Brain Research, 93 (1975) 241-252
241
(© Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
S T R U C T U R A L O R G A N I Z A T I O N OF ' C A L L C S A L ' OBg IN H U M A N C O R P U S CALLOSUM AGENESIS
K A Z U H I K O S H O U M U R A , TAKASHI A N D O AND K A Z U O K A T O
Departments ofAnatomy, Pathology and Surgery, GifuUniversitySchoolofMedicme, Tsukasamach# 40, Gifu500 (Japan) (Accepted February 28th, 1975)
SUMMARY
The structural organization of the 'callosal' OBg was studied in Nissl and Well stained sections of two human brains completely lacking in the corpus callosum. OBg of the normal brain contains a set of distinctive large pyramidal cells in layer I11. By contrast, in the brains with absence of the corpus callosum, layer III of OBg contained a slightly reduced number of smaller pyramidal cells than normal, and the characteristic large pyramidal cells were scarsely detectable. Other layers of OBg were not definitely changed. Furthermore, 'acallosal' striate cortex revealed no specific changes. From these observations, it was suggested that the large layer III pyramids of OBg might be closely related to callosal connections.
INTRODUCTION
In the previous study 14, we have shown that the transition zone between area 17 and 18 of the cat is especially dense in 'callosal' connections (interhemispheric connections via the corpus callosum) and that in this narrow zone of the cortex there are several large pyramidal cells of layer Ill. This layer does not only give rise to many callosal fibers but receives a large amount of their terminals as well. F r o m these observations we consider that these large pyramidal cells are very related to callosal connections. Callcsal connections of areas 17, 18 and 19 (ref. 17) of monkeys are limited to the narrow cortical zone (OB7 of von Economo6; OBg of von Bonin2; juxtastriate area 18 of Myers 11) of area 18 adjacent to area 17 with some extension into the latter, and to the anterior limit of area 194,9,11,18 . These observations have been obtained by unilateral large ablation of the occipital cortex or section of the corpus callosum. In our preliminary experiments in macaque monkeys which received unilateral lesions
242 affecting OBg, this region of the cerebral cortex sends a large amotmt of callosat fibers to the corresponding part of the cortex and a smaller amount of fibers to the anterior limit of area 19 and the posterior bank of the superior temporal sulcus on the opposite side (see also ref. 19). It is, thus, strongly suggested that OBg is a specialized zone of the cortex which is relevant to interhemispheric transfer of visual information. In cytoarchitecture, OBg of monkeys and man is characterized by the outstanding large pyramidal cells of layer Ille, 6 like those in the transition zone between area 17 and 18 of the cat H. Although over 100 cases of human corpus callosum agenesis have been reported, there are only a few studies in which an account is made of the cortical structure of these brains (see refs. 10 and 15 for review of the literature). In the present study, we analyze the structural organization of OBg in two human brains lacking in the corpus callosum with special reference to the above mentioned large pyramidal cells of layer III. MATERIALS AND METHODS
Case 1
This female infant was the second-born of a 25-year-old mother, who had been diagnosed as schizophrenic, Delivery occurred about 60 days before the term. Birth weight was 2950 g, Shortly after birth she was noted for poor sucking. Later, several developmental disturbances became apparent. Insufficient fixation o f the neck persisted throughout her short life, and even at 1 year of age she could neither roll nor sit alone (quadriparesis). At the age o f 2 years and 10 months, she died of acute pneumonia, which might be caused in part by weak gag and cough reflexes. Case 2
This female infant was the first-born of a 27-year-old mother, and the product of a full-term pregnancy complicated by polyhydroamnios. Birth weight was 1850 g. She needed tube feeding because of poor sucking and swallowing. Her physical development was hopelessly restrained and she died 115 days after birth by severe disturbance of nutrition; severe anemia and weight loss, 1280 g at the time of autopsy, in which retarded growth of various visceral organs and multiple erosion of the small intestine was observed. In either case. the brain revealed complete agenesis of the corpus callosum. After gross examination of the brains, the whole brain of case 2 and the relevant blocks of the brain of case 1 including the parietal and occipital lobes were dehydrated and embedded in celloidin. Brains were sectioned at 30/~m in coronal planes except for the occipital lobe of one hemisphere of case 2, which was sectioned horizontally. Each half of serial sections was stained with cresyl-violet for Nissl substance or by the method of Weil for myelinated fibers. In addition, several 30-,urn thick Nissl sections from the normal brains of a 50-year-old woman and a 3-month-old mate infant, and from a microencepha~ic brain
243
Fig. 1. Corpus callosum agenesis, case 1. A: medial aspect of the right cerebral hemisphere. B-F: representative coronal planes of the brain. Abbreviations: R, right cerebral hemisphere; ac, anterior commissure; ai, adhesio interthalamica; cal, calcarine sulcus; cf. column of fornix; ci, cingulate gyrus; f, fornix; fi, fimbria hippocampi; ig, indusium griseum; po, parieto-occipital sulcus; pt, paraterminal gyrus; sc, area subcallosa; sp, subparietal sulcus.
