Sex Differences in the Inferior Parietal Lobule

Melissa E. Frederikse1, Angela Lu1, Elizabeth Aylward1,2, Patrick Barta1 and Godfrey Pearlson1

1 Division of Psychiatric Neuro-Imaging, Department of Psychiatry and Behavioral Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287 and , 2 Department of Radiology, University of Washington School of Medicine, Seattle, WA 98195, USA

Address correspondence to Godfrey D. Pearlson, MD, Division of Psychiatric Neuro-Imaging, Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA. Email: godfr{at}jhmi.edu.


    Abstract
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The inferior parietal lobule (IPL) – a neocortical region and part of the heteromodal association cortex (HASC) – has been hypothesized to exhibit sexual dimorphism, as do other HASC regions, particularly with regard to asymmetry. Using a reliable method for measuring IPL gray matter volume based upon individual sulcal–gyral landmarks, we measured this region on magnetic resonance imaging scans from a sample of 15 individually matched pairs of normal male and female subjects. Male subjects showed significantly larger left, but not right, IPL volumes when compared to females. Males also showed a leftward (left > right) asymmetry for the IPL, with a less marked opposite asymmetry in females. Such sexual dimorphisms may possibly underlie the subtle cognitive differences observed between the sexes.


    Introduction
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The inferior parietal lobule (IPL), a neocortical region, also referred to as the posterior parietal cortex (Mesulam, 1998Go), consists of the supramarginal gyrus, an arched lobule surrounding the end of the lateral fissure, and the angular gyrus, a lobule surrounding the parallel sulcus' ascending posterior segment (Fig. 1Go) (Duvernoy, 1991Go). It corresponds, in part, to Brodmann areas 39 and 40 (Brodmann, 1909Go), and is part of the heteromodal association cortex (HASC), which also includes the planum temporale (PT), the dorsolateral prefrontal cortex (DLPFC) and the inferior prefrontal area (Broca's area) (Mesulam, 1985Go, 1998Go). Previously, HASC regions, in conjunction with other cortical areas, were believed to serve as sites of higher-order multimodal convergence integrating all aspects of mental function (Mesulam, 1985Go, 1998Go). More recently, however, this view has been modified in that these regions not only have interconnections with one another, but also reciprocal connections with lower-order unimodal areas (Mesulam, 1998Go). According to Mesulam, these regions serve as ‘epicentres for a large-scale network' with each epicentre ‘potentially belong[ing] to several intersecting networks' (Mesulam, 1998Go). Similarly, the IPL has been noted to have a role in processing information from the visual, auditory and somatosensory association cortices (Geschwind, 1964Go), as well as having connections with other HASC regions, the limbic system and the hypothalamus (Zec and Weinberger, 1986Go).



View larger version (59K):
[in this window]
[in a new window]
 
Figure 1.  Surface (three-dimesnional) view of brain (reconstructed from MR images) with inferior parietal lobule (IPL) highlighted. The supramarginal and angular gyri are labeled.

 
The IPL, like other HASC regions, is among the latest both to evolve and to develop, based on phylogenetic and myelogenetic evidence (Geschwind, 1964Go; Mesulam and Geschwind, 1978Go). These regions have often been noted on magnetic resonance imaging (MRI) or neuropathology to be usually highly lateralized, with the region in one hemisphere having greater area or volume compared to the other (Geschwind and Levitsky, 1968Go; Galaburda et al., 1978Go; Eidelberg and Galaburda, 1984Go; Foundas et al., 1995Go, 1998Go; Pearlson et al., 1996Go; Raz et al., 1997Go; Honeycutt and Frederikse, 1999Go). For example, in a neuroanatomical study, Eidelberg and Galaburda found leftward asymmetry in the angular gyrus (Eidelberg and Galaburda, 1984Go). These regions also exhibit normal sex differences, especially with regard to asymmetry (Geschwind and Galaburda, 1985Go; Gur et al., 1991Go; Witelson and Kigar, 1992Go; Kulynych et al., 1994Go; Barta et al., 1995Go; Marsh and Casper, 1998Go; Honeycutt and Frederikse, 1999Go) and relative volume (Schlaepfer et al., 1995Go; Harasty et al., 1997Go; Kennedy et al., 1998Go). Such sexual dimorphisms may underlie some of the normally observed subtle but significant cognitive differences between the sexes (Maccoby and Jacklin, 1974Go). For example, men tend to perform better on visuospatial tasks, whereas women generally have greater verbal abilities (Bakan and Putnam, 1974Go; Benbow and Stanley, 1980Go; Gladue et al., 1990Go; Holden, 1991Go).

