Grey and white matter abnormalities are associated with impaired spatial working memory ability in first-episode schizophrenia

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Abstract

Spatial working memory (SWM) dysfunction has been suggested as a trait marker of schizophrenia and implicates a diffuse network involving prefrontal, temporal and parietal cortices. However, structural abnormalities in both grey and white matter in relation to SWM deficits are largely unexplored. The current magnetic resonance imaging (MRI) study examined this relationship in a sample of young first-episode schizophrenia (FES) patients using a whole-brain voxel-based method.

SWM ability of 21 FES patients and 41 comparable controls was assessed by the CANTAB SWM task. Using an automated morphometric analysis of brain MRI scans, we assessed the relationship between SWM abilities and both grey matter volume and white matter density in both groups.

Our findings demonstrated the different directionality of the association between SWM errors and grey matter volume in left frontal regions and white matter tracts connecting these regions with temporal and occipital areas between FES patients and controls. This suggests that the substrate underpinning the normal variability in SWM function in healthy individuals may be abnormal in FES, and that the normal neurodevelopmental processes that drive the development of SWM networks are disrupted in schizophrenia.

Introduction

Impairment of spatial working memory (SWM) is considered a core cognitive dysfunction in schizophrenia (Park and Holzman, 1992, Pantelis et al., 1997, Pantelis and Maruff, 2002, Piskulic et al., 2007), and may be a trait marker for the illness (Wood et al., 2003, Seidman et al., 2006, Smith et al., 2006). SWM deficits in schizophrenia were originally thought to relate to prefrontal abnormalities (Goldman-Rakic, 1994, Goldman-Rakic and Selemon, 1997), but recent functional magnetic resonance imaging (fMRI) (Meyer-Lindenberg et al., 2005, Ragland et al., 2007) and diffusion tensor imaging (DTI) (Karlsgodt et al., 2008) findings suggest that abnormalities in fronto-parietal and fronto-temporal networks may underlie impairments in SWM ability in schizophrenia.

Most evidence from neuroimaging studies suggests that schizophrenia is associated with subtle but widespread morphologic brain changes, predominantly in the frontal, temporolimbic and paralimbic regions (Shenton et al., 2001, Fornito et al., 2009). However, more recent findings have implicated changes in parietal regions in the pathophysiology of the illness (Paulus et al., 2002, Kim et al., 2003, Danckert et al., 2004, Zhou et al., 2007). Similar findings have been demonstrated in first-episode schizophrenia (FES) patients (Whitford et al., 2005), suggesting that these deficits are present at illness onset, with evidence that they progress over the initial years of the disorder (Pantelis et al., 2003, Whitford et al., 2006, Sun et al., 2008).

Increasing evidence also points to a role for white matter abnormalities in schizophrenia (Davis et al., 2003, Walterfang et al., 2006) and it has been suggested that progressive grey matter reductions following the illness progression are related to changes in white matter (Friedman et al., 2008, Peters et al., 2008). Only a few recent voxel-based morphometry (VBM) studies, which allow for the investigation of the distribution of regional structural changes of both grey and white matter components within the whole brain, have investigated the relationship between white and grey matter abnormalities in schizophrenia (Douaud et al., 2007, Miyata et al., 2009, Spoletini et al., 2009). These studies suggest that changes in the two tissue compartments are related, and may be due to the same pathological processes.

MRI studies that have compared schizophrenia patients to healthy controls have demonstrated a series of brain regions and networks disrupted by the illness (Glahn et al., 2008, Fornito et al., 2009). A number of VBM analyses have explored the relationship between these brain changes and clinical features of the illness, such as level of psychotic symptoms (e.g. Shapleske et al., 2002, Yoshihara et al., 2008, Lui et al., 2009) or neuropsychological deficits (Antonova et al., 2005, Spoletini et al., 2009), however, the structural underpinnings of SWM ability in schizophrenia have not been well-documented. In their recent study combining Tract-Based Spatial Statistics (TBSS) and VBM analyses, Spoletini et al. (2009) demonstrated that verbal working memory deficits in chronic schizophrenia were associated with grey matter abnormalities in frontal regions as well as reduced fronto-parietal connectivity. However, this study failed to find morphologic changes specifically related to visuo-spatial working memory dysfunctions, possibly due to confounding factors associated with analyzing chronic patients, such as the effects of chronic medication and the impact of relapses. The study of FES populations could reduce the influence of such confounding factors, but no VBM study has attempted to determine the structural underpinnings of SWM ability in young FES patients.

In the present study, we sought to characterize the relationships between grey and white matter structure and SWM performance in young FES patients and healthy controls, and to compare the relationships in these two groups. Based on previous work (Wood et al., 2003, Smith et al., 2006, Cocchi et al., 2009), we predicted that FES would exhibit poorer SWM performance compared to controls, and that these SWM deficits would be related to grey and white matter abnormalities in the brain regions involving fronto-parietal and fronto-temporal networks.

Section snippets

Subjects

A total of 21 FES patients and 41 comparable control subjects were included in the study. All participants were selected from a larger database at the Melbourne Neuropsychiatry Centre. Patients that had a MRI scan, completed the SWM task and were right handed were included in the study. Subjects were screened for comorbid medical and psychiatric conditions by clinical assessment and physical and neurological examination. Patients were excluded if there was poor (uncorrectable) eyesight, history

Demographics and clinical variables

Controls and FES were matched for age (t(59.887) = 0.748, p = 0.458) and gender (X2 = 0.027, df = 1, phi = 0.021, p = 0.868), but controls underwent more years of formal education (t(59) = 4.519, p < 0.001) and had a higher premorbid and current IQ [premorbid IQ (PM-IQ) t(59) = 2.350, p = 0.022; current IQ (FS-IQ) t(57) = 5.427, p < 0.001]. Premorbid IQ was used as covariate of interest for SWM BSEs because this measure may be considered as independent of illness. SWM BSEs were not significantly correlated with PM-IQ

Discussion

To our knowledge this is the first study that has examined the relationship between both grey and white matter structure and SWM function in young FES patients and control participants. We have shown that the normal relationships between structure and function are lost in the disorder, but that the regions where these relationships break down are not the same as those regions which differentiate patients and controls more generally. Our findings tend to implicate a dissociation between the

Role of funding source

The funding sources had no role in the study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication.

Contributors

Luca Cocchi, Mark Walterfang, Renée Testa, Stephen J. Wood, Bridget Soulsby, Dennis Velakoulis, and Christos Pantelis designed the study and wrote the protocol. Luca Cocchi managed the literature searches, conducted the statistical analyses, and wrote the first draft of the manuscript. Patrick McGorry, Tina-Marie Proffitt, and Warrick J. Brewer made major contributions to the data set. Tsutomu Takahashi, Stephen J. Wood, John Suckling, Marc Seal, Christopher Adamson, and Bridget Soulsby helped

Conflict of interest

All authors report no competing interests.

Acknowledgements

The Swiss National Foundation for the Scientific Research supported this study (LC) PBLAB-119622 and PBLAB3-119622; SJW was supported by a NHMRC Clinical Career Development Award (359223) (SJW 578) and MW was supported by a Pfizer NSR grant and by Melbourne Health. This study was also supported by NHMRC Program Grants (566529 579 and 350241) and NHMRC Project Grants (145627, 145737, 981112, 970598, and 970599).

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