244
Fig. 2. Corpus callosum agenesis, case 2. A: medial aspect of the right cerebral hemisphere: n this photograph, anterior commissure and paraterminal gyrus are not distinguishable from the surrounding structure, but are identified in coronal planes. Abbreviations are the same as those in Fig. I. B: left cerebral hemisphere, Weil stain. Abbreviations: cd, caudate nucleus; ci, cingulatc gyrus; pc, posterior commissure. C and D: Weil (C) and Nissl (D) stained sections at the level of B, showing a small cluster of neurons of indusium griseum (ig), a small bundle of poorly myelinated longitudinal fibers, probably, striae of Lancisi (sL), and fornix-aberrant callosal fiber complex (fc). The choroid plexus of the lateral ventricle has been torn off by handling.
245 (210 g) of a newborn infant with normal corpus callosum were used for the comparative studies.
RESULTS
(1) Gross appearance of the brains Brains of both cases are small (microencephaly), 710 g in case 1 and 280 g in case 2. They are characterized by foreshortening of the frontal, and in case 2 also the parietal, cortices and are completely lacking in the corpus callosum (Figs. 1A and 2A). The olfactory bulbi and tracts, optic chiasma and the anterior commissure (Fig. I C) appear normal. The lateral surfaces of both brains show no marked changes in gyral patterns. However, on the medial surfaces, the right cingulate sulcus of either brain is lacking in the pars marginalis, and in case 2 the subparietal sulcus is also missing. Therefore, the caudal cingulate gyrus is fused with the overlying paracentral lobule and the precuneus to form a dorsoventrally elongated and radially arranged convolution (Figs. IA and 2A). In case 2, the parieto-occipital sulcus of either side does not meet with the calcarine sulcus (Fig. 2A). In coronal planes, it is apparent that the longitudinal cerebral fissure is extended ventrally and communicates with the transverse fissure (Fig. I D and E). Furthermore, the third ventricle is dilated dorsally and the foramen of Monro is enlarged (Fig. I C). At the levels of the optic chiasma and the anteric.r commissure, the paraterminal gyrus continues dorsolaterally bordering medially the anterior horn of the lateral ventricle to attach ventrolateral to the cingulate gyrus, and the anterior horn provides a slit-like appearance (Fig. 1B). The dorsomedial wall of the anterior horn is, according to Loeser and Alvord 10, the septum pellucidum in the acallosal brain. The column of the fornix of either side is far apart from the other and between them stretches a thin plate-like structure (Fig. 1C), which may correspond with the dorsal part of the 'primitive' lamina terminalis (commissural plate) where, in normal brains, the corpus callosum develops. Two halves of the body of the fornix are also separated throughout their course and the fornicate cc.mmissure is absent (Figs. 1D, E and 2B). Between the fornix and the cingulate gyrus runs the sulcus of the corpus callosum which, in normal brains, borders between the cingulate gyrus and the corpus callosum. In the bottom of the sulcus of the corpus callosum is located the gray which is the caudal continuity of the paraterminal gyrus - - indusium griseum (Figs. 1C, D, E and 2D). The fornix in case 1 is a sheet of white matter attached to the gray of the indusium griseum (Fig. 1C, D, E). In case 2, a club-shaped process of white matter protrudes from the dorsal wall of the lateral ventricle (Fig. 2B, C and D). In Wellstained sections, this protrusion seems to contain not only the fornix but other fiber bundles as well, such as the longitudinal striae of Lancisi and some aberrant callosal fibers known as 'Balkenl~ingsbfindel' of Probst 13, although their boundaries cannot be defined clearly (Fig. 2C). More caudally, the fornix and the indusium griseum can be traced, as in normal brains, to the fimbria hippocampi (Fig. 1F) and the poorly developed dentate gyrus respectively. In addition, in case 1, the third ventricle and
Fig. 3. The border region between the striate (Str.) and OBg cortices. A: 3-month-old normal infanl ; note several typical large pyramidal cells (encircled) in the deeper portion of layer IH of OBg. l~: corpus callosum agenesis, case I C: case 2. Nissl stain with cresyl-,Aolet.
