be considered a highly heritable disease as well as a neurodevelopmental disease (Sullivan et al., 2003). Studies with subjects at genetic high risk (GHR) for psychosis (i.e., nonpsychotic relatives who share genetic factors with patients) can provide useful information about the etiology of schizophrenia while avoiding such confounders as symptoms and treatment effects. Findings reported in the last few years have indicated that certain structural and functional aspects of the brains of GHR subjects differ from those of normal subjects (Keshavan et al., 2005, Gogtay et al., 2007, Jang et al., 2011). Moreover, GHR populations often exhibit abnormalities (Johnstone et al., 2002, Snitz et al., 2006) similar to those in patients with schizophrenia (Allen et al., 2009). Although a few studies have examined the cortical folding patterns of the ACC in individuals with genetic loading for psychosis, most have focused on patients or subjects at ultra-high risk (UHR) (Yücel et al., 2003, Wood et al., 2005). One study found that the left cingulate sulcus (CS) was interrupted and the right PCS was less prominent in male subjects at GHR (Meredith et al., 2012). However, further analysis of relatively homogenous GHR subjects who had remained healthy compared with normal controls was not included.

The degree to which genetic factors are associated with the alterations in ACC morphology observed in schizophrenia regardless of symptoms has not yet been clarified. Additionally, whether anatomical changes in the PCS/CS reflect genetic vulnerabilities and/or the neurodevelopmental etiology of schizophrenia has not yet been established. In this study, we assessed variations in sulcal/gyral morphology and asymmetry patterns to determine whether subjects at greater genetic risk for psychosis show morphological alterations that imply early neurodevelopmental abnormalities in the ACC. We also explored relationships between the morphological pattern in the ACC and performance on cognitive tasks related to executive control including verbal fluency, to investigate functional associations with this variation.

Section snippets

Participants

Initially, 224 of the 241 individuals meeting the inclusion criteria underwent scans and two (1 with schizophrenia and 1 of the GHR group) were excluded after scanning due to mental retardation and missing information. Ninety patients with schizophrenia were included from the Seoul National University Hospital (SNUH). These patients fulfilled the DSM-IV criteria for schizophrenia according to the Structured Clinical Interview for DSM-IV (SCID-IV) (First et al., 1996). A total of 103 healthy

Sulcal morphology

Data on demographic characteristics and scores are presented in Table 1. The three groups differed significantly in age, IQ, and educational level, but no differences in sex or handedness and ICV were observed.

No significant group differences were observed with respect to CS continuity. Only two (one with schizophrenia and the other in the control group) of 222 subjects had an interrupted CS.

The three groups differed significantly in left PCS classifications (Table 2). This result persisted

Discussion

In the present study, GHR individuals and patients with schizophrenia were less likely than normal controls to show a well-developed left PCS. Results in schizophrenia confirm previous evidence concerning PCS morphology (Yücel et al., 2002, Le Provost et al., 2003). Regarding the right PCS, a classification of “absent” was most common in all groups, and no significant group differences were found, similar to earlier findings (Le Provost et al., 2003, Yücel et al., 2003). In published papers,

Role of funding source

This study was supported by a grant of the Korea Healthcare technology R&D project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A120476). The Ministry for Health, Welfare & Family Affairs had no further role in study design; in the collection of data, analysis and interpretation of result; in the writing of the report; and in the decision to submit the paper for publication.

Contributors

H.Y. Park was involved in designing the study, analyzing the data as well as writing the draft of the manuscript. Author J.Y. Hwang and G. Shim recruited the subjects, undertook clinical assessments of the participants and helped as independent raters for reliability. Author W.H. Jung was involved in MRI acquisition, pre-processing, analysis of imaging data. Author N.Y. Shin administered neurocognitive tests to the subjects. Author J.H. Jang was involved in recruiting the subjects and

Conflict of interest

The authors declare that they have no conflict of interest for this study.

Acknowledgments

None.

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