The parietal lobes subserve cognitive functions primarily involving attention and perception. More specifically, the IPL is involved in selective attention (Petersen et al., 1989Go; Mirsky et al., 1992Go; Heilman et al., 1993Go) and visuospatial processing (Keating and Gooley, 1988Go; Petersen et al., 1989Go). Some of these cognitive tasks appear to lateralize to either the right or the left parietal lobe. For example, the right parietal lobe may be more involved in spatial working memory tasks (Jonides et al., 1993Go), sensing relationships between body parts (Cutting, 1991Go) and the recognition of affect (Borod et al., 1986Go; Cleghorn et al., 1989aGo,bGo). The left IPL is more involved in cognitive tasks related to perception, such as mental rotation of three-dimensional figures (Alivisatos and Petrides, 1997Go), judgments of target speed (Corbetta et al., 1991Go) and position (Lacquaniti et al., 1997Go), time estimation (Maquet et al., 1996Go), complex motor planning (Winstein et al., 1997Go) and non-semantic aspects of verbal processing (Vandenberghe et al., 1996Go).

Thus, given normal sex differences in brain structure and function, especially with regard to asymmetries in HASC regions, and normal lateralization of cognitive functions, it is reasonable to hypothesize that sex differences in structural IPL asymmetry may underlie some sex differences in cognitive functioning. Indeed, in an MRI study of cortical volumes Kennedy et al. found normal sex differences in the parietal lobe, but although left and right hemispheric measurements were obtained, the authors did not specifically examine sex-by-hemisphere interactions (Kennedy et al., 1998Go). As sex-based asymmetries in the IPL have not previously been examined, we thus made the following hypotheses: (i) males have greater total IPL volumes compared to women, (ii) males have larger left versus right IPL volumes and (iii) males have larger left IPL volumes compared to women.


    Materials and Methods
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Subjects

We examined 15 pairs of normal male and female subjects who were individually matched on age (±5 years), race, handedness and parental socioeconomic status (Hollingshead, 1975Go), giving a total of 30 subjects. The male versus female groups did not differ significantly on age (mean age of males = 39.7 years, range = 24–58 years; mean age of females = 38.4 years, range = 23–53 years), race (86.67% Caucasian and 13.33% non-Caucasian in both gender groups) or family socioeconomic status (20% of level 2 and 80% of level 3 in both gender groups). All 30 subjects were right-handed as assessed by the Chapman inventory (Chapman and Chapman, 1987Go).

Volunteer study subjects were recruited from the community via advertisement (n = 12), via random telephone-digit dialing as part of a community-based aging study (n = 4), as well as from the Epidemiologic Catchment Area (ECA) study (Regier et al., 1984Go) (n = 5). In addition, nine subjects served as normal controls in a study by a collaborator in London. No subjects had a history or MRI evidence of overt brain disease (via radiological interpretation), lifetime history of substance abuse/ dependence or any medical illnesses known to affect the brain, e.g. severe head injury with loss of consciousness >1 h, severe hypertension (e.g. requiring treatment with two or more medications), or significant cardiovascular disease requiring medical or surgical treatment. In addition, subjects had no current or history of major mental illness as assessed by the Schedules for Clinical Assessment in Neuropsychiatry (Wing et al., 1990Go) and DSM III-R criteria, or in any first-degree relatives (assessed by questionnaire).

Magnetic Resonance Imaging

All subjects gave written informed consent in accordance with institutional standards. MRI scans were obtained on one of three GE Signa 1.5 T units all using the same edition of GE software and identical scanning sequences. Approximately equal numbers of male and female subjects were scanned on each MRI unit. Contiguous slices were acquired through the entire brain in the coronal plane using a spoiled gradient recall acquisition in the steady state (GRASS) sequence (TR = 35, TE = 5) with a flip angle of 45°. Slices were 1.5 mm thick with a field of view of 20 or 24 and a matrix size of 256 x 256.

Image Processing and Measurement

All raters were blind to subject sex. Using the software ‘Measure' developed in our laboratory (Barta et al., 1997Go), raters stripped all brains of skull and dura via reliable semi-automated techniques (Aylward et al., 1997Go; Buchanan et al., 1998Go). Realistic three-dimensional brain images were rendered, enabling easy visualization of sulcal–gyral patterns. All brains were aligned along the anterior–posterior commissural (AC–PC) line and the interhemispheric fissure.