247
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Fig. 4. Layer Ill of the striate (A, C, E) and OBg (B, D, F) cortices from a 50-year-old normal woman (A and B), 3-month-old normal infant (C, D) and microencephalic newborn infant (E, F). Nissl stain with cresyl-violet. bilateral posterior horns of the lateral ventricle are considerably dilated (Fig. 1D, E and F).
(2) Structure of the striate and OBg cortices The striate cortex of case 1 shows approximately normal width (1.4- 1.6 ram). However, the striate cortex of case 2 is much thinner than normal (1.2 1.3 ram). in both brains, 6 cortical layers are distinguishable although in case 1 the limits of layer Ill are slightly indistinct (Fig. 3B and C). The thickness (or the relative thickness in case 2) of each lamina appears normal. The internal granular layer shows its normal
248
Fig. 5. Layer IIl of the striate (A C) and OBg (B, D) cortices from corpus callosum agenesis case 1 (A, B) and case 2 (C, D). Nissl stain with cresyl-violet.
249 subdivision into 3 sublayers of IVA, IVB and IVC 3. Furthermore, layer IVC can be divided into the more superficial IVCa and the deeper IVCfla2; this is more apparent in case 2 (Fig. 3C). Neurons of the striate cortex of case 1 show no obvious changes (Fig. 5A). However, in case 2, each lamina of the striate cortex contains smaller and more densely arranged neurons than normal (compare Fig. 5C with Fig. 4C). Furthermore, several neurons of the striate cortex of case 2 are swollen and chromatolytic, and some others are shrunk and stained darkly (Fig. 5C); these degenerative changes are found in various layers and over extensive regions of the cerebral cortex including OBg (Fig. 5D), so they may be attributable to other pathologic conditions, such as hypoxia caused by severe anemia, than the absence of the corpus callosum. In either case, layer VI is well developed and contains densely arranged medium sized neurons (Fig. 3B and C). OBg of both brains shows no marked alterations in the cortical lamination except that OBg of case 2 is much thinner than normal and that in both cases the limits of layer 111 are less sharply defined than normal (Fig. 3B and C). The thickness (or the relative thickness in case 2) of each lamina is not so definitely changed. In both brains, the most conspicuous structural alterations are observed in layer III. This layer contains mostly smaller neurons (4-7 #m) than normal which are comparable to layer l lI neurons of the striate cortex in their size, and the characteristic large pyramidal cells are scarsely detectable (Fig. 5B and D). By contrast, in the brain of a 3-month-old normal infant, layer llI of OBg contains several large pyramidal cells (7-10/~m, Fig. 4D) and is indicative of their proper growth and maturation into the giant pyramidal cells as seen in OBg of the normal adult brain (Fig. 4B). Furthermore, even in the microencephalic brain of a newborn infant with normal corpus callosum, layer IIl of OBg contains apparently larger neurons (3-4/~m, Fig. 4F) than those of the striate cortex (2-3/,m, Fig. 4E), although the size of neurons is considerably small. Thus, we cannot detect any definite sign of the characteristic neuronal development in layer i I I of OBg of the brains with absence of the corpus callosum. In both cases, other layers of OBg reveal less marked changes. Layers II and IV are filled with many small neurons. There are many medium-sized neurons in layer V, but no definite changes are detectable. Layer VI is as well developed as that of the striate cortex and contains largest neurons among each layer. In Well-stained sections, fibers of the optic (visual) radiations are sufficiently stained and can be traced into the internal granular layer