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A factor analysis of the human's corpus callosum
Brain Research, 548 (1991) 126-132 © 1991 Elsevier Science Publishers B.V. 0006-8993/91/$03.50 ADONIS 0006899391165660
126
BRES 16566
A factor analysis of the human's corpus callosum Victor H. Denenberg 1, Andrew Kertesz 2 and Patricia E.
Cowell 1
1Biobehavioral Sciences Graduate Degree Program, University of Connecticut, Storrs, CT 06269-4154 (U.S.A.) and 2St. Joseph's Hospital Lawson Research Institute, London, Ont. (Canada) (Accepted 4 December 1990)
Key words: Callosal width; Factor analysis, Callosal isthmus; Sex difference
We have recently developed a computer program for measuring midsagittal sections of the human corpus callosum, similar to one used for the rat. Callosal area, perimeter, axis length, and 99 widths for 104 subjects were entered into a factor analysis in order to define regional clusters. Seven width factors were obtained. Regional widths were found to be sensitive to Sex × Handedness interactions in the anterior body, with right-handed females and left-handed males being larger. In the posterior body males had wider callosa than females. A further analysis within the 'isthmus' region compared consistent and non-consistent right-handed males and females. Consistent right-handed males and both female groups had smaller callosa than non-consistent right-handed males. These findings confirmed the use of consistency of handedness as an important independent variable with respect to human callosal morphology. INTRODUCTION A recent series of studies with the rat found that the corpus callosum is larger in the male 1'7'9. The callosum is a heterogeneous fiber tract; therefore, global measures only give limited information. In order to study regional parameters we developed a computer program which calculated 99 callosal widths, taken along equally spaced intervals of the longitudinal axis, as well as callosal area, perimeter, and length 7. Factor analyses of the caUosal parameters obtained in the Berrebi et al. l study plus brain weight found 7 width factors. The locations of the width loadings on these factors, starting at the anterior (genu) end were: widths 1-5 (Wl-5), W6-17, W24-38, W46-57, W62-72, W79-95, and W96-99. An eighth factor contained the variables of brain weight, callosal length, and callosal perimeter, while callosal area did not load significantly on any of these dimensions 7. Use of the factor scores revealed that the sex differences in the rat corpus callosum were most pronounced in the genu and the splenium 7. These same regions were also significantly affected by neonatal interventions, including handling stimulation i and gonadal hormones9-1~. Because of the effectiveness of the multiple measurement approach in studying the rat's callosum, we had a similar program developed for the human callosum s. We have used this program to reanalyze the MRI callosal tracings of a well-defined human population of left- and right-handed males and females 16. We then factor-
analysed these data. Following this, we used the factor scores to assess the effects of sex and handedness upon the several callosal regions. DESCRIPTION OF COMPUTER PROGRAM A detailed description of the human Stereology program is given in Denenberg et al. s. A brief summary is presented here along with the final products of the Stereology program shown in Fig. 1. Each corpus callosum outline was traced on a digitizing tablet. Terminal points of the genu, t(g), and the splenium, t(s), were selected. The computer then divided the dorsal perimeter [t(g)-t(s)] from left to right into 99 equally spaced points and did the same for the ventral aspect. Correspondingly numbered points were connected to obtain 99 widths. Each width was bisected and the bisecting points connected to form the callosal axis. The Stereology program displayed on the screen the tracing of the callosum, the bisecting catlosal axis (axis length), the 99 widths, and the statistic Z'W which is the sum of the 99 widths. The values t(g) and t(s) were adjusted until XW was a minimum. Fig. 1A is an example of a final callosum solution. The next step in processing is shown in Fig. lB. The callosum was enclosed by a rectangle formed by the joining of the parallel horizontal and vertical tangents. Stereology computed the length, L(r), and the width, W(r), of this rectangle. The experimenter then marked
Correspondence: V. Denenberg, Biobehavioral Sciences Graduate Degree Program, University of Connecticut, Storrs, CT 06269-4154, U.S.A.
127 the point where the callosal apex met the superior length of the rectangle, L ( a ) , and the point at which the genu extended below the body of the callosum, L(g). Additional parameters of apex asymmetry were: A ( a ) = L ( a ) / L ( r ) ; genu asymmetry, G(a) = L(g)/L(r); and circularity, C(c) = L ( r ) / W ( r ) .
~
Each callosum was traced 5 times to average out
ttg)
t(s)
deviations due to h a n d jerkiness and other forms of sampling error. T h e n a m e a n , standard deviation and coefficient of variation (CV) were obtained for all widths.
A
If the CV at any particular width was greater than 10%, the scores were examined to determine if one or more
I
L(g)
were deviant. If so, that score was removed and the m e a n
Lta)
recalculated. In the present sample approx. 20% of the
~
~
tracings had several widths with CVs higher than 10%, usually in the 11-12% range. W h e n a callosum had m a n y high CVs, a new set of 5 tracings was taken and averaged.
T w (r) /
1
FACTOR ANALYSIS OF CALLOSAL WIDTHS
L(r),
Subjects The subjects consisted of 104 normal adults used in previous m o r p h o m e t r i c studies 15'16. They were university students and hospital staff with an age range from 18 to
a
Fig. 1. A: stereology tracing of a human corpus callosum showing 99 widths and central axis. Placement of t(g) and t(s) are based upon the minimum ZW criterion. B: the measurement definitions obtained from enclosing a human callosum within a rectangle.