By using a ‘paint and point-counting' method similar to that described by Buchanan et al. for subparcellating the frontal lobe (Buchanan et al., 1998Go), the IPL was first delineated by painting along the IPL sulcal–gyral landmarks on a cortical surface three-dimensional rendering. These painted boundaries would later (see below) be superimposed upon two-dimensional orthogonal slices in order to select grid points lying within the boundaries. Utilizing such surface renderings for determining sulcal–gyral landmarks and transferring these boundaries to serial sections has been described by other authors (Damasio and Frank, 1992Go; Barta et al., 1995Go; Kulynych et al., 1996). For a more in-depth discussion of these techniques, as well as a detailed description of our IPL measurement methodology, see M.E. Frederikse et al. (submitted). The IPL boundaries included the postcentral sulcus anteriorally and the intraparietal sulcus superiorally. The inferior boundary consisted of: (i) the Sylvian fissure from the postcentral sulcus to the planum temporale (PT) posterior lateral edge; (ii) a plane passing through the PT posterior lateral edge and the temporo-occipital incisure to the superior temporal (or parallel) sulcus; and (iii) the parallel sulcus to its horizontal segment (anterior occipital sulcus) and its connection with the intraparietal sulcus.

The SPGR data set was filtered using locally developed anisotropic diffusion filtering software (K = 1.5 x average sigma value of ten random values within the caudate nucleus; number of iterations = 3) to better visualize the gray-white boundary (Gerig et al., 1990Go). A three-dimensional grid of points spaced 4.5 mm apart and yielding ~200 points per IPL was superimposed on the entire volume. ‘Paint' demarcating the IPL anatomical borders was then superimposed upon the filtered image set, and gray matter points lying within the painted borders were selected. Both this stereological volume estimation method (‘Cavalieri') (Barta et al., 1997Go) and the paint method (Buchanan et al., 1998Go) have been discussed in previous publications. Due to imprecise white matter boundaries for this and other cortical regions, IPL white matter volumes were not obtained. Interrater reliability for the volume measurement yielded an unbiased intraclass coefficient (of Bartko and Carpenter) of 0.98 in five randomly selected brains.


    Results
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Total brain volume (TBV), calculated from the total stripped brain via voxel tally (Aylward et al., 1998Go), left IPL gray matter volume and right IPL gray matter volume were calculated using locally developed software (Barta et al., 1997Go). Total IPL volume was derived from the sum of left and right IPL volume. Table 1Go summarizes the mean measurement data.


View this table:
[in this window]
[in a new window]
 
Table 1 Measurement data (mean ± SD; all data, except asymmetry index, are volumes in cm3)
 
Using three separate one-way analyses of variance (ANOVA), there was no effect of MRI scanner on TBV (F = 0.20, df = 2,29, P = 0.82), left IPL volume (F = 0.60, df = 2,29, P = 0.56) or right IPL volume (F = 0.02, df = 2,29, P = 0.98).

In order to determine if TBV need be a covariate in the statistical analysis, ANOVA of TBV between males and females was first conducted. This analysis revealed no significant difference in TBV between males and females (F = 2.63, df = 1,29, P = 0.12), indicating no need to covary for TBV. Repeated- measures ANOVA was then conducted with hemisphere as the repeated measure and sex as the between-subjects variable. This analysis revealed a main effect of sex (F = 11.66, df = 1,28, P < 0.01), with males having significantly larger total IPL volume than females. Although there was no main effect of hemisphere (F = 2.60, df = 1,28, P = 0.66), the hemisphere-by-sex interaction approached statistical significance (F = 3.47, df = 1,28, P = 0.07).

Given our hypothesis that the left IPL is larger than the right in men, repeated-measures ANOVA was performed in males only with hemisphere as the repeated measure. In this analysis, left IPL volume was not significantly greater than right IPL volume in men (F = 3.03, df = 1,14, P = 0.10).

Because of the significant sex difference in total IPL volume, as well as our a priori hypotheses, we wanted to examine which side contributed most to the male/female total IPL volume difference. Analyses of variance revealed that men had significantly larger left IPL volumes compared to females (F = 11.54, df = 1,29, P = 0.02). The right IPL, however, showed no significant sex differences on ANOVA (F = 3.18, df = 1,29, P = 0.09). Figure 2Go depicts mean IPL volume/TBV ratios in the left and right IPLs for males versus females, demonstrating that the left, but not the right, IPL is significantly larger in males compared to females.