of the striate cortex, whereas the callcsal radiations .6 are not apparent. The anterior limit of area 19 which is another callosal zone of the visual cortex has not been clearly defined in cytoarchitecture 17. This region of the cerebral cortex does not exhibit such an outstanding feature as seen in OBg. In the present study, the anterior limit of area 19 could not be sufficiently identified. Therefore, this region of the cerebral cortex was not referred for detailed analysis. Lastly, bilateral cerebral pedunculi of case 1 are severely atrophic and this fits with the observation that the precentral gyri of both hemispheres are lacking in the characteristic giant pyramids of layer V and contain mostly a reduced number of smaller neurons. Again, layer Ill of this region of the cerebral cortex is filled with small neurons.
250 DISCUSSION
The findings obtained by us through anterograde degeneration studies (see Introduction) and by other authors 4,9,11,1s,19 in monkeys indicate that OBg is a specialized zone of the cortex which sends and receives callosal fibers. In viewing the general concept that each field of the cerebral cortex is a sector possessing certain cytoarchitectonic characteristics by which it is defined, and that the cytoarchitectonic differences describe the differences in neuronal connections, the following question arises. What kind of structural variant of the cortex is responsible for callosal connections of areas 17, 18 and 19 being so highly heterogeneous, and restricted to the narrow cortical zones of OBg and the anterior limit of area 19? The callosal OBg differs from the rest of area 18 in that it contains outstanding large pyramidal cells in layer 1112,6. From the present observations in human corpus callosum agenesis, it is suggested that large layer Ill pyramids of OBg may be much related to callosal connections. This receives strong support from the recent study of Glickstein and Whitteridge 7, who found that OBg large pyramids of macaque monkeys were shrunk and reduced in number following section of the corpus callosum. In the normal brain, there also exist small- to medium-sized neurons in layer Ill of OBg (Fig. 4B and D). However, these neurons seem less seriously affected by the absence of the corpus callosum, since in the present brain a moderate population of them with approximately normal appearance is detectable in layer III of OBg (Fig. 5B). An important comment upon the present study has been provided by Van Valkenburg 16. He described that in agenesis of the corpus callosum, there are generally other developmental disturbances in the brain which make it very difficult to arrive at definite conclusions. Two brains examined in this study are microencephalic and there are several abnormal running of the cerebral sulci and gyri. In gross appearance, the smallness of these brains seems to be caused largely by foreshortening of the frontal and parietal cortices, and the occipital cortex seems less seriously disturbed except that in case 2 the parieto-occipital sulcus does not meet with the calcarine sulcus. Furthermore, the laminar structure and neurons of the 'acallosal' striate cortex show no specific changes. In addition, the extent and location of the striate cortex which was reconstructed using serial N issl sections appear within normal limits; this was examined with reference to the study of Polyak 12. Despite these observations, one may make a comment that the brain of case 2 is considerably small, and the striate and OBg cortices are much thinner than normal indicating diffuse retardation of neuronal development. This is true; however, the following observations should be emphasized. When the corpus catlosum is normally developed, even