Can the corpus callosum predict gender, age, handedness, or cognitive differences?

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672-674 23 Fraser, N. W., Lawrence, W.C., Mims, C. A. Brain (in press) Wroblewska, Z., Gilden, D.H. and 12 Sullivan, C. B., Visscher, B. R. and Detels, Koprowski, H. (1981) Proc. Nail Acad. Sei. R. (1984) Neurology 34, 1144-1148 USA 78, 6461-6465 13 Anderson, O., Dalton, M., Vahlne, A. and Lindberg, C. (1985)J. Neurol. 232 (Suppl.), 24 Cremer, N. E., Johnson, K. P., Fein, G. and Likosky, W. H. (1980) Arch. Neurol. 37, 104 610-615 14 Kurtzke, J. F., Beebe, G. W. and Norman, 25 Coyle, P. K. and Procyk-Dougherty, Z. J. E. (1985) Neurology 35,672-678 (1984) Ann. Neurol. 16, 660-667 15 Dean, G. and Kurtzke, J. F. (1971) Br. Med. 26 Reunanen, M., Salmi, A. and Salonen, R. J. 3,725-729 (1980) Acta Neurol. Scand. 62 (suppl. 78), 16 Alter, M., Leibowitz, U. and Speer, J. 31-32 (1966) Arch. Neurol. 15,234-237 17 Biton, V. and Abramsky, O. (1986) Neurol- 27 Utermohlen, V. and Zabriskie, J. B. (1973) J. Exp. Med. 138, 1591-1596 ogy 36 (Suppl. 1), 184 18 Ebers, G. C. and Bulman, D. (1986) 28 Jacobson, S., Flerlage, M. L. and McFarland, H.F. (1985) J. Exp. Med. 162, Neurology 36 (Suppl. 1), 108 839-850 19 Sibley, W. A., Bamford, C. R. and Clark, 29 Stohlman, S. A. and Weiner, L. P. (1981) K. (1985) Lancet i, 1313-1315 Neurology 31, 38-44 20 Gay, D., Dick, G. and Upton, G. (1986) 30 Dal Canto, M. C. and Rabinowitz, S. G. Lancet i, 815-819 (1982) Ann. Neurol. 11, 109--127 21 Johnson, R. T. (1985) in Handbook of 31 Watanabe, R., Wege, H. and ter Meulen, V. Clinical Neurology (Revised Series 3) (Vol. (1983) Nature 305, 150-153 47: Demyelinating Diseases) (Koetsier, J. C., 32 Clements, J. E. (1985) Rev. Infect. Dis. 7, ed.), pp. 319-336, Elsevier 22 Haase, A. T., Ventura, P., Gibbs, C. J., Jr 68-74 33 Johnson, R. T., Griffin, D. E. and Gendeland Tourtellotte, W. W. (1981) Science 212, E., McDonald, W. I., Batchelor, J. R. and

Can the corpus callosum predict gender, age, handedness, or cognitive differences? There is increasing interest in finding anatomical correlates in the brain for presumed gender-related differences in cognitive functioning. Recent attention has been drawn to reported sex differences in the human corpus callosum as reflecting sex differences in hemispheric lateralization of visuospatial functions. The question is whether or not existing knowledge of the corpus callosum permits interpretations that relate differing cognitive functions to variations in size and shape of the callosum. The striking variations in callosal size and shape among individuals regardless of gender, when viewed in the context of a growing body of experimental findings, suggest that postnatal maturational processes of the corpus callosum are significantly affected by experience. In recent years these has been a heightened interest in finding gender differences in brain structure and function to explain presumed genderrelated differences in cognitive ability. The focus has been mainly on the question of hemispheric lateralization in cognitive processing, and in particular, visuospatial processing. The dominant theory holds that males process visuospatial information predominantly with the right hemisphere, and are thus said to be more lateralized, while females use both hemispheres, and are said to be less lateralized or more symmetrical than males. This difference in functional lateralization, or 'specialization', is viewed as an explanation for a presumed gender difference in visuospatial abilities, with males being superior to females.