TABLE I
Oblique factor loadings for CC widths (decima~ omitted) W = CC width percentile; FL = factor loading; X = o~hogonal variable
W3-18
W22-39
14149-62
W65-74
W77-85
W89-94
W95-99
W
FL
W
FL
W
FL
W
FL
W
FL
W
FL
W
FL
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
647 691 756 854 874 894 928 930 934 939 941 936 902 851 791 684
19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 4O 41 42 43 44
X X X 636 660 698 732 737 748 743 746 739 750 754 729 702 712 674 636 662 606 X X X X X
46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64
X X X 635 653 709 700 698 726 709 746 755 741 745 716 654 650 X X
63 64 65 66 67 68 69 70 71 72 73 74 75
X X 686 767 815 874 865 853 851 783 736 665 X
75 76 77 78 79 80 81 82 83 84 85 86 87 88
X X 673 725 723 782 789 762 694 659 652 X X
86 87 88 89 90 91 92 93 94
X X 744 736 731 781 777 770
95 96 97 98 99
662 X 886 787
128 49 (mean = 26.9, S.D. = 7.19). Fifty-two were r i handed (25 men, 27 women) and 52 were left-handed (26 men, 26 women), based upon reported handedness for writing.
g
h
t
-
~
~
v
Procedure
95-99
Callosa were received in the form of projected images drawn on paper. These were photographically enlarged (2×) to accomodate our tracing procedure. Factor
5PLENtUPI Fig. 2. A human callosum upon which widths comprising the seven factors have been superimposed. otto
analysis was performed on the following corpus callosum parameters: 99 widths, area, axis length, and perimeter. In addition, we included a measure of brain area from Kertesz et al. 16 calculated from the total cortical surface digitized at the first horizontal section above the third ventricle. One subject, a right-handed male, was dropped from the factor analysis because a missing brain area score eliminated the remainder of his data from the analysis, Scores were first standardized via z-scores within the 4 sex-handedness groups to eliminate possible mean and variance differences that could bias the correlation matrix needed for factor analysis. Because adjacent widths were highly correlated and since there were approx, as many variables as there were subjects, 3 separate analyses were performed and their results combined for final interpretation. The first analysis was on widths 3,6,9 ..... 96,99; the second analysis on widths 2,5,8 ...... 95,98; and the third on widths 1,4,7 ..... 94,97. The 3 callosal variables of area, axis length, and perimeter, as well as brain area, were included in all 3 analyses. A Principal Components analysis was the method of extraction. Although both orthogonal and oblique rotations were performed on the unrotated factor pattern, the oblique reference structure matrix was used in the final solution because of interfactor correlations. In addition, it provided a simpler structure. The criterion used for retaining factors was an eigen value greater than unity, and 0.600 was the cutoff for deciding whether or not variables loaded on a particular factor 7.
Results
The area scores obtained with our tracing procedure were highly correlated with those reported by Kertesz et al. (r = 0.965), thus establishing the validity of our procedure. Kaiser's measure of sampling adequacy for the 3 factor analyses were 0.737, 0.752, and 0.770. These are within the acceptable range for defining a homogeneous set of variables 17. The 3 factor analyses yielded identical factor structures. There were 8 factors with eigen values greater than one, 7 of which included the callosal widths and one which only included brain area. Table I lists the 99 widths and their configuration of loadings upon the 7 oblique factors arranged in sequence from Width 1 (anterior) to Width 99 (posterior). In addition, the limits of the orthogonal analyses are indicated by Xs (based on factor loadings of 0.600 or greater). As can be seen, the widths present in the oblique solution are always identical to, or a subset of, those found in the orthogonal solution. The first factor contained widths 3 through 18 followed by factor two with widths 22 through 39. A gap separated factor two from 3 which then extended from width 49 through 62, closely succeeded by factor 4 containing widths 65 through 74, factor 5 with widths 77 through 85, and factor 6 with widths 89 through 94. Perimeter and axis length loaded upon the 7th factor which included the posterior-most callosal widths, 95-99. Fig. 2 shows the width factors schematically. Brain area loaded highly on its own factor (factor
TABLE II Mean scores (ram) for callosal parameters as a function o f Sex and Handedness (S. E. in brackets) Group
Area +
Axis length
perimeter
L (r)
W (r)
A (a) ~
G (a) #
C (c) #*
Female right n = 27 Female left n = 26 Male right n = 25 Male left n = 26
721.978 [23.589] 703.162 [18.516] 731.208 [20.858] 725.827 [24.011]
95.783 [1.478] 95.785 [1.644] 96.364 [2.078] 93.971 [1.519]
218.215 [2.997] 220.763 [3.045] 220.763 [3.861] 2t6.223 [3.479]
74.754 [0.751] 75.91 [1.001] 76.651 [0.8571 75.474 [1.181]
27.786 [0.603] 27.997 [0.419] 27.226 [0.731] 27.046 [0.621]
0.511 [0.015] 0.582 [0.011] 0.576 [0.015] 0.588 [0.013]
0.777 [0.0O6] 0.804 [0.01] 0.784 [0.0121 0.785 [0.008]
2.717 [0.054] 2.719 [0.036] 2.862 [0~081] 2.821 [0.071]
+ mm2; # no units; * Sex, P < 0,05.
