Elsevier

Schizophrenia Research

Volume 115, Issue 1, November 2009, Pages 12-16
Schizophrenia Research

General absence of abnormal cortical asymmetry in childhood-onset schizophrenia: A longitudinal study

https://doi.org/10.1016/j.schres.2009.07.026Get rights and content

Abstract

Background

Childhood-onset schizophrenia (COS) is a rare, severe form of the adult-onset illness, with more salient neurobiological causes. Previous cross-sectional structural neuroimaging research has suggested that normal cortical asymmetry patterns [(R  L)/(R +L)] may be altered in adult schizophrenia, although these findings were not well replicated. Recent studies show dynamic changes in brain asymmetry during childhood and adolescence. We hypothesized that COS patients would show a lack of normal development of asymmetry and decreased overall asymmetry.

Methods

Prospective structural magnetic resonance scans were obtained at baseline and at two-year follow-up visits in 49 right-handed COS patients (mean baseline age: 14.72 ± 2.63, 117 scans) and 50 age and sex-matched, right-handed healthy controls (mean baseline age: 15.15 ± 3.37, 125 scans). Cortical thickness was calculated at 40,962 homologous points across each cerebral hemisphere using a fully automated, validated method. Differences in developmental asymmetry patterns across the cortical surface were analyzed using a linear mixed effects regression model.

Results

No significant asymmetry differences were found either for cross-sectional comparisons of COS and healthy controls across the lateral and medial cortical surfaces or with respect to timing of developmental changes in asymmetry.

Conclusions

The present findings do not support asymmetry differences for this severe, early form of schizophrenia.

Introduction

Childhood-onset schizophrenia (COS) is a rare, debilitating form of the illness characterized by onset of psychotic symptoms prior to the thirteenth birthday and premorbid I.Q. of at least 70 (American Psychiatric Association, 2000). Current research suggests COS as neurobiologically continuous with adult-onset schizophrenia (AOS), with a more severe clinical presentation and generally poor prognosis. The cause of schizophrenia is unknown, but research increasingly supports a neurodevelopmental model with a strong genetic predisposition (Rapoport et al., 2005).

Deviance from normal cortical asymmetry has been implicated in the pathogenesis of schizophrenia (Crow, 1990, Bilder et al., 1994). Cortical asymmetry is a defining feature of the healthy human brain. Lateralized specialization of the two hemispheres has evolved over time with implications for a multitude of sensorimotor functions. A typical developmental course of structural asymmetries in the human brain has been associated with normal motor and cognitive lateralization (Toga and Thompson 2003).

Normal asymmetry is widely defined by petalias, which describe right frontal and left occipital hemispheric protrusions (Kertesz et al., 1990, Chance et al., 2005). This pattern (also known as cerebral “torque,” indicative of a counter-clockwise rotational force) has been believed to be related to the structure and development of language (Crow, 1998, Angrilli et al., 2009), with the role of left hemisphere dominance in human language processing (Angrilli et al., 2009). Established findings include greater degrees of asymmetry in right-handed compared to non-right handed individuals (defined as both left handed and ambidextrous individuals). More specifically, the typically leftward asymmetry of the planum temporale is reduced or even reversed in left-handed individuals (Narr et al., 2007). Other reported normal asymmetry findings include leftward lateralization in the minicolumn structure of the planum temporale (Buxhoeveden et al., 2001), a longer, more horizontally placed left Sylvian fissure (Galaburda et al., 1978), and leftward lateralization of the pars triangularis (PTR) and pars opercularis (POP), implicated in speech-language production (Foundas et al., 1998).

Crow et al. theorized that abnormal hemispheric lateralization patterns are keys to the pathogenesis of schizophrenia (Crow and Ball, 1989, Crow, 1990, Crow, 1997). Specifically, previous findings in schizophrenia patients included increased left ventricular enlargement (Crow, 1990, James et al., 1999), reduced left temporal lobe surface area (Johnstone et al., 1989, Rossi et al., 1990), reduced GM in the left superior temporal gyrus (Barta et al., 1990, Shenton and Kikinis, 1992), reduced left greater than right (L > R) asymmetry in the occipito-parietal region, and reduced R > L asymmetry in the premotor and prefrontal regions (Bilder et al., 1994, DeLisi et al., 1994).

