Reduced cortical thickness in first episode schizophrenia

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Abstract

Objective

Previous morphometric studies are suggesting altered cortical thickness mainly in prefronto-temporal regions in first episode schizophrenia. In an extension of these earlier studies, we used an entire cortex vertex-wise approach and an automated clustering for the detection and exact quantification of cortical thickness alterations in first episode schizophrenia.

Methods

A group of 54 patients with first episode schizophrenia according to DSM-IV and 54 age and gender matched healthy control subjects were included. All participants underwent high-resolution T1-weighted MRI scans on a 1.5 T scanner. Cortical thickness was estimated as the distance between the gray–white matter border and the pial surface using an automated computerized algorithm (Freesurfer Software). Statistical cortical maps were created to estimate differences of cortical thickness between groups based on this entire cortex analysis.

Results

Significant cortical thinning was observed in first episode schizophrenia patients relative to controls in a number of cortical areas including the dorsolateral and frontopolar cortices, the anterior cingulate cortex, a ventrolateral–orbitofrontal cluster, as well as the superior temporal cortices and superior parietal lobe. Cortical thinning within these regions was on average 4.4–5.7% with strongest reductions in orbitofrontal regions (7.1%).

Conclusions

The present findings suggest widespread reduction of cortical thickness, mostly in heteromodal cortices of fronto-temporal networks to be present at an early stage of schizophrenia. Taken together, the present morphometric data in first episode schizophrenia provide further evidence for potential neurodevelopmental deficits and disruption of cortical maturation in this disorder.

Introduction

In recent years, a wealth of literature has been accumulated with regard to morphometric changes in schizophrenia using voxel-based morphometric approaches (Honea et al., 2005, Williams, 2008). More recently available automated data analysis strategies focusing on cortical thickness are adding complemental information to these data. There is now growing evidence for reduced cortical thickness predominantly in fronto-temporal regions in chronic schizophrenia (Kuperberg et al., 2003, Nesvag et al., 2008).

In first episode schizophrenia patients reduced cortical thickness could be demonstrated for the anterior cingulate cortex (Fornito et al., 2008) and the prefrontal cortex (Venkatasubramanian et al., 2008) using surface-based regions of interest (ROI) analyses. However, using a ROI strategy, Wiegand et al. (2004) could not demonstrate differences in prefrontal cortical thickness between first episode patients and matched healthy controls.

Narr et al., 2005a, Narr et al., 2005b computed cortical thickness as a three-dimensional shortest distance from the gray–white matter boundary to the gray matter–CSF boundary and resampled the data to a 0.33 mm3 voxel size to obtain distance measures at a sub-voxel resolution. They examined cortical thickness in first episode schizophrenia separately for lateral cortical and mesial cortical regions. The study demonstrated cortical thinning of frontal and temporal but also occipital areas.

In addition, reduced cortical thickness could also be demonstrated for unaffected siblings of patients with schizophrenia (Goldman et al., 2009) suggesting a potential relationship of these cortical alterations findings to the genetic liability for developing schizophrenia.

However, to date there were no studies based on a two-dimensional cortical surface model, which investigated cortical thickness using an entire cortex and vertex-wise comparison to detect brain areas with a significant cortical thinning in first episode schizophrenia. A two-dimensional surface model most likely reflects the genuine two-dimensional structure of the human cerebral cortex (Dale et al., 1999). Vertex-wise analysis of cortical thickness allows for an entire cortex exploratory data analysis without any a priori constraints and it is therefore not restricted to a limited brain region as a search space for anatomical alterations. Subsequently, clusters of statistically significant vertex-wise findings can be defined. Average cortical thickness data extracted from these clusters can then be used for the exact comparison of cortical thickness differences between diagnostic groups. Hence, significant cortical thickness differences can be quantified independently from predefined cortical parcellation schemes or manual tracing.

Previous surface-based studies (Kuperberg et al., 2003, Nesvag et al., 2008) used atlas based anatomical parcellations or manual tracing of brain regions to define anatomical labels, which are mapped to the individual subjects for data extraction and group comparisons.

In an methodological extension of these earlier studies we performed an entire cortex vertex-wise analysis and employed an automated clustering approach to detect and quantify potential differences of cortical thickness between first episode schizophrenia patients and healthy controls. According to previous studies we hypothesized cortical thinning to be present in mainly prefronto-temporal cortical areas.

Section snippets

Participants

Fiftyfour patients with first episode schizophrenia and 54 matched healthy controls were included. All participants were right-handed (Annett, 1967) and groups were matched according to age and gender. Diagnoses were established based on the Structured Clinical Interview for DSM-IV (M. R.) and were confirmed by two independent psychiatrists (R.S. and Ch.S.). All patients met DSM-IV criteria for schizophrenia and had no second psychiatric diagnosis. They were in remission from a psychotic

Automated clustering

Cluster analysis revealed four clusters in the left hemisphere and five clusters in the right hemisphere, which demonstrated significantly reduced cortical thickness in first episode schizophrenia (Fig. 1, Table 2). These clusters comprised prefronto-temporal, anterior cingulate and parietal cortical areas. Reduced cortical thickness in the left cortex included inferior parietal (BA 43), ventro- and dorsolateral prefrontal (BA 44–47; 9), superiorfrontal (BA 6;8), frontopolar (BA 10) and

Discussion

We present the first surface-based entire cortex analysis of cortical thickness in first episode schizophrenia. Our analysis revealed significant reduced cortical thickness in prefronto-temporal, anterior cingulate and parietal cortex areas in patients with first episode schizophrenia.

Our results are in line with the studies by Narr et al., 2005a, Narr et al., 2005b, although a direct comparison can only be performed with some limitations due to different methodological approaches of the

Concluding remarks

In conclusion, our data demonstrate, that even patients with first episode schizophrenia show a discrete but distinct and under functional aspects well characterizable pattern of cortical thinning. The automated clustering approach used in our study for the exact quantification of cortical thickness alterations provides a deeper insight into how different brain regions are affected in first episode schizophrenia. Against the background of a potentially varying velocity of cortical thinning

Role of funding source

Our sponsor, recognized in the acknowledgments, served no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

Contributors

Drs. Schlösser, Sauer, Schultz, Koch and Wagner were involved in the design of this study and contributed to the writing of the manuscript. Dr. Schultz performed the cortical thickness data analyses. Dr. Gaser and Dr. Reichenbach contributed technical expertise to the MRI imaging processing and cortical thickness analysis. Dr. Roebel and Dr. Nenadic were involved in diagnosing subjects and psychopathological data collection. Ms. Schachtzabel was involved in the recruitment of subjects. Dr.

Conflict of interest

All of the authors reported no financial interests or potential conflicts of interest.

Acknowledgment

This work was supported by the Bundesministerium für Bildung und Forschung, BMBF Grant 01GW0740.

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