View larger version (79K):
[in this window]
[in a new window]
 
Figure 2.  Bar graph of IPL volume/total brain volume ratios for left (blue bars) and right (red bars) IPL in males (left side of graph) versus females (right side of graph).

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
In summary, this study demonstrates that men have larger total IPL volumes when compared to women, with this difference being largely due to greater left male IPL volume. The total brain volumes in this study are in reasonable accordance with those of other studies (Schlaepfer et al., 1995Go; Aylward et al., 1998Go; Goldstein et al., 1999Go) with differences likely due to methodological variability. In addition, the IPL volumes obtained in this study are remarkably similar to those found by other authors (Kennedy et al., 1998Go) as seen in Table 2Go. While we measured the IPL region as a whole, as opposed to individual gyri as did Kennedy et al. (Kennedy et al., 1998Go), our volumes closely approximate the sum of their mean volumes obtained for angular gyrus, anterior and posterior supramarginal gyri, and parietal operculum. These similarities are evident not only for left versus right IPL volumes, but also for males versus females (see Table 2Go).


View this table:
[in this window]
[in a new window]
 
Table 2 Comparison of mean IPL Volumes (in cm3) between Kennedy et al. (Kennedy et al., 1998) and the current study
 
This study replicates previous studies in which the IPL showed leftward asymmetry (Eidelberg and Galaburda, 1984Go; Iwasaki et al., 1986Go, 1990Go; Raz et al., 1997Go). However, this study is the first to identify sex differences with respect to left, but not right, IPL gray matter volume, i.e. that the left IPL is larger in male subjects as compared to females. Furthermore, while our results were not statistically significant, this study also supports data from other studies demonstrating that males tend to have more leftward-lateralized brains than do females (Witelson and Kigar, 1992Go; Kulynych et al., 1994Go), with females generally having either no lateralization or a rightward asymmetry [reviewed by Marsh and Casper (Marsh and Casper, 1998Go)]. It is possible that with a larger sample, the leftward-lateralized male pattern would then be significant.

In a cytoarchitectonic parcellation of the parietal lobes of eight human brains, Eidelberg and Galaburda showed leftward asymmetry for most of the angular gyrus (area ‘PG'), correlating with a larger left planum temporale (Eidelberg and Galaburda, 1984Go). Conversely, another, yet smaller, portion of the angular gyrus (area ‘PEG'), corresponding to the most posterior– superior aspect of the gyrus, showed rightward asymmetry (Eidelberg and Galaburda, 1984Go). As reported by the authors, there was no significant effect of sex or age, although this analysis would have likely required a larger sample as only four male and four female brains were examined. Other limitations of the Eidelberg and Galaburda study included widely varying subject age (males 25–86 years; females 4–67 years), lack of handedness information, and volumetric analyses of only the angular (not the supramarginal) gyrus. Because our study did not separate the angular and the supramarginal gyri, we are unable to compare our volumes with those of the Eidelberg and Galaburda study.

Iwasaki et al. found more intricate and extensive folding of the left IPL in 500 adults by examining cerebral white matter medullary branching patterns on CT (Iwasaki et al., 1986Go). In a later study with 276 children, the same group (Iwasaki et al., 1990Go) demonstrated that childhood patterns did not differ significantly from those found in adults. Similarly, in a MRI study of 149 healthy subjects, Raz et al. showed asymmetry in the IPL, again with the left side being larger (Raz et al., 1997Go). While the Raz study used neuroanatomical landmarks to define the region, IPL volume was estimated from a small number (5–10) of 0.86 mm coronal slices, 1.5 mm apart. Their delineation of the IPL corresponds approximately to Brodmann area 40 (supramarginal gyrus), but also includes portions of primary and secondary visual cortex (Brodmann areas 17 and 18). While their measurement technique may produce highly reliable data, it may be of more modest validity because of lack of anatomical precision.

