Investigating relationships between cortical thickness and cognitive performance in patients with schizophrenia and healthy adults
Introduction
Cognitive impairment is considered a core feature of schizophrenia (Kurtz, 2005) and has been found to be a good predictor of poor functional outcome in this disease (Green et al., 2000). Some of the most prominent cognitive problems include impairment in general intellectual ability, attention, memory and problem solving (Heinrichs and Zakzanis, 1998).
Cognitive abilities are in part related to grey matter in neocortical brain areas (Lezak, 1995). Brain lesion studies have demonstrated highly specific structure–function relationships (Stuss et al., 2000, Stuss et al., 2001), for instance that the labeling of nouns of animals and fruits depends on separate parts of the left temporal lobe (Damasio et al., 1996). In addition, it has been proposed that localized brain areas represent nodes in a distributed neural system underpinning cognitive function (Jung and Haier, 2007). Cognitive deficits in schizophrenia might arise as functional consequences of alterations of central nodes in the neural networks.
Magnetic resonance imaging (MRI) provides a method for in vivo investigations of possible neural substrates for cognitive alterations. Structural MRI studies have shown frontal and temporal grey matter volume reduction (Shenton et al., 2001, Honea et al., 2005) and cortical thinning in schizophrenia (Kuperberg et al., 2003). The latter finding was replicated in a subject sample substantially overlapping with the sample of the present study (Nesvag et al., 2008).
MRI studies have reported specific structure–function relationships in schizophrenia, but the findings are not consistent. Antonova et al. (2004) reviewed region-of-interest (ROI) studies including both healthy controls and patients with schizophrenia, and reported positive relationships between total brain and grey matter volumes and global cognitive ability. Moreover, size of prefrontal cortical volume was related to executive functioning, whereas size of temporal lobe volume was correlated with memory, executive functioning and verbal abilities. Some of the relationships between the medial temporal lobe and cognitive abilities tended to be specific to schizophrenia (Antonova et al., 2004). Interestingly, only a limited number of studies have demonstrated altered relationships between volumes of the superior temporal gyrus (Vita et al., 1995, Gur et al., 2000b, Nestor et al., 2007), which is one of the most consistently reported brain structure alterations in schizophrenia (Shenton et al., 2001, Honea et al., 2005), and cognitive test scores. Consequently, marked brain structure alteration may not necessarily be related to changes in cognitive function, a conclusion that was suggested by a recent study demonstrating grey matter reduction in schizophrenia patients with near intact cognitive skills (Wexler et al., 2009). Thus, these data implicate a need for exploratory studies investigating altered structure–function relationships in areas that are not predefined, as in ROI studies, and not selected on the basis of significant structural case-control differences.
Furthermore, ROI studies often employ relatively gross volume measurements. A study investigating structure–function relationships in both cortical and subcortical grey matter volumes (Lawyer et al., 2006) demonstrated weaker associations between predefined cortical than subcortical volumes in the comparison with neurocognitive test scores. The neural substrates for functional cognitive abnormalities might be localized to subsections within the volume structures that were predefined, indicating a risk that possible structure–function relationships might have been obscured.
Previous studies analyzing cortical thickness of healthy subjects have successfully related localized variations in thickness to scores of intelligence (Shaw et al., 2006, Narr et al., 2007), memory (Walhovd et al., 2006, Dickerson et al., 2008) and set shifting (Dickerson et al., 2008). In schizophrenia however, relationships between localized grey matter areas and neurocognition have only been investigated with volumetric measurements (Antonova et al., 2005, Rusch et al., 2007, Wolf et al., 2008, Bonilha et al., 2008), such as voxel-based morphometry (VBM) methods, which afford a relatively unbiased assessment of grey matter changes across the brain. However, those studies have small sample sizes, lack direct comparisons of relationships between patients and controls, or find few relationships specific to schizophrenia.
In this study we applied a detailed high-resolution method analyzing cortical thickness to localize possible structure–function relationships and, to our knowledge, for the first time extended the search to schizophrenia. Cortical thickness measurements, as opposed to volumetric measurements, may provide additional information regarding possible local cytoarchitectural differences across groups. In order not to restrict the findings to a predefined brain area, an exploratory search was performed.
More specifically, our aim was to identify regions where cortical thickness and neuropsychological performance were statistically related in a combined sample of patients with schizophrenia and healthy controls. Furthermore, in regions with suggested relationships we tested for differences in regression slopes between patients and controls, in order to test for diagnostic interaction. On the basis of previous literature we predicted that localized areas within prefrontal and temporal cortices were associated with cognitive performance. We also predicted some of these relationships to be different in patients with schizophrenia as compared to healthy control subjects.
Section snippets
Subjects
All subjects were unrelated individuals of Caucasian origin recruited in Stockholm, Sweden, between 1999 and 2003, as part of a larger study as previously described (Jonsson et al., 2003, Jonsson et al., 2006). All subjects participated after giving informed written consent. The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee at Karolinska Institutet and the Swedish Data Inspection Board (“Datainspektionen”).
Patients diagnosed with
Patient–control differences
Patients were significantly impaired on all selected cognitive domains when compared to healthy control subjects (Table 2). The effect sizes were all in the order of large effect, except for verbal IQ which was moderate (Cohen, 1988).
Significantly thinner cortices in the patients were demonstrated in the temporal pole, superior temporal gyrus, and orbital and inferior frontal gyri in the left hemisphere, and the superior temporal gyrus, insula, orbital frontal, and middle and superior frontal
Discussion
In this study we have shown that relationships between cortical thickness in occipital regions and verbal IQ in both hemispheres were different in patients with schizophrenia than in healthy control subjects. We have also confirmed that localized variations in cortical thickness are related to cognitive performance and extended the findings to schizophrenia patients; thicker frontal, temporal and occipital cortical brain areas were significantly related to better performance in verbal IQ,
Acknowledgements
We thank Monica Hellberg and Kjerstin Lind and the staff at the Neuroimaging Analysis Lab at the Center for the Study of Human Cognition, Institute of Psychology, University of Oslo, for performing processing of MR images using FreeSurfer. This work was supported by the Swedish Medical Research Council [grant numbers 2003-5845, 2007-3687, K2004-21X-15078-01A, 2006-986, 2006-2992], the Karolinska Institutet, the Wallenberg Foundation, the Research Council of Norway [grant number 160181/V50,
References (72)
- et al.
The relationship of structural alterations to cognitive deficits in schizophrenia: a voxel-based morphometry study
Biological Psychiatry
(2005) - et al.
The relationship between brain structure and neurocognition in schizophrenia: a selective review
Schizophrenia Research
(2004) - et al.
Volumetric analysis of frontal lobe regions in schizophrenia: relation to cognitive function and symptomatology
Biological Psychiatry
(1999) - et al.
Neurocognitive deficits and prefrontal cortical atrophy in patients with schizophrenia
Schizophrenia Research
(2008) - et al.
Distributed brain sites for the g-factor of intelligence
Neuroimage
(2006) - et al.
Cortical surface-based analysis. I. Segmentation and surface reconstruction
Neuroimage
(1999) - et al.
Brain morphology in first-episode schizophrenic-like psychotic patients: a quantitative magnetic resonance imaging study
Biological Psychiatry
(1991) - et al.
Detection of cortical thickness correlates of cognitive performance: reliability across MRI scan sessions, scanners, and field strengths
Neuroimage
(2008) - et al.
Cortical surface-based analysis. II: inflation, flattening, and a surface-based coordinate system
Neuroimage
(1999) - et al.
IQ and brain size in schizophrenia
Psychiatry Research
(1994)