129 TABLE III Mean factor width scores (mm) as a function o f Sex and Handedness (S. E. in brackets) Group
W3-18
W22-39 a
W49-62 ~
W65- 74b
W77-85 c
W89-94
W95-99
Female fight n = 27 Female left n = 26 Male right n = 25 Male left n = 26
10.6% [0.371] 10.713 [0.522] 10.756 [0.462] 11.372 [0.497]
8.757 [0.426] 7.767 [0.274] 7.945 [0.314] 8.454 [0.326]
6.578 [0.298] 5.998 [0.188] 6.212 [0.182] 6.674 [0.233]
6.399 [0.218] 6.344 [0.239] 7.289 [0.314] 6.509 [0.276]
10.324 [0.275] 10.218 [0.334] 11.21 [0.379] 10.573 [0.341]
11.5q [0.273] 11.441 [0.288] 11.625 [0.221] 11.526 [0.331]
5.646 [0.596] 5.657 [0.714] 5.613 [0.128] 5.539 [0.154]
a Sex x Hand, P < 0.05; b Sex, P < 0.05; c Sex, P < 0.10. loading = 0.813, 0.847, and 0.851 for the 3 factor analyses), while callosal area did not load highly on any factor (factor loadings from 0.073 to 0.340 across all factor analyses). Since the brain area measure was independent both of callosal area and the 99 widths, it was not necessary to adjust callosal data for brain size differences in subsequent statistical analyses. The regional factor widths from Table I were then used in two subsequent analyses. First, the 7 factors were evaluated for the effects of sex and handedness. Next, factors W 6 5 - 7 4 and W77-85, which cover approx, the same callosal region as Witelson's 'isthmus', were evaluated with respect to Witelson's dimension of consistent and non-consistent right-handers 24.
shows the first 8 variables and Table III contains the factor widths. The data were classified by sex and handedness, based upon writing hand in the same manner as Kertesz et al., and evaluated via A N O V A . Results Callosal p a r a m e t e r s e x c l u d i n g widths. There were no
significant main effects or interactions for perimeter or axis length; nor were there any significant main effects or interactions for any of the 'rectangle parameters' except the circularity index. Females had significantly lower C(c)
W65-85
SEX AND HANDEDNESS EFFECTS
lo.o
/
9.5'
Procedure
=
For all 104 subjects the following data were available: corpus callosum area, axis length, and perimeter; the 5 scores derived from the 'rectangle analysis' shown in Fig. 1B (length, width, apex asymmetry, genu asymmetry, and circularity); and the 7 factor width scores. Table II
= a ~
o.o.
~
:
FEMALE
MALE
i-
s s. 8.0
c~
~:~
HAND PREFERENCE
TABLE IV ISTHMUS
Mean factor width scores (mm) as a function o f Sex and Hand consistency (S. E. in brackets)
9o
CRH = consistent right-handers; NCRH = non-consistent fighthanders,
a0
Group
Female CRH n = 12 Female NCRH n = 15 Male CRH n = l1 Male NCRH n = 14
W65-85 ",b,c
8.285 [0.500] 8.423 [0.447] 8.329 [0.522] 9.972 [0.463]
a Sex, P < 0.05; b Hand consistency, P < 0.05; c Sex x Hand consistency, P < 0.05.
~
| z_
,
~
70
.---o---
< l,u
~<
•
60
7 7
FEMALE MALE
~
so c~ HAND PREFERENCE
Fig. 3. Mean scores of male (closed circles) and female (open squares) consistent and non-consistent right handers (CRH and NCRH) for our factor region W65-85 and Witelson's (1989) isthmus.
130 values than did males (F = 3.97, df = 1/100, P < 0.049). Their corpora callosa were more circular than males, Callosal factor widths. An overall A N O V A was performed with the 7 Width factors as a within-subject variable, and with Sex and Handedness as betweensubjects variables. A significant 3-way interaction was found (F = 2.37, df = 6/600, P < 0.029). Therefore, 2-way analyses of variance for Sex and Handedness were performed separately for each factor. Despite the loading of perimeter and axis length with W95-99, this factor was analyzed without these two parameters to assess the nature of the width dimension itself, Significant interaction effects for Sex x Handedness were found for W22-39 (F = 4.79, df = 1/100, P < 0.031) and W49-62 (F = 5.13, df = 1/100, P < 0.026). Among right-handers, females had wider callosa in these two regions than males while among left-handers the converse was true. A significant main effect of Sex favoring males was found for W65-74 (F = 4.04, df = 1/100, P < 0.047). This particular phenomenon extended through the next factor, W77-85, but only at a marginally significant level (F = 3.48, df = 1/100, P < 0.065). When W65-74 and W77-85 were pooled, Sex was significant at the 0.03 level, EVALUATION OF THE 'ISTHMUS' REGION The callosal region covered by Factors W65-74 and W77-85 is in approximately the same place as Witelson's 'isthmus '24. She had reported that an analysis of that region found a significant main effect of Handedness and a Sex × Handedness interaction. Eighty-six percent of her subjects were right-handed writers and were subdivided into consistent and non-consistent right handers (the latter group included 6 left-handed writers). Witelson's interaction finding was that non-consistent righthanded males has a significantly larger isthmus area than the other 3 groups, with consistent right-handed males having the smallest area of the 4 groups. We also classified our right-handed subjects for consistency and non-consistency, to see if we could duplicate Witelson's isthmus findings in the region covered by our factor 5 and 6 combined (W65-85).
Procedure The subjects were given a 5-item handedness questionnaire originally developed by Bryden 2. These items asked the subject to indicate which hand was used for writing, drawing, toothbrushing, throwing a bali, and using scissors 16. Subjects were classified as consistent right-handers (CRH) when all 5 items were performed with the right hand, and non-consistent right-handers
(NCRH) when one or more of the 5 items was performed with the left or both hands (all N C R H were right-handed for writing).