though the brain is microencephalic, layer Ill of OBg contains apparently larger neurons than those of the striate cortex although their size is considerably small. Van Valkenburg TM further described that when no other disturbances are present, the difficulty remains as to whether the corpus callosum was actually absent, or whether it had not reached the opposite hemisphere. The anterior commissure has been shown relevant to interhemispheric transmission of the visual information (,see review by Doty et al.Z). There are several anatomical evidences indicating that the
251 cortical projections of the anterior commissure of monkeys are limited to the temporal regions of the cerebral cortex 2°. Furthermore, in the previous study 14, we could not detect any degenerated fibers in the anterior commissure following unilateral large ablation of areas 17, 18 and 19 o f the cat. Therefore, it is very probable that the anterior commissure contribution to visual function is largely by connecting the temporal visual region o f either side rather than 'direct' interhemispheric connections of areas 17, 18 and 19. However, in several cases of corpus callosum agenesis, hypertrophy of the anterior commissure has been notedL q~he hypertrophic anterior commissure may describe the possibility that some aberrant callosal fibers from areas 17, 18 and 19 arrive at the oppesite hemisphere via the anterior commissure. In the present cases, this seems unlikely because the anterior commissure shows approximately normal appearance. Because of the reasons discussed above, we consider that the absence of large layer III pyramids from OBg of the brains presented in this account may be largely attributable to the absence of the corpus callosum. Unfortunately, the brains examined in this study are those o f infants and it seems necessary to evaluate the present observations further in adult cases of corpus callosum agenesis. In addition, Akert et al. 1 found in the biolzsied postcentral cortex of a 26-year-old woman, who had been proved lacking in the corpus callcsum by pneumoencephalography, that layer II1 was considerably reduced in width and pyramidal cells of this layer were smaller than normal, while other layers revealed less marked changes. ACKNOWLEDGEMENTS The authors are grateful to Profs. A. Ojima, I. H i r o n o and Dr. I. Sasaoka, Department of Pathology, Gifu University School of Medicine, and Dr. A. Aoki, Laboratory of Pathology, Gifu Prefectural Hospital for their kind allowance to examine the brains presented in this report.
REFERENCES I AKERT, K., PULETT1, F., AND ERICKSON, T. C., Abnormalities of the cerebral cortex associated with agenesis of corpus callosum and focal cortical seizures, Trans. Amer. neurol. Ass., 79 (1954) 151 153. 2 BON1N,G. vorq, The striate area of primates, J. comp. NeuroL, 77 (1942) 405-429. 3 BRODMANN,K., Beitrfi,ge zur histologischen Lokalisation der Grosshirnrinde. Dritte Mitteilung. Die Rindenfclder der niederen Affen, J. Psychol. Neurol. (Lpz.), 4 (1905) 177 226. 4 CRAGG, B. G., The topography of the afferent projections in the circumstriate visual cortex of the monkey studied by the Nauta method, Vision Res., 9 (1969) 733-747. 5 DOTY, R. W., NEGRO,O, N., AND PAULO,S., Forebrain commissures and vision. In R. JUNG(Ed.), Handbook o f Sensory Physiology, Vol. VII/3B, Springer, Berlin, 1973, pp. 543-582. 6 ECONOMO,C. YON,Ze[laufbau der Grosshirnrinde des Menschen, Springer, Berlin, 1927, pp. 84 95. 7 GLICKSTEIN, M., AND WHITTERIDGE, D., Degeneration of layer III pyramidal cells in area 18 following destruction of callosal input, Anat. Rec., 178 (1974) 362 363. 8 ITO, M., YASHIKI,K., AND HIRATA, T., Agenesis of the corpus callosum in man, Acta anat. nippon, 47 0972) 391-402.