As for sex differences in the IPL, we are only aware of the Kennedy et al. study cited earlier, which found sexual dimorphism in the IPL, specifically the angular gyrus (Kennedy et al., 1998Go). Kennedy et al. found the parietal lobe to be larger in volume in men compared to women, likely due to greater angular gyrus volume. While the volumes obtained between the Kennedy study and our study were very similar, our study differs in that we also examined sex-by-hemisphere interactions. Furthermore, while following sulcal–gyral landmarks in two-dimensional views, Kennedy et al. utilized a coarser measurement methodology (Rademacher et al., 1992Go; Caviness et al., 1996Go) using 3 mm thick coronal slices (as opposed to our 1.5 mm thick coronal slices), as well as anterior and posterior borders defined by anatomically landmarked coronal planes. Other differences in their study include a smaller sample size (10 men, 10 women) and using both right- and left-handed subjects. Further inspection of their study reveals widely ranging interrater reliability coefficients from 0.29 to 0.96 for parietal regions. Such methodological differences suggest that the measurement methodology utilized in our study is as good as, if not superior to, the method employed by Kennedy et al., given our delineation of the IPL based upon surface sulcal–gyral landmarks, visualization of the region in three orthogonal views and highly reliable measures.

Several studies have demonstrated global and regional brain sexual structural dimorphisms, in both normal children and adults (Witelsen and Kigar, 1992; Dreisen and Raz, 1995Go; Schlaepfer et al., 1995Go; Raz et al., 1995Go, 1997Go; Reiss et al., 1996Go; Giedd et al., 1997Go; Kennedy et al., 1998Go). These studies indicate the presence of sex-associated differences in cerebral development and organization, processes most likely beginning during fetal development [reviewed by Marsh and Casper (Marsh and Casper, 1998Go)]. Of note, Schlaepfer et al., using 5 mm MRI sections and approximations to cortical regions of interest, demonstrated that in addition to women having significantly smaller brains compared to men, regional brain sex differences also existed. However, total IPL gray matter percentages were not significantly different between men and women (Schlaepfer et al., 1995Go).

While our study was conducted in an exceptionally well-matched sample population and utilized a highly reliable measurement method, the lack of accompanying detailed neuropsychological data makes direct comparison between brain findings and cognitive data speculative. Other possible methodological deficiencies of this study include: (i) lack of IPL white matter measurements, (ii) using right-handed subjects only and (iii) raters not being blind to hemisphere being measured. As there are no precise white matter boundaries for the IPL, as well as other cortical structures, we are unable as yet to develop reliable measurement techniques for the white matter. As for the issue of handedness, many asymmetrical brain measures, e.g. planum temporale and radius of gyration, have correlated with handedness (Steinmetz et al., 1991Go; Bullmore et al., 1995Go). Thus, it is possible that left-handed individuals show variants of the pattern we demonstrated. Whereas raters were blind to subject gender, the current imaging software does not allow for techniques such as counterbalanced mirroring which would blind raters to hemisphere, and thus experimenter bias may conceivably be a factor in these measures.

As described previously, men tend to outperform women on tasks of visuospatial processing, a function subserved by the IPL, particularly the left side. Given the finding of larger left IPL volume in males compared to females, this study provides a possible structural brain basis for such sex-based cognitive differences. In addition, this cross-sectional study only attempts to describe male–female structural differences in the IPL, and does not permit making conclusions as to male–female brain developmental differences. Future studies, e.g. functional neuroimaging studies, assessing activation during cognitive tests specific to parietal regions, as well as longitudinal studies, with an emphasis on sex differences, lateralization and development, in normal states would be useful.


    Acknowledgments
 
Supported in part by NIH grants MH43775 and AG11859, the NIH General Clinical Research Center (RR-00722) and the Stanley Foundation (to G.P.).


    References
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Alivisatos B, Petrides M (1997) Functional activation of the human brain during mental rotation. Neuropsychologia 35:111–118.[ISI][Medline]

Aylward EA, Augustine A, Li Q, Barta PE, Pearlson GD (1997) Measurement of frontal lobe volume on magnetic resonance imaging scans. Psychiat Res 75:23–30.[Medline]

Aylward EA, Anderson NB, Bylsma FW, Wagster MV, Barta PE, Sherr M, Feeney J, Davis A, Rosenblatt A, Pearlson GD, Ross CA (1998) Frontal lobe volume in patients with Huntington's disease. Neurology 50:252–258.[Abstract]

Bakan P, Putnam W (1974) Right–left discrimination and brain lateralization. Sex differences. Arch Neurol 30:334–335.[ISI][Medline]

Barta PE, Petty RG, McGilchrist I, Lewis RW, Jerram M, Casanova MF, Powers RE, Brill LB, Pearlson GD (1995) Asymmetry of the planum temporale: methodological considerations and clinical associations. Psychiat Res 61:137–150.[Medline]