Results The mean callosal widths in the region W65-85 are listed in Table IV along with their standard errors and the N per group. An analysis of variance found significant effects for Sex, Hand Consistency, and their interaction (Fs of 5.42, 6.76, and 4.83 resp.; df = 1/48, P < 0.05). All 3 effects were due to the non-consistent males whose mean width was significantly greater than the widths of the other 3 groups. This interaction is similar to that reported by Witelson. Fig. 3 compares Witelson's and our interaction patterns. DISCUSSION We have demonstrated the ability of our Stereology program and our statistical procedure to both replicate and expand upon some of Kertesz' original findings. Kertesz et al. failed to find significant sex or handedness effects for callosal area or their length parameter, which is equivalent to our L(r) measure. As expected, we replicated these findings. Division of the callosum into multiple width measures and the resulting factor structure enabled us to assess particular callosal regions relative to variables of sex and handedness, and to uncover interactions not revealed in analyses of more global measures such as area, perimeter, and length. Furthermore, the lack of correlation between callosal width measures and brain size (as measured by brain area), a dissociation we also found in the rat 7, establishes that in both species callosal widths are independent of overall brain size. Sex x Handedness (based on writing hand) interactions were found in two factor regions, W22-39 and W49-62, with right-handed females and left-handed males having the larger widths. The functional implication of this finding is difficult to assess, because there is no detailed map relating cailosal location with the cortical site from which the fibers arise for humans. However, such a map has been worked out by Pandya and his associates for the non-human primate 21. Using their maps as a first approximation to the human callosum, the region encompassed by W22-39 includes the pre-motor and supplementary motor areas, while W49-62 involves the somatosensory areas. One empirical finding appears to have been firmly substantiated: namely, the Witelson report that nonconsistent right-handed males have a larger callosal area in the isthmus region than do females and consistent right-handed males. Our replication of that finding (Fig.
131 3) establishes its robustness and is impressive given the considerable differences between the Witelson and the Kertesz samples. First, there are differences in measurement procedure since Witelson's regions were subareas, while ours were averages from clusters of adjacent widths. Second, Witelson's hand preference rating was based on behavioral observation of patients' performance on a 12-item scale which did not include writing, while Kertesz used responses to a questionnaire with only 5 items that included writing. Third, Witelson had some left-handed writers in her NCRH group (6 of 50 were left-handed) while none of the left-handed writers in the Kertesz data set was included in the NCRH group. Fourth, the Witelson data were all obtained post-mortem while Kertesz' data were MRIs. The importance of this distinction has been highlighted by Clarke et al. 4 who have found sex and age differences as a function of MRI vs post-mortem measures of the human corpus callosum. Finally, the composition of the subjects was vastly different with respect to age and health: Witelson's subjects were terminally ill cancer patients (mean age = 50.8 years) while Kertesz' were presumably healthy (mean age = 26.9 years), In sum, 'consistency of hand usage' appears to be an important dimension that needs to be considered in human studies of hand-brain-behavior relationships, Witelson's findings in the isthmus in conjunction with our replication have led us to expand that classification to include consistent and non-consistent left-handers and to examine all the callosal width factors. This analysis, which will be the subject of a separate report, is finding complex sex differences in various regions throughout the callosum, The isthmus area, involving factor regions W65-74 and W77-85, also exhibited sex effects with males having the larger widths. Examination of Table III reveals that the main effect for Sex in these two regions is primarily being carried by the right-handed writing males. Table IV and Fig. 3 show that the non-consistent right-handed males are the deviant group. Therefore, we do not believe the Sex main effect is relevant in this region, but that attention should be focused upon the non-consistent right-handed males (i.e. the interaction). Based upon the Pandya and Seltzer maps, region W65-74 appears to involve the posterior parietal area while W77-85 overlaps the superior and inferior temporal areas. Witelson 24 suggested that the isthmus is probably associated with the posterior language region, which occupies comparable zones in human cortex. The larger size of this region for the non-consistent right-handed males may reflect differences in number of callosal connections, myelinization, cell-packing density, fiber thickness, or some combination of these parameters, none of which is available from MRIs. Another important finding is that the factor structure
of the width measures of the human corpus callosum is quite similar to that of the rat. In both instances 7 factors were extracted with considerable degree of overlap. In one sense this is not suprising since there are similarities in callosal organization between the two species. Interhemispheric fibers from the visual area course through the posterior of the callosum 3'6A9'2°, ones from the somatosensory area go through the body 6'14, while fibers from the frontal area go through the anterior portion 6'2°. Whether any or all of the 7 overlapping factors represent analogies or homologies between the two species awaits further experimental investigation. In light of the sex differences found with the rat in the anterior and posterior portions of the callosum 1'7'9, and some of the reports in the human literature concerning sex differences in the rostrum/genu 4'24 and in the splenium 5'13, we expected to find effects in these regions. Our failure to do so could be attributed to parametric differences between the Kertesz sample and other sampies where sex differences have been reported (e.g. age, health, handedness, measurement procedure, method of obtaining the original tracing). However, this seems most unlikely since we did find a close match to Witelson's isthmus data despite the presence of these contaminating variables. Thus, the isthmus effect appears to be quite stable when sex and handedness are taken into account. In contrast, effects associated with the splenium and genu appear to be quite effervescent in light of the many conflicting reports in the literature. Perhaps more attention needs to be paid to the body of the callosum. There are two major benefits from our approach to callosal measurement. First, percentile scaling of widths along the medial axis of the callosum has been shown to eliminate major differences in morphological geometry between the human and the rat 8. Therefore this form of scaling is applicable for cross-species comparisons; for intraspecific developmental studies; and for the study of different clinical groups such as schizophrenics 18"22'23, alcoholics 12, and Alzheimer's patients 25 known to vary in gross callosal morphology. The second benefit is that our factor analysis approach gives a more satisfactory solution to the question of regional specificity within the callosum than the procedures used to date of dividing the callosum into halves, thirds, fourths, or fifths. Researchers have in the past used L(r) (see Fig. 1B) as the basis for making the divisions, yet this measure does not take into account the amount of genu folded underneath the caUosum. The flaws in this approach have also been emphasized by Clarke et al. 4. Finally, our multiple measurement and factor analytic approach has introduced a new and more informative methodology for the investigation of the corpus callosum,
132 w h i c h s h o u l d h e l p a d v a n c e the u n d e r s t a n d i n g of b r a i n b e h a v i o r processes,
Acknowledgements. We thank Garvin Boudle for photographing and enlarging the MRI tracings.