252 9 KAROL, E. A., AND PANDYA, D. N., The distribution of the corpus callosum in the rhesus monkey, Brain, 94 (1971l 471-486. 10 LOESER,J. D., AND ALVORD,E. C., JR., Agenesis of the corpus callosum, Brain, 91 0968) 553 ~570. 11 MYERS,R. E., Commissural connections between occipital lobes of the monkey, J. comp. Neurol., 118 (1962) 1-16. 12 POLYAK,S., The Vertebrate Visual System, Univ. Chicago Press, Chicago, Ill., 1957, pp. 446-539: 13 PROaST, M., Ueber den Bau des vollst~.ndig balkenlosen Grosshirnes, sowie fiber Mikrogyrie und Heterotopie der grauen Substanz, Arch. Psychiat. Nervenkr., 34 0901) 709--786. 14 SHOtJMURA, K., An attempt to relate the origin and distribution of commissural fibers to the presence of large and medium pyramids in layer III in the cat's visual cortex, Brain Research, 67 0974) 13-25. 15 SLAGER, U. T., KELLY, A. B., AND WAGNER, J. A., Congenital absence of the corpus callosum; report of a case and review of the literature, New Engl. J. Med., 256 (1957) 1171-1176. 16 VAN VALKENBURG,C. T., Experimental and pathologico-anatomical researches on the corpus callosum, Brain, 36 (1913) 119-165. 17 ZEK1, S. M., The secondary visual areas of the monkey, Brain Research, 13 (1969) 197-226. 18 ZEKI, S. M., Interhemispheric connections of prestriate cortex in monkey, Brain Research, 19 (1970) 63-75. 19 ZEKI, S. M., Cortical projections from two prestriate areas in the monkey, Brain Research, 34 (1971) 19-35. 20 ZEK~, S. M., Comparison of the cortical degeneration in the visual regions of the temporal lobe of the monkey following section of the anterior commissure and the splenium, J. comp. Neurot., 148 (1973) 167-176.
241
(© Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
S T R U C T U R A L O R G A N I Z A T I O N OF ' C A L L C S A L ' OBg IN H U M A N C O R P U S CALLOSUM AGENESIS
K A Z U H I K O S H O U M U R A , TAKASHI A N D O AND K A Z U O K A T O
Departments ofAnatomy, Pathology and Surgery, GifuUniversitySchoolofMedicme, Tsukasamach# 40, Gifu500 (Japan) (Accepted February 28th, 1975)
SUMMARY
The structural organization of the 'callosal' OBg was studied in Nissl and Well stained sections of two human brains completely lacking in the corpus callosum. OBg of the normal brain contains a set of distinctive large pyramidal cells in layer I11. By contrast, in the brains with absence of the corpus callosum, layer III of OBg contained a slightly reduced number of smaller pyramidal cells than normal, and the characteristic large pyramidal cells were scarsely detectable. Other layers of OBg were not definitely changed. Furthermore, 'acallosal' striate cortex revealed no specific changes. From these observations, it was suggested that the large layer III pyramids of OBg might be closely related to callosal connections.
INTRODUCTION
In the previous study 14, we have shown that the transition zone between area 17 and 18 of the cat is especially dense in 'callosal' connections (interhemispheric connections via the corpus callosum) and that in this narrow zone of the cortex there are several large pyramidal cells of layer Ill. This layer does not only give rise to many callosal fibers but receives a large amount of their terminals as well. F r o m these observations we consider that these large pyramidal cells are very related to callosal connections. Callcsal connections of areas 17, 18 and 19 (ref. 17) of monkeys are limited to the narrow cortical zone (OB7 of von Economo6; OBg of von Bonin2; juxtastriate area 18 of Myers 11) of area 18 adjacent to area 17 with some extension into the latter, and to the anterior limit of area 194,9,11,18 . These observations have been obtained by unilateral large ablation of the occipital cortex or section of the corpus callosum. In our preliminary experiments in macaque monkeys which received unilateral lesions