Evidence for gender-related differences in cognitive functions The validity of the evidence for such gender-related differences in either cognitive functioning or hemispheric lateralization of visuospatial functioning remains highly controversial, as recent exhaustive reviews of the literature have documented 1-~. These reviews show that the body of literature on gender differences in spatial ability is seriously flawed by findings of marginal, if any, statistical significance; by conflicting results and failures of replication; by poor experimental design and lack of sufficient controls for variables; by a lack of consensus in defining the term 'spatial ability', and, thus, the function being measured by the variety of (often incomparable) tests used in different studies; and, finally, by the

man, H.E. (1985) Semin. Neurol. 5, 180-190 34 Fujinami, R. S. and Oldstone, M. B. A. (1985) Science 230, 1043-1045 35 Lisak, R. P. and Zweiman, B. (1977) N. Engl. J. Med. 297,850-853 36 Massa, P. T., D6rries, R. and ter Meulen, V. (1986) Nature 320, 543-546 37 McCarron, R. M., Kempski, O., Spatz, M. and McFarlin, D. E. (1985) J. Immunol. 134, 3100-3103 38 Fierz, W., Endler, B., Reske, K., Wekerle, H. and Fontana, A. (1985)J. Immunol. 134, 3785-3793 39 Traugott, U., Scheinberg, L. C. and Raine, C. S. (1985)J. Neuroimmunol. 8, 1-14 40 Panitsch, H. S., Haley, A. S., Hirsch, R. L. and Johnson, K.P. (1986) Neurology 36 (Suppl. 1), 285

BYRON H. WAKSMANAND STEPHEN C. REINGOLD

National Multiple Sclerosis Society, 205 East 42nd Street, New York, NY 10017, USA.

paucity of evidence that 'spatial ability' is a legitimate, unitary construct 1. These reviews further demonstrate that as many published studies find no gender differences as do find them. Meta-analysis of the body of studies on cognitive sex differences has found that when gender-related differences are found, they account for no more than 1-5% of the population variance, and the difference between mean scores is only one-quarter to one-half of a standard deviation 5. The variation within each sex is far greater than the variation between them. Furthermore, gender differences on a particular test can be eradicated in a single practice session t. These are not promising bases for the construction of theories of gender differences. In his review of the literature on cognitive sex differences, Hugh Fairweather concluded 'that the majority of studies reviewed here and elsewhere are both ill-thought and illperformed... We cannot pretend that we are testing a theory of sex differences, since at present none can exist.'2 The further problem is that even if gender differences in hemispheric lateralization of visuospatial function were clearly demonstrated, there is no evidence that there is any correlation between hemispheric lateralization and visuospatial ability. It is equally possible that symmetrical hemispheric processing of visuospatial information is superior. In fact, so little is known

(~) 1986,ElsevierSciencePublishersB.V. Amsterdam 0378- 5912/86/$0200

392 about how or which brain structures and processes account for any intellectual abilities - verbal fluency, mathematical skills, musical genius - that there is presently no scientific rationale for proposing a theory of gender differences in intellectual functioning, especially when the existence itself of such differences is in serious doubt. In spite of this, two recent and widely accepted studies assume a correlation between hemispheric lateralization and cognitive ability and postulate developmental or structural bases for gender differences in lateralization and cognitive ability. Testosterone and right hemispheric dominance One study 6 reported an association between left handedness, certain disorders of the immune system, and developmental learning disabilities such as autism, dyslexia, or stuttering, which are more common in boys. To explain this association of left handedness and, it was assumed, right hemispheric dominance in boys, the authors cited a study of human fetal brains v indicating that two convolutions of the right hemisphere develop one to two weeks earlier during gestation than their partners on the left. Geschwind and Behan then proposed that testosterone (secreted by the fetal testes) has the effect in u t e r o of slowing the development of the left hemispheric cortex, resulting in right hemispheric dominance in males and, as stated in a subsequent commentary, in "superior right hemispheric talents, such as artistic, musical, or mathematical talent 's . Aside from the lack of evidence for such an effect of testosterone on cortical development or for the suggestion that circulating testosterone could selectively affect only two convolutions on the left side alone, the authors failed to note that the study they cited by Chi et al. 7 of 507 fetal brains found no significant sex differences in their measurements. This finding directly contradicts the hypothesis of Geschwind and Behan 6 that testosterone inhibits left hemispheric development, resulting in right hemispheric dominance. The corpus callosum and hemispheric lateralization The second study, using brains obtained at autopsy, reported that the splenium (the posterior portion of the corpus callosum) is larger and more

T I N S - S e p t e m b e r 1986

Fig. I. Magnetic resonance images showing midsagittal plane o] corpu,s callosum. (AI .t ~ide body and b ulbous .wlenium from a 36-year-old matt;/B) a comparably wide body arid bulbous sph'niam J)'om a 28~ear-old woman; (C} a narrow body attd narrow splenium from a 43-year-old nian; (D) an average bodl and narrow splenium J?ont a 31-year-old,.~,oman. The scale in ( (') indic atl's JTve l. O cnt int erl a~. The ~atne ,,ale applies to all the MRI~.