REFERENCES
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126
BRES 16566
A factor analysis of the human's corpus callosum Victor H. Denenberg 1, Andrew Kertesz 2 and Patricia E.
Cowell 1
1Biobehavioral Sciences Graduate Degree Program, University of Connecticut, Storrs, CT 06269-4154 (U.S.A.) and 2St. Joseph's Hospital Lawson Research Institute, London, Ont. (Canada) (Accepted 4 December 1990)
Key words: Callosal width; Factor analysis, Callosal isthmus; Sex difference
We have recently developed a computer program for measuring midsagittal sections of the human corpus callosum, similar to one used for the rat. Callosal area, perimeter, axis length, and 99 widths for 104 subjects were entered into a factor analysis in order to define regional clusters. Seven width factors were obtained. Regional widths were found to be sensitive to Sex × Handedness interactions in the anterior body, with right-handed females and left-handed males being larger. In the posterior body males had wider callosa than females. A further analysis within the 'isthmus' region compared consistent and non-consistent right-handed males and females. Consistent right-handed males and both female groups had smaller callosa than non-consistent right-handed males. These findings confirmed the use of consistency of handedness as an important independent variable with respect to human callosal morphology. INTRODUCTION A recent series of studies with the rat found that the corpus callosum is larger in the male 1'7'9. The callosum is a heterogeneous fiber tract; therefore, global measures only give limited information. In order to study regional parameters we developed a computer program which calculated 99 callosal widths, taken along equally spaced intervals of the longitudinal axis, as well as callosal area, perimeter, and length 7. Factor analyses of the caUosal parameters obtained in the Berrebi et al. l study plus brain weight found 7 width factors. The locations of the width loadings on these factors, starting at the anterior (genu) end were: widths 1-5 (Wl-5), W6-17, W24-38, W46-57, W62-72, W79-95, and W96-99. An eighth factor contained the variables of brain weight, callosal length, and callosal perimeter, while callosal area did not load significantly on any of these dimensions 7. Use of the factor scores revealed that the sex differences in the rat corpus callosum were most pronounced in the genu and the splenium 7. These same regions were also significantly affected by neonatal interventions, including handling stimulation i and gonadal hormones9-1~. Because of the effectiveness of the multiple measurement approach in studying the rat's callosum, we had a similar program developed for the human callosum s. We have used this program to reanalyze the MRI callosal tracings of a well-defined human population of left- and right-handed males and females 16. We then factor-
analysed these data. Following this, we used the factor scores to assess the effects of sex and handedness upon the several callosal regions. DESCRIPTION OF COMPUTER PROGRAM A detailed description of the human Stereology program is given in Denenberg et al. s. A brief summary is presented here along with the final products of the Stereology program shown in Fig. 1. Each corpus callosum outline was traced on a digitizing tablet. Terminal points of the genu, t(g), and the splenium, t(s), were selected. The computer then divided the dorsal perimeter [t(g)-t(s)] from left to right into 99 equally spaced points and did the same for the ventral aspect. Correspondingly numbered points were connected to obtain 99 widths. Each width was bisected and the bisecting points connected to form the callosal axis. The Stereology program displayed on the screen the tracing of the callosum, the bisecting catlosal axis (axis length), the 99 widths, and the statistic Z'W which is the sum of the 99 widths. The values t(g) and t(s) were adjusted until XW was a minimum. Fig. 1A is an example of a final callosum solution. The next step in processing is shown in Fig. lB. The callosum was enclosed by a rectangle formed by the joining of the parallel horizontal and vertical tangents. Stereology computed the length, L(r), and the width, W(r), of this rectangle. The experimenter then marked
Correspondence: V. Denenberg, Biobehavioral Sciences Graduate Degree Program, University of Connecticut, Storrs, CT 06269-4154, U.S.A.
127 the point where the callosal apex met the superior length of the rectangle, L ( a ) , and the point at which the genu extended below the body of the callosum, L(g). Additional parameters of apex asymmetry were: A ( a ) = L ( a ) / L ( r ) ; genu asymmetry, G(a) = L(g)/L(r); and circularity, C(c) = L ( r ) / W ( r ) .
~
Each callosum was traced 5 times to average out
ttg)
t(s)
deviations due to h a n d jerkiness and other forms of sampling error. T h e n a m e a n , standard deviation and coefficient of variation (CV) were obtained for all widths.
A
If the CV at any particular width was greater than 10%, the scores were examined to determine if one or more
I
L(g)
were deviant. If so, that score was removed and the m e a n
Lta)
recalculated. In the present sample approx. 20% of the
~
~
tracings had several widths with CVs higher than 10%, usually in the 11-12% range. W h e n a callosum had m a n y high CVs, a new set of 5 tracings was taken and averaged.
T w (r) /
1
FACTOR ANALYSIS OF CALLOSAL WIDTHS
L(r),
Subjects The subjects consisted of 104 normal adults used in previous m o r p h o m e t r i c studies 15'16. They were university students and hospital staff with an age range from 18 to
a
Fig. 1. A: stereology tracing of a human corpus callosum showing 99 widths and central axis. Placement of t(g) and t(s) are based upon the minimum ZW criterion. B: the measurement definitions obtained from enclosing a human callosum within a rectangle.