242 affecting OBg, this region of the cerebral cortex sends a large amotmt of callosat fibers to the corresponding part of the cortex and a smaller amount of fibers to the anterior limit of area 19 and the posterior bank of the superior temporal sulcus on the opposite side (see also ref. 19). It is, thus, strongly suggested that OBg is a specialized zone of the cortex which is relevant to interhemispheric transfer of visual information. In cytoarchitecture, OBg of monkeys and man is characterized by the outstanding large pyramidal cells of layer Ille, 6 like those in the transition zone between area 17 and 18 of the cat H. Although over 100 cases of human corpus callosum agenesis have been reported, there are only a few studies in which an account is made of the cortical structure of these brains (see refs. 10 and 15 for review of the literature). In the present study, we analyze the structural organization of OBg in two human brains lacking in the corpus callosum with special reference to the above mentioned large pyramidal cells of layer III. MATERIALS AND METHODS
Case 1
This female infant was the second-born of a 25-year-old mother, who had been diagnosed as schizophrenic, Delivery occurred about 60 days before the term. Birth weight was 2950 g, Shortly after birth she was noted for poor sucking. Later, several developmental disturbances became apparent. Insufficient fixation o f the neck persisted throughout her short life, and even at 1 year of age she could neither roll nor sit alone (quadriparesis). At the age o f 2 years and 10 months, she died of acute pneumonia, which might be caused in part by weak gag and cough reflexes. Case 2
This female infant was the first-born of a 27-year-old mother, and the product of a full-term pregnancy complicated by polyhydroamnios. Birth weight was 1850 g. She needed tube feeding because of poor sucking and swallowing. Her physical development was hopelessly restrained and she died 115 days after birth by severe disturbance of nutrition; severe anemia and weight loss, 1280 g at the time of autopsy, in which retarded growth of various visceral organs and multiple erosion of the small intestine was observed. In either case. the brain revealed complete agenesis of the corpus callosum. After gross examination of the brains, the whole brain of case 2 and the relevant blocks of the brain of case 1 including the parietal and occipital lobes were dehydrated and embedded in celloidin. Brains were sectioned at 30/~m in coronal planes except for the occipital lobe of one hemisphere of case 2, which was sectioned horizontally. Each half of serial sections was stained with cresyl-violet for Nissl substance or by the method of Weil for myelinated fibers. In addition, several 30-,urn thick Nissl sections from the normal brains of a 50-year-old woman and a 3-month-old mate infant, and from a microencepha~ic brain
243
Fig. 1. Corpus callosum agenesis, case 1. A: medial aspect of the right cerebral hemisphere. B-F: representative coronal planes of the brain. Abbreviations: R, right cerebral hemisphere; ac, anterior commissure; ai, adhesio interthalamica; cal, calcarine sulcus; cf. column of fornix; ci, cingulate gyrus; f, fornix; fi, fimbria hippocampi; ig, indusium griseum; po, parieto-occipital sulcus; pt, paraterminal gyrus; sc, area subcallosa; sp, subparietal sulcus.
244
Fig. 2. Corpus callosum agenesis, case 2. A: medial aspect of the right cerebral hemisphere: n this photograph, anterior commissure and paraterminal gyrus are not distinguishable from the surrounding structure, but are identified in coronal planes. Abbreviations are the same as those in Fig. I. B: left cerebral hemisphere, Weil stain. Abbreviations: cd, caudate nucleus; ci, cingulatc gyrus; pc, posterior commissure. C and D: Weil (C) and Nissl (D) stained sections at the level of B, showing a small cluster of neurons of indusium griseum (ig), a small bundle of poorly myelinated longitudinal fibers, probably, striae of Lancisi (sL), and fornix-aberrant callosal fiber complex (fc). The choroid plexus of the lateral ventricle has been torn off by handling.
245 (210 g) of a newborn infant with normal corpus callosum were used for the comparative studies.