Barta PE, Pearlson GD, Brill LB, Royall R, McGilchrist IK, Pulver AE, Powers RE, Casanova MF, Tien AY, Frangou S, Petty RG (1997) Planum temporale asymmetry reversal in schizophrenia: replication and relationship to gray matter abnormalities. Am J Psychiat 154:661–667.[Abstract]

Barta PE, Dhingra L, Royall R, Schwartz E (1997) Improving stereological estimates for the volume of structures identified in three-dimensional arrays of spatial data. J Neurosci Methods 75:111–118.[ISI][Medline]

Benbow CP, Stanley JC (1980) Sex differences in mathematical ability: fact or artifact? Science 210:1262–1264.[Medline]

Borod JC, Koff E, Perlman LM, Nicholas M (1986) The expression and perception of facial emotion in brain-damaged patients. Neuropsychologia 24:169–180.[ISI][Medline]

Brodmann K (1909) Vergleichende Lokalisationslehre der Gross-hirnrinde, in ihren Prinzipien dargestellt auf Grund des Zellenbaues. Leipzig: Barth.

Buchanan RW, Vladar K, Barta PE, Pearlson GD (1998) Structural evaluation of the prefrontal cortex in schizophrenia. Am J Psychiat 155:1049–1055.[Abstract/Free Full Text]

Bullmore E, Brammer M, Harvey I, Murray R, Ron M (1995) Cerebral hemispheric asymmetry revisited: effects of handedness, gender and schizophrenia measured by radius of gyration in magnetic resonance images. Psychol Med 25:349–363.[ISI][Medline]

Caviness VS Jr, Makris N, Meyer J, Kennedy D (1996) MRI-based parcellation of human neocortex: an anatomically specified method with estimate of reliability. J Cogn Neurosci 8:566–588.[ISI]

Chapman LJ, Chapman JP (1987) The measurement of handedness. Brain Cogn 6:175–183.[ISI][Medline]

Cleghorn JM, Garnett ES, Nahmias C, Firnau G, Brown GM, Kaplan R, Szechtman H, Szechtman B (1989a) Increased frontal and reduced parietal glucose metabolism in acute untreated schizophrenia. Psychiat Res 28:119–133.[ISI][Medline]

Cleghorn JM, Kaplan RD, Nahmias C, Garnett ES, Szechtman H, Szechtman B (1989b) Inferior parietal region implicated in neurocognitive impairment in schizophrenia. Arch Gen Psychiat 46:758–760.

Corbetta M, Miezin FM, Dobmeyer S, Shulman GL, Petersen SE (1991) Selective and divided attention during visual discriminations of shape, color, and speed: functional anatomy by positron emission tomography. J Neurosci 11:2383–2402.[Abstract]

Cutting J (1991) Delusional misidentification and the role of the right hemisphere in the appreciation of identity. Br J Psychiat Suppl 70–75.

Damasio H, Frank R (1992) Three-dimensional in vivo mapping of brain lesions in humans. Arch Neurol 49:137–143.[Abstract]

Dreisen NR, Raz N (1995) The influence of sex, age, and handedness on corpus callosum morphology: a meta-analysis. Psychobiology 23:240–247.[ISI]

Duvernoy HM (1991) The human brain: surface, three-dimensional sectional anatomy, and MRI, pp. 10–11. New York: Springer-Verlag.

Eidelberg D, Galaburda AM (1984) Inferior parietal lobule. Divergent architectonic asymmetries in the human brain. Arch Neurol 41:843–852.[Abstract]

Foundas AL, Leonard CM, Heilman KM (1995) Morphologic cerebral asymmetries and handedness. The pars triangularis and planum temporale. Arch Neurol 52:501–508.[Abstract]

Foundas AL, Eure KF, Luevano LF, Weinberger DR (1998) MRI asymmetries of Broca's area: the pars triangularis and pars opercularis. Brain Lang 64:282–296.[ISI][Medline]

Galaburda AM, LeMay M, Kemper TL, Geschwind N (1978) Right–left asymmetrics in the brain. Science 199:852–856.[ISI][Medline]

Gerig G, Kikinis R, Kubler O (1990) Significant improvement of MR image data quality using anisotropic diffusion filtering. In: Technical Report BIWI-TR-124. Communication Technology Laboratory, Image Science Division, ETH-Zurich, Switzerland.