TABLE I
Oblique factor loadings for CC widths (decima~ omitted) W = CC width percentile; FL = factor loading; X = o~hogonal variable
W3-18
W22-39
14149-62
W65-74
W77-85
W89-94
W95-99
W
FL
W
FL
W
FL
W
FL
W
FL
W
FL
W
FL
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
647 691 756 854 874 894 928 930 934 939 941 936 902 851 791 684
19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 4O 41 42 43 44
X X X 636 660 698 732 737 748 743 746 739 750 754 729 702 712 674 636 662 606 X X X X X
46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64
X X X 635 653 709 700 698 726 709 746 755 741 745 716 654 650 X X
63 64 65 66 67 68 69 70 71 72 73 74 75
X X 686 767 815 874 865 853 851 783 736 665 X
75 76 77 78 79 80 81 82 83 84 85 86 87 88
X X 673 725 723 782 789 762 694 659 652 X X
86 87 88 89 90 91 92 93 94
X X 744 736 731 781 777 770
95 96 97 98 99
662 X 886 787
128 49 (mean = 26.9, S.D. = 7.19). Fifty-two were r i handed (25 men, 27 women) and 52 were left-handed (26 men, 26 women), based upon reported handedness for writing.
g
h
t
-
~
~
v
Procedure
95-99
Callosa were received in the form of projected images drawn on paper. These were photographically enlarged (2×) to accomodate our tracing procedure. Factor
5PLENtUPI Fig. 2. A human callosum upon which widths comprising the seven factors have been superimposed. otto
analysis was performed on the following corpus callosum parameters: 99 widths, area, axis length, and perimeter. In addition, we included a measure of brain area from Kertesz et al. 16 calculated from the total cortical surface digitized at the first horizontal section above the third ventricle. One subject, a right-handed male, was dropped from the factor analysis because a missing brain area score eliminated the remainder of his data from the analysis, Scores were first standardized via z-scores within the 4 sex-handedness groups to eliminate possible mean and variance differences that could bias the correlation matrix needed for factor analysis. Because adjacent widths were highly correlated and since there were approx, as many variables as there were subjects, 3 separate analyses were performed and their results combined for final interpretation. The first analysis was on widths 3,6,9 ..... 96,99; the second analysis on widths 2,5,8 ...... 95,98; and the third on widths 1,4,7 ..... 94,97. The 3 callosal variables of area, axis length, and perimeter, as well as brain area, were included in all 3 analyses. A Principal Components analysis was the method of extraction. Although both orthogonal and oblique rotations were performed on the unrotated factor pattern, the oblique reference structure matrix was used in the final solution because of interfactor correlations. In addition, it provided a simpler structure. The criterion used for retaining factors was an eigen value greater than unity, and 0.600 was the cutoff for deciding whether or not variables loaded on a particular factor 7.
Results
The area scores obtained with our tracing procedure were highly correlated with those reported by Kertesz et al. (r = 0.965), thus establishing the validity of our procedure. Kaiser's measure of sampling adequacy for the 3 factor analyses were 0.737, 0.752, and 0.770. These are within the acceptable range for defining a homogeneous set of variables 17. The 3 factor analyses yielded identical factor structures. There were 8 factors with eigen values greater than one, 7 of which included the callosal widths and one which only included brain area. Table I lists the 99 widths and their configuration of loadings upon the 7 oblique factors arranged in sequence from Width 1 (anterior) to Width 99 (posterior). In addition, the limits of the orthogonal analyses are indicated by Xs (based on factor loadings of 0.600 or greater). As can be seen, the widths present in the oblique solution are always identical to, or a subset of, those found in the orthogonal solution. The first factor contained widths 3 through 18 followed by factor two with widths 22 through 39. A gap separated factor two from 3 which then extended from width 49 through 62, closely succeeded by factor 4 containing widths 65 through 74, factor 5 with widths 77 through 85, and factor 6 with widths 89 through 94. Perimeter and axis length loaded upon the 7th factor which included the posterior-most callosal widths, 95-99. Fig. 2 shows the width factors schematically. Brain area loaded highly on its own factor (factor
TABLE II Mean scores (ram) for callosal parameters as a function o f Sex and Handedness (S. E. in brackets) Group
Area +
Axis length
perimeter
L (r)
W (r)
A (a) ~
G (a) #
C (c) #*
Female right n = 27 Female left n = 26 Male right n = 25 Male left n = 26
721.978 [23.589] 703.162 [18.516] 731.208 [20.858] 725.827 [24.011]
95.783 [1.478] 95.785 [1.644] 96.364 [2.078] 93.971 [1.519]
218.215 [2.997] 220.763 [3.045] 220.763 [3.861] 2t6.223 [3.479]
74.754 [0.751] 75.91 [1.001] 76.651 [0.8571 75.474 [1.181]
27.786 [0.603] 27.997 [0.419] 27.226 [0.731] 27.046 [0.621]
0.511 [0.015] 0.582 [0.011] 0.576 [0.015] 0.588 [0.013]
0.777 [0.0O6] 0.804 [0.01] 0.784 [0.0121 0.785 [0.008]
2.717 [0.054] 2.719 [0.036] 2.862 [0~081] 2.821 [0.071]
+ mm2; # no units; * Sex, P < 0,05.
129 TABLE III Mean factor width scores (mm) as a function o f Sex and Handedness (S. E. in brackets) Group
W3-18
W22-39 a
W49-62 ~
W65- 74b
W77-85 c
W89-94
W95-99
Female fight n = 27 Female left n = 26 Male right n = 25 Male left n = 26
10.6% [0.371] 10.713 [0.522] 10.756 [0.462] 11.372 [0.497]
8.757 [0.426] 7.767 [0.274] 7.945 [0.314] 8.454 [0.326]
6.578 [0.298] 5.998 [0.188] 6.212 [0.182] 6.674 [0.233]
6.399 [0.218] 6.344 [0.239] 7.289 [0.314] 6.509 [0.276]
10.324 [0.275] 10.218 [0.334] 11.21 [0.379] 10.573 [0.341]
11.5q [0.273] 11.441 [0.288] 11.625 [0.221] 11.526 [0.331]
5.646 [0.596] 5.657 [0.714] 5.613 [0.128] 5.539 [0.154]
a Sex x Hand, P < 0.05; b Sex, P < 0.05; c Sex, P < 0.10. loading = 0.813, 0.847, and 0.851 for the 3 factor analyses), while callosal area did not load highly on any factor (factor loadings from 0.073 to 0.340 across all factor analyses). Since the brain area measure was independent both of callosal area and the 99 widths, it was not necessary to adjust callosal data for brain size differences in subsequent statistical analyses. The regional factor widths from Table I were then used in two subsequent analyses. First, the 7 factors were evaluated for the effects of sex and handedness. Next, factors W 6 5 - 7 4 and W77-85, which cover approx, the same callosal region as Witelson's 'isthmus', were evaluated with respect to Witelson's dimension of consistent and non-consistent right-handers 24.
