Sex-related differences in behavior are extensive, but their neuroanatomic substrate is unclear. Indirect perfusion data have suggested a higher percentage of gray matter (GM) in left hemisphere cortex and in women, but differences in volumes of the major cranial compartments have not been examined for the entire brain in association with cognitive performance. We used volumetric segmentation of dual echo (proton density and T2-weighted) magnetic resonance imaging (MRI) scans in healthy volunteers (40 men, 40 women) age 18-45. Supertentorial volume was segmented into GM, white matter (WM), and CSF. We confirmed that women have a higher percentage of GM, whereas men have a higher percentage of WM and of CSF. These differences sustained a correction for total intracranial volume. In men the slope of the relation between cranial volume and GM paralleled that for WM, whereas in women the increase in WM as a function of cranial volume was at a lower rate. In men the percentage of GM was higher in the left hemisphere, the percentage of WM was symmetric, and the percentage of CSF was higher in the right. Women showed no asymmetries. Both GM and WM volumes correlated moderately with global, verbal, and spatial performance across groups. However, the regression of cognitive performance and WM volume was significantly steeper in women. Because GM consists of the somatodendritic tissue of neurons whereas WM comprises myelinated connecting axons, the higher percentage of GM makes more tissue available for computation relative to transfer across distant regions. This could compensate for smaller intracranial space in women. Sex difference in the percentage and asymmetry of the principal cranial tissue volumes may contribute to differences in cognitive functioning.

There is increased need for efficient computerized methods to collect reliable data on a range of cognitive domains that can be linked to specific brain systems. Such need arises in functional neuroimaging studies, where individual differences in cognitive performance are variables of interest or serve as confounds. In genetic studies of complex behavior, which require particularly large samples, such trait measures can serve as endophenotypes. Traditional neuropsychological tests, based on clinical pathological correlations, are protracted, require extensive training in administration and scoring, and leave lengthy paper trails (double-entry for analysis). We present a computerized battery that takes an average of 1 hour and provides measures of accuracy and speed on 9 neurocognitive domains. They are cognitive neuroscience-based in that have been linked experimentally to specific brain systems with functional neuroimaging studies. We describe the process of translating tasks used in functional neuroimaging to tests for assessing individual differences. Data are presented on each test with samples ranging from 139 (81 female) to 536 (311 female) of carefully screened healthy individuals ranging in age from 18 to 84. Item consistency was established with acceptable to high Cronbach alpha coefficients. Inter-item correlations were moderate to high within domain and low to nil across domains, indicating construct validity. Initial criterion validity was demonstrated by sensitivity to sex differences and the effects of age, education and parental education. These results encourage the use of this battery in studies needing an efficient assessment of major neurocognitive domains such as multisite genetic studies and clinical trials.

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This study confirms previous findings of reduced frontotemporal volumes and suggests new hypotheses, especially involving occipital association and speech production areas. It also suggests finer localization of volume reduction in the hippocampus and other limbic structures and in the frontal lobe. Pattern classification showed high sensitivity and specificity for the diagnosis of schizophrenia, suggesting the potential utility of magnetic resonance imaging as a diagnostic aid.

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