bulbous in women than in men v. It seemed important to us to follow up that report with measurements on a larger series of subjects in view of the small sample size in that study (5 females, 9 males), and of a number of unstated though possibly relevant variables, such as method of selection of the particular 14 brains from all available autopsy specimens, age of subjects, cause of death, and extent of post-mortem changes. These important methodological questions were particularly troublesome because: (1) the authors stated that they undertook measurements of the callosum a f t e r the "serendipitous' observation of a sex difference in the shape of the splenium in a series of brains they had been studying; (2) the reported distribution of values for splenial maximum width for males and females was completely himodal (0.9-1.4 cm for males and 1.4-1.8 cm for females), which is an improbability for any biological paralneter (except reproductive) in randomly selected populations of males and females; and (3) the authors attributed forensic, evolutionary and neuropsychological significance to the finding, even though the reported sex difference in the area of the posterior fifth of the splenium (defined by the authors to represent splenial surface area), lacked statistical significance (P=0.08). The authors made the further assumptions, for which there is no evidence, that size of splenium is directly related to the degree of symmetry of hemispheric functioning, and that their finding of a larger splenium in females reflects less hemispheric specialization (or greater symmetry) for visuospatial functions. The question is whether or not existing knowledge of the corpus callosum and

of the cortical functions its axons subserve permits interpretations relating differing cognitive functions to variations in size and shape of the callosum. Individual variations in human corpus callosum Our own measurements of the corpus callosum in 17 men and 22 women, using magnetic resonance images (MRI) on file in the MRI unit at this institution (excluding all subjects with brain pathology affecting the corpus callosum), failed to confirm a gender-related difference in splenial area or maximum splenial width (Byne, W.. Houston, L. and Bleier, R., unpublished observations). We did find a marginally significant genderassociated difference in minimum body width, a difference that was most evident in the over-40-year-old age groups, and an age-associated decrease in anteroposterior distance. It is possible that some decrease in callosal size may be related to variable neuronal loss with age, though this has yet to be demonstrated. The most striking and significant findings in our study were the large variations in callosal size and shape among individuals irrespective of sex and age. It is not possible to predict gender or age by the size or shape of any individual corpus callosum (Figs 1 and 2). The failure to confirm the reported finding of a larger splenium in females has also been reported elsewhere in two recent studies of the corpt, s callosum I°'ll . Both studies used brains obtained at autopsy, but in larger numbers than were used in the study by de Lacoste-Utamsing and Holloway. One of these studies ~° found that the

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corpus cailosum is 11% larger in lefthanded and ambidextrous people than in those with right-hand preference. The study found no significant sexrelated differences in any of their measurements of the callosum but suggested there may be a complex interaction between sex and hand preference, with mixed-handed males tending to have a relatively larger posterior half. The findings of a larger callosum in left-handers presents interesting contradictions with regard to the other two studies described above: Geschwind suggested that left-handedness, which is considered to be more common in males, is associated with superior visuospatial and mathematical ability8, and de Lacoste-Utamsing and Holloway 9 implied that a smaller splenium, which was characteristic of males in their study, is associated with superior visuospatial ability. It should also be noted that every study of the human callosum thus far, including our own, has found some variation in the callosum correlated with whatever variable the authors chose or had available to examine, but has failed to confirm the findings in previous studies. This may serve as a warning about hasty interpretations of findings based on limited sample sizes and limited knowledge of the corpus callosum. De Lacoste-Utamsing and Holloway suggested 9 that sex differences in the splenium may reflect sex differences in hemispheric lateralization of visuospatial functions, and that a larger splenium implied a lesser degree of hemispheric lateralization or 'specialization' of cognitive functioning. But if variations in callosal size or shape are to be interpreted to indicate differences in some parameter of cognitive functioning, then such interpretations must be based upon known correlations between callosal size or shape and particular cognitive functions. To date no evidence exists for such correlations. Experimental neuroanatomical and electrophysiological studies have begun to reveal the enormous complexity of the patterns of both intrahemispheric and interhemispheric (callosal) corticocortical connections, yet the functional implications of these connections are incompletely understood. In general, the orderly combination or convergence of intrahemispheric and interhemispheric inputs to cortical areas results in the construction of continuous receptive fields that extend

