W.F.C. Baaré

The association between brain volume and intelligence is of genetic origin

83 TO THE EDITOR—The recent study by Thompson and colleagues1 reported high heritability of gray-matter volume in several cortical regions using voxel-based MRI techniques. Gray matter substantially correlated with general intelligence, or ‘g’. These findings prompt three major questions: (i) is the high heritability specific to gray-matter volume, (ii) is the correlation with g specific to gray-matter volume and (iii) is the correlation between gray-matter volume and g of genetic or environmental origin? We addressed the first question in a large Dutch sample of twins and their siblings (258 Dutch adults from 112 extended twin families)2. We found high heritability for total brain gray-matter volume (Table 1), comparable to the estimate reported by Thompson and colleagues1. In addition, we found high heritability for total brain white-matter volume. As stated in a commentary3 on the recent report in Nature Neuroscience1, high heritability of gray matter implies that interindividual variation in cell-body volume is not modified by experience. Because white matter reflects the degree of interconnection between different neurons, interindividual variance in whitematter volume might be expected to be more under the influence of experience and less under genetic control. Our results clearly suggest otherwise. Either environmental experience barely contributes to interindividual variation in white-matter volume or, alternatively, with the genes that influence g. The extent of the overlap is reflected by the magnitude of the genetic correlation. When the cross-trait/cross-twin correlations are similar for MZ and DZ twins, this suggests that environmental factors contribute to the observed phenotypic correlation between brain volume and g. Given a heritability of 0.85 for brain volume2, a heritability of 0.80 for g (ref. 5) and a correlation between brain volume and g of 0.40 (ref. 7), at least 17 MZ and 17 DZ pairs are needed to detect a genetic correlation with 80% power (and α = 0.05) that explains the observed correlation. In 24 MZ pairs, 31 DZ pairs and 25 additional siblings, we decomposed the correlation between brain volumes and g into genetic and environmental components by using structural equation modeling for a multivariate genetic design (gray matter, white matter and g)6. This showed that the correlation between gray-matter volume and g was due completely to genetic factors and not to environmental factors. We obtained the same result for the correlation between white-matter volume and g. Thus, the answer to the third question is The association between brain volume and intelligence is of genetic origin

Genetic contributions to human brain morphology and intelligence

Variation in gray matter (GM) and white matter (WM) volume of the adult human brain is primarily genetically determined. Moreover, total brain volume is positively correlated with general intelligence, and both share a common genetic origin. However, although genetic effects on morphology of specific GM areas in the brain have been studied, the heritability of focal WM is unknown. Similarly, it is unresolved whether there is a common genetic origin of focal GM and WM structures with intelligence. We explored the genetic influence on focal GM and WM densities in magnetic resonance brain images of 54 monozygotic and 58 dizygotic twin pairs and 34 of their siblings. For genetic analyses, we used structural equation modeling and voxel-based morphometry. To explore the common genetic origin of focal GM and WM areas with intelligence, we obtained cross-trait/cross-twin correlations in which the focal GM and WM densities of each twin are correlated with the psychometric intelligence quotient of his/her cotwin. Genes influenced individual differences in left and right superior occipitofrontal fascicle (heritability up to 0.79 and 0.77), corpus callosum (0.82, 0.80), optic radiation (0.69, 0.79), corticospinal tract (0.78, 0.79), medial frontal cortex (0.78, 0.83), superior frontal cortex (0.76, 0.80), superior temporal cortex (0.80, 0.77), left occipital cortex (0.85), left postcentral cortex (0.83), left posterior cingulate cortex (0.83), right parahippocampal cortex (0.69), and amygdala (0.80, 0.55). Intelligence shared a common genetic origin with superior occipitofrontal, callosal, and left optical radiation WM and frontal, occipital, and parahippocampal GM (phenotypic correlations up to 0.35). These findings point to a neural network that shares a common genetic origin with human intelligence.

ANIMAL+INSECT: Improved Cortical Structure Segmentation

An algorithm for improved automatic segmentation of gross anatomical structures of the human brain is presented that merges the output of a tissue classification process with gross anatomical region masks, automatically defined by non-linear registration of a given data set with a probabilistic anatomical atlas. Experiments with 20 real MRI volumes demonstrate that the method is reliable, robust and accurate. Manually and automatically defined labels of specific gyri of the frontal lobe are similar, with a Kappa index of 0.657.