However, there are numerous studies that do not support abnormal asymmetry as a characteristic of schizophrenia, finding normal L > R Sylvian fissure length (Bartley et al., 1993) and normal temporal lobe asymmetries in AOS (Frangou et al., 1997, Crespo-Facorro et al., 2004). Levitt et al. conducted a small volumetric MRI study of COS patients (n = 13, mean age: 14.2 ± 3.8) and found no departure from normal temporal lobe asymmetry patterns (Levitt et al., 2001).

As part of a large prospective COS study, the abnormal cortical asymmetry issue was revisited. COS is a rare, severe phenotype with early neurodevelopmental delays, salient genetic influences (Addington and Rapoport 2009), and more prominent neurobiological features when compared to AOS (Rapoport et al., 2009). Thus, we hypothesized that COS patients might be more sensitive to potential departures from normal asymmetry development.

A recent longitudinal study in our group included developmental cortical asymmetry analysis in healthy children and adolescents (Shaw et al., 2009). Our healthy subjects manifested L > R cortical thickness in the orbitofrontal/inferior frontal gyrus progressing into a R > L pattern during adolescence, indicative of a relative right hemispheric gain. The reverse was found in the medial occipital and angular gyri where children showed a relative gain in left hemispheric thickness during adolescence. These findings indicate that normal adult patterns of cortical asymmetry emerge in childhood and develop progressively through adolescence. While cortical thickness is not a direct measure of torque, the distinct increases in right frontal and left occipital thickness are suggestive of potential torque development. In the present study, we compared COS and control subjects during childhood through young adulthood. We hypothesized that our COS cohort might manifest abnormal asymmetry at baseline or progressively during development.

Section snippets

Participants

Patients were recruited as part of an ongoing COS study at the National Institute of Mental Health (NIMH) in Bethesda, MD. The sample has been described at length elsewhere (Rapoport et al., 2009). All right-handed subjects with at least one MRI scan were selected (n = 49, baseline age: 14.72 ±2.63). Handedness was assessed using the Physical and Neurological Examination for Soft Signs (PANESS) where subjects indicate use of the right or left hand for twelve commonplace activities (Denckla 1985).

Results

Demographic data are shown in Table 1. As expected for the healthy controls (n = 50), current findings are consistent with previously published data from our group which also includes a depiction of longitudinal cortical thickness progression in our typically developing population (Shaw et al., 2009). With age, left cortical thickness increased relative to right in the superior frontal, superior temporal, and temporo-occipital regions. Also, over time the R > L difference became more extensive in

Discussion

We present the first longitudinal MRI findings reporting no abnormal progression of cortical asymmetry in the COS population. Our healthy control sample demonstrated comparable asymmetry patterns and trajectories as seen in our recent study (Shaw et al., 2009). We did not see abnormal asymmetry patterns as have been reported in some studies of AOS, although results from studies of AOS remain inconsistent. Similarly, we did not find reduced L > R asymmetry of the anterior cingulate gyrus as

Role of funding source

The present research was funded by the Intramural Research Program (IRP) at the National Institute of Mental Health in Bethesda, MD.

Contributors

Jennifer L. Bakalar, BA was the primary author of the manuscript. Deanna K. Greenstein, PhD and Liv Clasen, PhD performed the neuroimaging and statistical data analysis for the project. Julia W. Tossell, MD and Rachel Miller, PhD oversaw clinical management of COS patients in the sample. Anand A. Mattai, MD assisted with the composition and editing of the manuscript. Alan C. Evans, PhD was our primary collaborator and consultant for the image-processing pipeline. Judith L. Rapoport, MD and

Conflict of interest

The authors have nothing to disclose financially and report no conflicts of interest.

Acknowledgements

The authors would like to thank Dr. Philip Shaw and Dr. Jay Giedd for their advice and assistance with this project.

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