Males

Females

Fig. 2. Drawings of corpora callosa measured in the study by Byne, Houston and Bleier (unpublished observations). The splenium is to the right. For each sex, drawings were arranged in order of age and alternate drawings were selected for illustration here; youngest is at the top. The lower five callosa in both groups are from subjects 40 years of age or over. The third and fourth male callosa (from the top) are shown in Figs 1 (A) and (C), respectively; the third and fourth female callosa are shown in Figs 1 (B) and (D), respectively. Scale bar is 2 cm.

across the vertical meridian of the visual field and across the midline of the body (somatosensory) 12-14. In the case of the auditory system, the callosum appears to carry a specific subset of binaural information between the hemispheres 15. Goldman-Rakic and Schwartz 16 have demonstrated a pattern of interdigitation of contralateral (callosal) and ipsilateral cortical columnar projections to frontal association cortex, and suggest that this arrangement may provide for the bilateral integration of spatial and temporal information underlying the cognitive and behavioral functions associated with the frontal cortex. Some experimental findings, as well as clinical observations that corpus callosal section in cases of severe epilepsy may be followed by a marked decrease in generalized seizures but by more intense focal seizures, have suggested that the callosum carries tonic inhibitory interhemispheric fibers in addition to axons that facilitate transmission of

cortical activity between the hemispheres 17. However, what relationship these bilateral integrative functions of the corpus callosum have to visuospatial or other cognitive abilities has not been demonstrated. Neither can it be predicted how variations in these patterns of cortical callosai projections may affect size or shape of the cailosum or, conversely, what variations in callosal size or shape imply for cortical representation and function. Furthermore, when it is estimated that only about 2% of cortical neurons send their axons through the callosum TM, callosal neurons (and therefore the callosum itself) can tell us only a small fraction of the whole story about cognitive functions. The large variations in size and shape that we found among individual corpora callosa may be significantly related to individual differences in the postnatal development of the corpus callosum. These differences in postnatal development may, in turn, follow

394 significant individual variations in postnatal sensory and motor experiences as well as other environmental influences. At birth, callosal neurons are distributed uniformly across the visual, auditory and somatosensory cortex in kittens and rodents, unlike the mosaic pattern of distribution in adults 19-21. This restriction of callosal projections characteristic of the adult pattern is thought to result from selective elimination of callosal collaterals and/or callosal neurons in the postnatal period. For example, at birth the corpus callosum of the rhesus monkey has three times the adult number of axons, which is attained at about six months of age 22. Experimental manipulations in kittens, such as ocular enucleation, suturing of the eyelids, and induction of squint, have been followed by changes in the number, packing density and distribution of labelled, callosally projecting cortical neurons and in the density of labelled callosal terminals 2~25. While it is not known how or whether these changes are reflected in callosal structure, these results suggest that specific patterns of callosal connections can be shaped by sensory, and perhaps motor, experience during the postnatal period. Additional evidence for this possibility is provided by a recent study that found significantly larger (1517%) middle and posterior thirds of the corpus callosum in rats reared in a complex environment, compared with rats reared in isolation 26. No sexrelated differences were found. In summary, large variations in callosal size and shape exist among individuals. Virtually nothing is known about the relationship of callosal size or projections to cognitive abilities, or about the cortical structural and functional bases for individual cognitive differences. Thus, it is premature to propose functional or evolutionary implications either for the sizable variations in callosal size and shape among individuals or for the few modest differences that may appear between groups that have been classified by age, hand preference, or gender.

Acknowledgements William Byne was a predoctoral fellow in the Neuroscience Training Program at the University of Wisconsin, Madison at the time of this study. We are grateful to Inge Siggelkow for her assistance in this rescarch, to Cliff Gilman for computer and statistical consultations, to Shirley ttunsaker for photographic assistance, and

T I N S - September 1986 to Yvonne Slusser for reproduction of the tracings. We thank John Brugge and Richard Reale for their very helpful comments on the manuscript drafts. This research was supported by grants from the National Institutes of Health (NS16643 and HD03352).

Selected references l Caplan, P. J., MacPherson, G . M . and Tobin, P. (1985) Am. Psychologist 4(1, 786-799 2 Fairweather, H. (19761 Cognition 4,231-280 3 McGIone, J. (1980) Behav. Brain. Sci, 3, 215-263 4 Kimball, M. M. (19811 Int. J. Women's Studies 4,318-338 5 Hyde, J. (1981) Am. P6ychol. 36, 892-9(11 6 Geschwind, N. and Behan, P. (1982) Proc, Natl Acad. Sci. USA 79, 5097-5100 7 Chi, J. G., Dooling, E. C. and Gilles, F. H. (19771 Ann. Neurol. 1, 86-93 8 Kolata. G. (1983) Science 222, 1312 9 De Lacoste-Utamsing, C. and Holloway, R. L. (1982) Science 216, 1431-1432 10 Witelson, S. F. (1985) Science 229, 665~,68 I I Demeter, S., Ringo, J. and Doty, R. W. (1985) Soc. Neurosci. Abstr. 11, 868 12 Antonini, A.. Berlucehi, G. and Lepore. F. (1983) J. Neurophysiol. 49, 902-921 13 Joncs, E. G., Coulter, J. D. and Wise, S. P. (1979) J. Comp, Neurol. 188, 11,3-136 14 Kiltackey, H, P., Gould, H. J., 111, Cusick. ('. G., Pons, T. P. and Kaas, J. H. (19831 J ('omp. Neurol. 219,384-419