Volumetric analysis of frontal lobe regions in schizophrenia : relation to cognitive function and symptomatology

BACKGROUND The purpose of this study was to examine the structure of dorsolateral, medial, and orbital regions of the frontal lobe in schizophrenia, and to determine whether their volumetric measurements were related to cognitive function and symptomatology. METHODS High resolution magnetic resonance imaging scans of the brains of 14 schizophrenic patients and 14 closely matched healthy controls were acquired. Volumes of gray and white matter of the left and right dorsolateral, medial, and orbital prefrontal brain regions were measured. Tests of verbal and visual memory and executive functions were used to assess cognitive function. The SANS and SAPS were used to obtain symptom ratings in patients. RESULTS Data of 13 schizophrenic patients were analyzed. Patients showed a general, though not significant, decrease in volumes of frontal regions as compared to controls. In patients, but not in controls, smaller left and right prefrontal gray matter volumes were significantly correlated with impaired performance on immediate recall in verbal and visual memory and semantic fluency. Furthermore, in patients, smaller total orbitofrontal gray matter volume was significantly correlated with more severe negative symptomatology (rs = -.76, p = .006). CONCLUSIONS These findings suggest that in schizophrenia, deficits in verbal and visual memory and semantic fluency and negative symptoms may be related to (subtle) abnormalities in frontal lobe structure.

Genetic correlations between brain volumes and the WAIS-III dimensions of verbal comprehension, working memory, perceptual organization, and processing speed

We recently showed that the correlation of gray and white matter volume with full scale IQ and the Working Memory dimension are completely mediated by common genetic factors (Posthuma et al., 2002). Here we examine whether the other WAIS III dimensions (Verbal Comprehension, Perceptual Organization, Processing Speed) are also related to gray and white matter volume, and whether any of the dimensions are related to cerebellar volume. Two overlapping samples provided 135 subjects from 60 extended twin families for whom both MRI scans and WAIS III data were available. All three brain volumes are related to Working Memory capacity (r = 0.27). This phenotypic correlation is completely due to a common underlying genetic factor. Processing Speed was genetically related to white matter volume (r(g) = 0.39). Perceptual Organization was both genetically (r(g) = 0.39) and environmentally (r(e) = -0.71) related to cerebellar volume. Verbal Comprehension was not related to any of the three brain volumes. It is concluded that brain volumes are genetically related to intelligence which suggests that genes that influence brain volume may also be important for intelligence. It is also noted however, that the direction of causation (i.e., do genes influence brain volume which in turn influences intelligence, or alternatively, do genes influence intelligence which in turn influences brain volume), or the presence or absence of pleiotropy has not been resolved yet.

Gray and white matter volume abnormalities in monozygotic and same-gender dizygotic twins discordant for schizophrenia.

Abstract Background Whole brain tissue volume decreases in schizophrenia have been related to both genetic risk factors and disease-related (possibly nongenetic) factors; however, whether genetic and environmental risk factors in the brains of patients with schizophrenia are differentially reflected in gray or white matter volume change is not known. Methods Magnetic resonance imaging (1.5 T) brain scans of 11 monozygotic and 11 same-gender dizygotic twin pairs discordant for schizophrenia were acquired and compared with 11 monozygotic and 11 same-gender dizygotic healthy control twin pairs. Results Repeated-measures volume analysis of covariance revealed decreased whole brain volume in the patients with schizophrenia as compared with their co-twins and with healthy twin pairs. Decreased white matter volume was found in discordant twin pairs compared with healthy twin pairs, particularly in the monozygotic twin pairs. A decrease in gray matter was found in the patients compared with their co-twins and compared with the healthy twins. Conclusions The results suggest that the decreases in white matter volume reflect the increased genetic risk to develop schizophrenia, whereas the decreases in gray matter volume are related to environmental risk factors. Study of genes involved in the (maintenance) of white matter structures may be particularly fruitful in schizophrenia.

Automated separation of gray and white matter from MR images of the human brain.

A simple automatic procedure for segmentation of gray and white matter in high resolution 1.5T T1-weighted MR human brain images was developed and validated. The algorithm is based on histogram shape analysis of MR images that were corrected for scanner nonuniformity. Calibration and validation was done on a set of 80 MR images of human brains. The automatic methods values for the gray and white matter volumes were compared with the values from thresholds set twice by the best three of six raters. The automatic procedure was shown to perform as good as the best rater, where the average result of the best three raters was taken as reference. The method was also compared with two other histogram-based threshold methods, which yielded comparable results. The conclusion of the study thus is that automated threshold based methods can separate gray and white matter from MR brain images as reliably as human raters using a thresholding procedure.