Geschwind N (1964) The development of the brain and the evolution of language. In: Report of the 15th annual RTM on linguistic and language studies (Stuart CIJM, ed.), pp. 155–169. Washington, DC: Georgetown University Press.

Geschwind N, Levitsky W (1968) Human brain: left–right asymmetries in temporal speech region. Science 161:186–187.[ISI][Medline]

Geschwind N, Galaburda AM (1985) Cerebral lateralization. Biological mechanisms, associations, and pathology: II. A hypothesis and a program for research. Arch Neurol 42:521–552.[ISI][Medline]

Giedd JN, Castellanos FX, Rajapakse JC, Vaituzis AC, Rapoport JL (1997) Sexual dimorphism of the developing human brain. Progr Neuro- psychopharmacol Biol Psychiat 21:1185–1201.

Gladue BA, Beatty WW, Larson J, Staton RD (1990) Sexual orientation and spatial ability in men and women. Psychobiology 101–108.

Goldstein JM, Goodman JM, Seidman LJ, Kennedy DN, Makris N, Lee H, Tourville J, Caviness VS Jr, Faraone SV, Tsuang MT (1999) Cortical abnormalities in schizophrenia identified by structural magnetic resonance imaging. Arch Gen Psychiat 56:537–547.[Abstract/Free Full Text]

Gur RC, Mozley PD, Resnick SM, Gottlieb GL, Kohn M, Zimmerman R, Herman G, Atlas S, Grossman R, Berretta D (1991) Gender differences in age effect on brain atrophy measured by magnetic resonance imaging. Proc Natl Acad Sci USA 88:2845–2849.[Abstract]

Harasty J, Double KL, Halliday GM, Kril JJ, McRitchie DA (1997) Language-associated cortical regions are proportionally larger in the female brain. Arch Neurol 54:171–176.[Abstract]

Heilman KM, Watson RT, Valenstein E, Damasio AR (1993) Localization of lesions in neglect. In: Localization in neuropsychology (Kertez A, ed.), pp. 471–492. New York: Academic Books.

Holden C (1991) Is ‘gender gap' narrowing? Science 253:959–960.[ISI][Medline]

Hollingshead AB (1975) Four factor index of social status. New Haven, CT: Yale University, Department of Sociology.

Honeycutt NA, Frederikse ME (1999) Brain asymmetries in schizophrenia. J Adv Schizophr Brain Res 1:98–105.

Iwasaki S, Kichikawa K, Nakagawa H, Ohishi H, Uchida H, Yaguchi K, Sumie H, Kuru Y (1986) Left–right asymmetry in the temporal and parietal region based on the medullary pattern of cerebral white matter. Acta Radiol Suppl 369:208–211.[Medline]

Iwasaki S, Nakagawa H, Fukusumi A, Kichikawa K, Kitamura K, Otsuji H, Uchida H, Ohishi H, Yaguchi K, Sumie H (1990) Left–right asymmetry of the temporal and parietal regions in children: based on the medullary pattern of cerebral white matter. Surg Radiol Anat 12:209–214.[ISI][Medline]

Jonides J, Smith EE, Koeppe RA, Awh E, Minoshima S, Mintun MA (1993) Spatial working memory in humans as revealed by PET. Nature 363:623–625.[ISI][Medline]

Keating EG, Gooley SG (1988) Disconnection of parietal and occipital access to the saccadic oculomotor system. Exp Brain Res 70:385–398.[ISI][Medline]

Kennedy DN, Lange N, Makris N, Bates J, Meyer J, Caviness VS Jr (1998) Gyri of the human neocortex: an MRI-based analysis of volume and variance. Cereb Cortex 8:372–384.[Abstract]

Kulynych JJ, Vladar K, Jones DW, Weinberger DR (1994) Gender differences in the normal lateralization of the supratemporal cortex: MRI surface-rendering morphometry of Heschl's gyrus and the planum temporale. Cereb Cortex 4:107–118.[Abstract]

Lacquaniti F, Perani D, Guigon E, Bettinardi V, Carrozzo M, Grassi F, Rossetti Y, Fazio F (1997) Visuomotor transformations for reaching to memorized targets: a PET study. NeuroImage 5:129–146.[ISI][Medline]

Maccoby E, Jacklin C (1974) The psychology of sex differences. Stanford, CA: Stanford University Press.