15 Imig, T. J. and Brugge, J. F. (1978) J, Comp. Neurol. 182, 637-660 16 Goldman-Rakic, P. and Schwartz, M. 1 (19821 Science 216, 755-757 17 Spencer, S. S., Spencer, l). D., Glaser, G . H . . Williamson, P . D . and Matlson, R. H. (19841 Ann. Neurol. 16,686--693 18 Berlucchi, G. (1981) in Brain Mechanisms and Perceptual Awareness (Pompeiano, O. and Marsan, C. A., eds), pp. 133-152~ Raven Press 19 lnnocenti, G. M . , Fiore, L and Caminiti, R (1977) Neurosci. Lett. 4,237-242 20 Ivy. G. O. and Killackey, H. ( 1981 ) J~ Comp. Neurol. 195,367-389 21 Feng, J. Z. and Brugge, J . F . (1983) .I. Comp. Neurol, 214, 416-426 22 LaMantia, A-S. and Rakic, P (19841 Sac. Neurosci. Abstr. 11), 1(181 23 Lund, R, D., Mitchell, D, E. and Henry, G. H. (1978) Brain Res. 144. 169-172 24 Innocenti, G, M. and Frost, D O. (1979) Nature 280, 231-234 25 Innocenti, G. M., Frost, D. O. and llles, J. (1985) J. Neurosci. 5, 255-267 26 Juraska. J. M. and Meyer, M. (1985) So~. Neurosci, Abstr. 11, 528 RUTH BLEIER, LANNING HOUSI'ON* AND WII.LIAM BYNEJDepartment o~ Neurophysiology, University o] Wisconsin, Madison, WI 53706, USA, *9240 University Avenue, Apt 118. l o o n Rapids, MN 55433, USA. and ~Albert Einstein School of Medicine, 1300 Morris Park A venue, Bronx, N Y 1046l. USA.

Inositol phosphates: concord or con sion? lnositol phospholipids play a vital role in receptot~effector transduction processes involving intracellular Ca2+ release and activation of protein kinase C. The simple proposal that activated receptors stimulate a phosphatidylinositol(4,5)-bisphosphate-specific phosphoinositidase C has recently been shaken by the discoveries of several novel inositol phosphate esters in stimulated cells. However, many of these compounds appear to be metabolites of inositol( l,4,5 )-trisphosphate, the putative Ca2+-mobilizing second messenger. One of them, inositol(1,3, 4.5 )-tetrakisphosphate is formed very rapidly folio wing muscarinic cholinergic stimulation of brain and parotid gland slices, and may have some regulator), function distinct from that of its precursor. Metabolic pathways accounting for the synthesis of inositol pentakis and hexakispho.sphates observed recently in GH4 pituitary cells have still to be defined, and the occurrence of inositol(1,2-cyc,4,5 )-trisphosphate, a product of in-vitro assays of phosphoinositidase C, has yet to be confirmed in living cells. Recent years have seen the elucidation of a mechanism that enables receptors on the cell surface to generate intracellular signals by the receptordependent hydrolysis of phosphatidylinositol(4,5)-bisphosphate [Ptdlns(4,5)P2]. The products of this reaction are 1,2-diacylglycerol, which activates protein kinase C, and inositol(1,4,5)trisphosphate [lns(1,4,51P3], which can release Ca 2+ from intracellular stores in the endoplasmic reticulum ~'2. Many receptors that utilize this mechanism

are found in the nervous system ~. Ptdlns(4,5)P2 breakdown is thus analogous to the stimulation or inhibition of adenylate cyclase that results from activation of two distinct groups of receptors, and this analogy is strengthened still further by the realization that all three mechanisms are coupled to cell surface receptors by a family of closely related guanine nucleotide binding proteins 4. Many recent studies of agoniststimulated hydrolysis of Ptdlns(4,5)P2

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