Gray and white matter density changes in monozygotic and same-sex dizygotic twins discordant for schizophrenia using voxel-based morphometry.

Global gray matter brain tissue volume decreases in schizophrenia have been associated to disease-related (possibly nongenetic) factors. Global white matter brain tissue volume decreases were related to genetic risk factors for the disease. However, which focal gray and white matter brain regions best reflect the genetic and environmental risk factors in the brains of patients with schizophrenia remains unresolved. 1.5-T MRI brain scans of 11 monozygotic and 11 same-sex dizygotic twin-pairs discordant for schizophrenia were compared to 11 monozygotic and 11 same-sex dizygotic healthy control twin-pairs using voxel-based morphometry. Linear regression analysis was done in each voxel for the average and difference in gray and white matter density separately, in each twin-pair, with group (discordant, healthy) and zygosity (monozygotic, dizygotic) as between subject variables, and age, sex and handedness as covariates. The t-maps (critical threshold value mid R:tmid R: > 6.0, P < 0.05) revealed a focal decrease in gray matter density accompanied by a focal increase in white matter density in the left medial orbitofrontal gyrus and a focal decrease in white matter density in the left sensory motor gyrus in twin-pairs discordant for schizophrenia as compared to healthy twin-pairs. Focal changes in left medial (orbito)frontal and left sensory motor gyri may reflect the increased genetic risk to develop schizophrenia. Focal changes in the left anterior hemisphere may therefore be particularly relevant as endophenotype in genetic studies of schizophrenia.

Differentiating between low and high susceptibility to schizophrenia in twins: the significance of dermatoglyphic indices in relation to other determinants of brain development

Both the skin and the brain develop from the same ectoderm and it is thought, therefore, that dermatoglyphics are informative for early disturbances in brain development in schizophrenia. This study was aimed at investigating the differences in both digital and palmar dermatoglyphic indices between twins discordant for schizophrenia and control twins. Furthermore, the significance of dermatoglyphic indices in relation to other determinants of brain development with regard to the susceptibility to schizophrenia was investigated. Data on dermatoglyphic indices of the hand and the palm were obtained from 21 same-sex discordant and 37 same-sex control twins. For 19 discordant and 25 control twins, there was also data available on brain volumes. Non-genetic intra-uterine circumstances early in pregnancy (10-13 weeks of gestation) are associated with a susceptibility to schizophrenia, since both the twins with schizophrenia and the unaffected co-twins showed more fluctuating asymmetry of the finger ridges (P<0.01), and marginally higher absolute finger ridge counts (P=0.06) than control twin pairs. Fluctuating asymmetry of the finger ridges was as important as whole brain and left hippocampal volumes in differentiating twins with a high susceptibility to schizophrenia from those with a low susceptibility.

Gray and white matter volume abnormalities in monozygotic and same-sex dizygotic twins discordant for schizophrenia

BACKGROUND Whole brain tissue volume decreases in schizophrenia have been related to both genetic risk factors and disease-related (possibly nongenetic) factors; however, whether genetic and environmental risk factors in the brains of patients with schizophrenia are differentially reflected in gray or white matter volume change is not known. METHODS Magnetic resonance imaging (1.5 T) brain scans of 11 monozygotic and 11 same-gender dizygotic twin pairs discordant for schizophrenia were acquired and compared with 11 monozygotic and 11 same-gender dizygotic healthy control twin pairs. RESULTS Repeated-measures volume analysis of covariance revealed decreased whole brain volume in the patients with schizophrenia as compared with their co-twins and with healthy twin pairs. Decreased white matter volume was found in discordant twin pairs compared with healthy twin pairs, particularly in the monozygotic twin pairs. A decrease in gray matter was found in the patients compared with their co-twins and compared with the healthy twins. CONCLUSIONS The results suggest that the decreases in white matter volume reflect the increased genetic risk to develop schizophrenia, whereas the decreases in gray matter volume are related to environmental risk factors. Study of genes involved in the (maintenance) of white matter structures may be particularly fruitful in schizophrenia.