Maquet P, Lejeune H, Pouthas V, Bonnet M, Casini L, Macar F, Timsit- Berthier M, Vidal F, Ferrara A, Degueldre C, Quaglia L, Delfiore G, Luxen A, Woods R, Mazziotta JC, Comar D (1996) Brain activation induced by estimation of duration: a PET study. NeuroImage 3:119–126.[ISI][Medline]

Marsh L, Casper R (1998) Gender differences in brain morphology and in psychiatric disorder. In: Women's health: hormones, emotions and behavior (Casper RC, ed.), pp. 53–82. Cambridge: Cambridge University Press.

Mesulam MM, Geschwind N (1978) On the possible role of neocortex and its limbic connections in the process of attention and schizophrenia: clinical cases of inattention in man and experimental anatomy in monkey. J Psychiatr Res 14:249–259.[ISI][Medline]

Mesulam MM (1985) Principles of behavioral neurology. Philadelphia: Davis.

Mesulam MM (1998) From sensation to cognition. Brain 121:1013–1052.[Abstract]

Mirsky AF, Lochhead SJ, Jones BP, Kugelmass S, Walsh D, Kendler KS (1992) On familial factors in the attentional deficit in schizophrenia: a review and report of two new subject samples. J Psychiatr Res 26:383–403.[ISI][Medline]

Pearlson GD, Petty RG, Ross CA, Tien AY (1996) Schizophrenia: a disease of heteromodal association cortex? Neuropsychopharmacology 14:1–17.[ISI][Medline]

Petersen SE, Robinson DL, Currie JN (1989) Influences of lesions of parietal cortex on visual spatial attention in humans. Exp Brain Res 76:267–280.[ISI][Medline]

Rademacher J, Galaburda AM, Kennedy DN, Filiped PA, Caviness VS Jr (1992) Human cerebral cortex: localization, parcellation, and morphometry with magnetic resonance imaging. J Cogn Neurosci 4:352–374.[ISI]

Raz N, Torres IJ, Acker JD (1995) Age, gender, and hemispheric differences in human striatum: a quantitative review and new data from in vivo MRI morphometry. Neurobiol Learn Mem 63:133–142.[ISI][Medline]

Raz N, Gunning FM, Head D, Dupuis JH, McQuain J, Briggs SD, Loken WJ, Thornton AE, Acker JD (1997) Selective aging of the human cerebral cortex observed in vivo: differential vulnerability of the prefrontal gray matter. Cereb Cortex 7:268–282.[Abstract]

Regier DA, Myers JK, Kramer M, Robins LN, Blazer DG, Hough RL, Eaton WW, Locke BZ (1984) The NIMH Epidemiologic Catchment Area program. Historical context, major objectives, and study population characteristics. Arch Gen Psychiat 41:934–941.[Abstract]

Reiss AL, Abrams MT, Singer HS, Ross JL, Denckla MB (1996) Brain development, gender and IQ in children. A volumetric imaging study. Brain 119:1763–1774.[Abstract]

Schlaepfer TE, Harris GJ, Tien AY, Peng L, Lee S, Pearlson GD (1995) Structural differences in the cerebral cortex of healthy female and male subjects: a magnetic resonance imaging study. Psychiat Res Neuroimag 61:129–135.[ISI]

Steinmetz H, Volkmann J, Jancke L, Freund HJ (1991) Anatomical left– right asymmetry of language-related temporal cortex is different in left- and right-handers. Ann Neurol 29:315–319.[ISI][Medline]

Vandenberghe R, Price C, Wise R, Josephs O, Frackowiak RS (1996) Functional anatomy of a common semantic system for words and pictures [see comments]. Nature 383:254–256.[ISI][Medline]

Wing JK, Babor T, Brugha T, Burke J, Cooper J, Giel R, Jablensky A, Regier D, Sartorius N (1990) SCAN: schedules for clinical assessment in neuropsychiatry. Arch Gen Psychiat 47:589–593.[Abstract]

Winstein CJ, Grafton ST, Pohl PS (1997) Motor task difficulty and brain activity: investigation of goal- directed reciprocal aiming using positron emission tomography. J Neurophysiol 77:1581–1594.[Abstract/Free Full Text]

Witelson SF, Kigar DL (1992) Sylvian fissure morphology and asymmetry in men and women: bilateral differences in relation to handedness in men. J Comp Neurol 323:326–340.[ISI][Medline]

Zec RF, Weinberger DR (1986) Handbook of schizophrenia, vol. 1: The neurology of schizophrenia. New York: Elsevier.