shows the first 8 variables and Table III contains the factor widths. The data were classified by sex and handedness, based upon writing hand in the same manner as Kertesz et al., and evaluated via A N O V A . Results Callosal p a r a m e t e r s e x c l u d i n g widths. There were no
significant main effects or interactions for perimeter or axis length; nor were there any significant main effects or interactions for any of the 'rectangle parameters' except the circularity index. Females had significantly lower C(c)
W65-85
SEX AND HANDEDNESS EFFECTS
lo.o
/
9.5'
Procedure
=
For all 104 subjects the following data were available: corpus callosum area, axis length, and perimeter; the 5 scores derived from the 'rectangle analysis' shown in Fig. 1B (length, width, apex asymmetry, genu asymmetry, and circularity); and the 7 factor width scores. Table II
= a ~
o.o.
~
:
FEMALE
MALE
i-
s s. 8.0
c~
~:~
HAND PREFERENCE
TABLE IV ISTHMUS
Mean factor width scores (mm) as a function o f Sex and Hand consistency (S. E. in brackets)
9o
CRH = consistent right-handers; NCRH = non-consistent fighthanders,
a0
Group
Female CRH n = 12 Female NCRH n = 15 Male CRH n = l1 Male NCRH n = 14
W65-85 ",b,c
8.285 [0.500] 8.423 [0.447] 8.329 [0.522] 9.972 [0.463]
a Sex, P < 0.05; b Hand consistency, P < 0.05; c Sex x Hand consistency, P < 0.05.
~
| z_
,
~
70
.---o---
< l,u
~<
•
60
7 7
FEMALE MALE
~
so c~ HAND PREFERENCE
Fig. 3. Mean scores of male (closed circles) and female (open squares) consistent and non-consistent right handers (CRH and NCRH) for our factor region W65-85 and Witelson's (1989) isthmus.
130 values than did males (F = 3.97, df = 1/100, P < 0.049). Their corpora callosa were more circular than males, Callosal factor widths. An overall A N O V A was performed with the 7 Width factors as a within-subject variable, and with Sex and Handedness as betweensubjects variables. A significant 3-way interaction was found (F = 2.37, df = 6/600, P < 0.029). Therefore, 2-way analyses of variance for Sex and Handedness were performed separately for each factor. Despite the loading of perimeter and axis length with W95-99, this factor was analyzed without these two parameters to assess the nature of the width dimension itself, Significant interaction effects for Sex x Handedness were found for W22-39 (F = 4.79, df = 1/100, P < 0.031) and W49-62 (F = 5.13, df = 1/100, P < 0.026). Among right-handers, females had wider callosa in these two regions than males while among left-handers the converse was true. A significant main effect of Sex favoring males was found for W65-74 (F = 4.04, df = 1/100, P < 0.047). This particular phenomenon extended through the next factor, W77-85, but only at a marginally significant level (F = 3.48, df = 1/100, P < 0.065). When W65-74 and W77-85 were pooled, Sex was significant at the 0.03 level, EVALUATION OF THE 'ISTHMUS' REGION The callosal region covered by Factors W65-74 and W77-85 is in approximately the same place as Witelson's 'isthmus '24. She had reported that an analysis of that region found a significant main effect of Handedness and a Sex × Handedness interaction. Eighty-six percent of her subjects were right-handed writers and were subdivided into consistent and non-consistent right handers (the latter group included 6 left-handed writers). Witelson's interaction finding was that non-consistent righthanded males has a significantly larger isthmus area than the other 3 groups, with consistent right-handed males having the smallest area of the 4 groups. We also classified our right-handed subjects for consistency and non-consistency, to see if we could duplicate Witelson's isthmus findings in the region covered by our factor 5 and 6 combined (W65-85).
Procedure The subjects were given a 5-item handedness questionnaire originally developed by Bryden 2. These items asked the subject to indicate which hand was used for writing, drawing, toothbrushing, throwing a bali, and using scissors 16. Subjects were classified as consistent right-handers (CRH) when all 5 items were performed with the right hand, and non-consistent right-handers
(NCRH) when one or more of the 5 items was performed with the left or both hands (all N C R H were right-handed for writing).
Results The mean callosal widths in the region W65-85 are listed in Table IV along with their standard errors and the N per group. An analysis of variance found significant effects for Sex, Hand Consistency, and their interaction (Fs of 5.42, 6.76, and 4.83 resp.; df = 1/48, P < 0.05). All 3 effects were due to the non-consistent males whose mean width was significantly greater than the widths of the other 3 groups. This interaction is similar to that reported by Witelson. Fig. 3 compares Witelson's and our interaction patterns. DISCUSSION We have demonstrated the ability of our Stereology program and our statistical procedure to both replicate and expand upon some of Kertesz' original findings. Kertesz et al. failed to find significant sex or handedness effects for callosal area or their length parameter, which is equivalent to our L(r) measure. As expected, we replicated these findings. Division of the callosum into multiple width measures and the resulting factor structure enabled us to assess particular callosal regions relative to variables of sex and handedness, and to uncover interactions not revealed in analyses of more global measures such as area, perimeter, and length. Furthermore, the lack of correlation between callosal width measures and brain size (as measured by brain area), a dissociation we also found in the rat 7, establishes that in both species callosal widths are independent of overall brain size. Sex x Handedness (based on writing hand) interactions were found in two factor regions, W22-39 and W49-62, with right-handed females and left-handed males having the larger widths. The functional implication of this finding is difficult to assess, because there is no detailed map relating cailosal location with the cortical site from which the fibers arise for humans. However, such a map has been worked out by Pandya and his associates for the non-human primate 21. Using their maps as a first approximation to the human callosum, the region encompassed by W22-39 includes the pre-motor and supplementary motor areas, while W49-62 involves the somatosensory areas. One empirical finding appears to have been firmly substantiated: namely, the Witelson report that nonconsistent right-handed males have a larger callosal area in the isthmus region than do females and consistent right-handed males. Our replication of that finding (Fig.
131 3) establishes its robustness and is impressive given the considerable differences between the Witelson and the Kertesz samples. First, there are differences in measurement procedure since Witelson's regions were subareas, while ours were averages from clusters of adjacent widths. Second, Witelson's hand preference rating was based on behavioral observation of patients' performance on a 12-item scale which did not include writing, while Kertesz used responses to a questionnaire with only 5 items that included writing. Third, Witelson had some left-handed writers in her NCRH group (6 of 50 were left-handed) while none of the left-handed writers in the Kertesz data set was included in the NCRH group. Fourth, the Witelson data were all obtained post-mortem while Kertesz' data were MRIs. The importance of this distinction has been highlighted by Clarke et al. 4 who have found sex and age differences as a function of MRI vs post-mortem measures of the human corpus callosum. Finally, the composition of the subjects was vastly different with respect to age and health: Witelson's subjects were terminally ill cancer patients (mean age = 50.8 years) while Kertesz' were presumably healthy (mean age = 26.9 years), In sum, 'consistency of hand usage' appears to be an important dimension that needs to be considered in human studies of hand-brain-behavior relationships, Witelson's findings in the isthmus in conjunction with our replication have led us to expand that classification to include consistent and non-consistent left-handers and to examine all the callosal width factors. This analysis, which will be the subject of a separate report, is finding complex sex differences in various regions throughout the callosum, The isthmus area, involving factor regions W65-74 and W77-85, also exhibited sex effects with males having the larger widths. Examination of Table III reveals that the main effect for Sex in these two regions is primarily being carried by the right-handed writing males. Table IV and Fig. 3 show that the non-consistent right-handed males are the deviant group. Therefore, we do not believe the Sex main effect is relevant in this region, but that attention should be focused upon the non-consistent right-handed males (i.e. the interaction). Based upon the Pandya and Seltzer maps, region W65-74 appears to involve the posterior parietal area while W77-85 overlaps the superior and inferior temporal areas. Witelson 24 suggested that the isthmus is probably associated with the posterior language region, which occupies comparable zones in human cortex. The larger size of this region for the non-consistent right-handed males may reflect differences in number of callosal connections, myelinization, cell-packing density, fiber thickness, or some combination of these parameters, none of which is available from MRIs. Another important finding is that the factor structure
of the width measures of the human corpus callosum is quite similar to that of the rat. In both instances 7 factors were extracted with considerable degree of overlap. In one sense this is not suprising since there are similarities in callosal organization between the two species. Interhemispheric fibers from the visual area course through the posterior of the callosum 3'6A9'2°, ones from the somatosensory area go through the body 6'14, while fibers from the frontal area go through the anterior portion 6'2°. Whether any or all of the 7 overlapping factors represent analogies or homologies between the two species awaits further experimental investigation. In light of the sex differences found with the rat in the anterior and posterior portions of the callosum 1'7'9, and some of the reports in the human literature concerning sex differences in the rostrum/genu 4'24 and in the splenium 5'13, we expected to find effects in these regions. Our failure to do so could be attributed to parametric differences between the Kertesz sample and other sampies where sex differences have been reported (e.g. age, health, handedness, measurement procedure, method of obtaining the original tracing). However, this seems most unlikely since we did find a close match to Witelson's isthmus data despite the presence of these contaminating variables. Thus, the isthmus effect appears to be quite stable when sex and handedness are taken into account. In contrast, effects associated with the splenium and genu appear to be quite effervescent in light of the many conflicting reports in the literature. Perhaps more attention needs to be paid to the body of the callosum. There are two major benefits from our approach to callosal measurement. First, percentile scaling of widths along the medial axis of the callosum has been shown to eliminate major differences in morphological geometry between the human and the rat 8. Therefore this form of scaling is applicable for cross-species comparisons; for intraspecific developmental studies; and for the study of different clinical groups such as schizophrenics 18"22'23, alcoholics 12, and Alzheimer's patients 25 known to vary in gross callosal morphology. The second benefit is that our factor analysis approach gives a more satisfactory solution to the question of regional specificity within the callosum than the procedures used to date of dividing the callosum into halves, thirds, fourths, or fifths. Researchers have in the past used L(r) (see Fig. 1B) as the basis for making the divisions, yet this measure does not take into account the amount of genu folded underneath the caUosum. The flaws in this approach have also been emphasized by Clarke et al. 4. Finally, our multiple measurement and factor analytic approach has introduced a new and more informative methodology for the investigation of the corpus callosum,
132 w h i c h s h o u l d h e l p a d v a n c e the u n d e r s t a n d i n g of b r a i n b e h a v i o r processes,
Acknowledgements. We thank Garvin Boudle for photographing and enlarging the MRI tracings.
REFERENCES
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