RESULTS
(1) Gross appearance of the brains Brains of both cases are small (microencephaly), 710 g in case 1 and 280 g in case 2. They are characterized by foreshortening of the frontal, and in case 2 also the parietal, cortices and are completely lacking in the corpus callosum (Figs. 1A and 2A). The olfactory bulbi and tracts, optic chiasma and the anterior commissure (Fig. I C) appear normal. The lateral surfaces of both brains show no marked changes in gyral patterns. However, on the medial surfaces, the right cingulate sulcus of either brain is lacking in the pars marginalis, and in case 2 the subparietal sulcus is also missing. Therefore, the caudal cingulate gyrus is fused with the overlying paracentral lobule and the precuneus to form a dorsoventrally elongated and radially arranged convolution (Figs. IA and 2A). In case 2, the parieto-occipital sulcus of either side does not meet with the calcarine sulcus (Fig. 2A). In coronal planes, it is apparent that the longitudinal cerebral fissure is extended ventrally and communicates with the transverse fissure (Fig. I D and E). Furthermore, the third ventricle is dilated dorsally and the foramen of Monro is enlarged (Fig. I C). At the levels of the optic chiasma and the anteric.r commissure, the paraterminal gyrus continues dorsolaterally bordering medially the anterior horn of the lateral ventricle to attach ventrolateral to the cingulate gyrus, and the anterior horn provides a slit-like appearance (Fig. 1B). The dorsomedial wall of the anterior horn is, according to Loeser and Alvord 10, the septum pellucidum in the acallosal brain. The column of the fornix of either side is far apart from the other and between them stretches a thin plate-like structure (Fig. 1C), which may correspond with the dorsal part of the 'primitive' lamina terminalis (commissural plate) where, in normal brains, the corpus callosum develops. Two halves of the body of the fornix are also separated throughout their course and the fornicate cc.mmissure is absent (Figs. 1D, E and 2B). Between the fornix and the cingulate gyrus runs the sulcus of the corpus callosum which, in normal brains, borders between the cingulate gyrus and the corpus callosum. In the bottom of the sulcus of the corpus callosum is located the gray which is the caudal continuity of the paraterminal gyrus - - indusium griseum (Figs. 1C, D, E and 2D). The fornix in case 1 is a sheet of white matter attached to the gray of the indusium griseum (Fig. 1C, D, E). In case 2, a club-shaped process of white matter protrudes from the dorsal wall of the lateral ventricle (Fig. 2B, C and D). In Wellstained sections, this protrusion seems to contain not only the fornix but other fiber bundles as well, such as the longitudinal striae of Lancisi and some aberrant callosal fibers known as 'Balkenl~ingsbfindel' of Probst 13, although their boundaries cannot be defined clearly (Fig. 2C). More caudally, the fornix and the indusium griseum can be traced, as in normal brains, to the fimbria hippocampi (Fig. 1F) and the poorly developed dentate gyrus respectively. In addition, in case 1, the third ventricle and
Fig. 3. The border region between the striate (Str.) and OBg cortices. A: 3-month-old normal infanl ; note several typical large pyramidal cells (encircled) in the deeper portion of layer IH of OBg. l~: corpus callosum agenesis, case I C: case 2. Nissl stain with cresyl-,Aolet.
247
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~50p, ~~
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i~
f
Fig. 4. Layer Ill of the striate (A, C, E) and OBg (B, D, F) cortices from a 50-year-old normal woman (A and B), 3-month-old normal infant (C, D) and microencephalic newborn infant (E, F). Nissl stain with cresyl-violet. bilateral posterior horns of the lateral ventricle are considerably dilated (Fig. 1D, E and F).
(2) Structure of the striate and OBg cortices The striate cortex of case 1 shows approximately normal width (1.4- 1.6 ram). However, the striate cortex of case 2 is much thinner than normal (1.2 1.3 ram). in both brains, 6 cortical layers are distinguishable although in case 1 the limits of layer Ill are slightly indistinct (Fig. 3B and C). The thickness (or the relative thickness in case 2) of each lamina appears normal. The internal granular layer shows its normal
248
Fig. 5. Layer IIl of the striate (A C) and OBg (B, D) cortices from corpus callosum agenesis case 1 (A, B) and case 2 (C, D). Nissl stain with cresyl-violet.
249 subdivision into 3 sublayers of IVA, IVB and IVC 3. Furthermore, layer IVC can be divided into the more superficial IVCa and the deeper IVCfla2; this is more apparent in case 2 (Fig. 3C). Neurons of the striate cortex of case 1 show no obvious changes (Fig. 5A). However, in case 2, each lamina of the striate cortex contains smaller and more densely arranged neurons than normal (compare Fig. 5C with Fig. 4C). Furthermore, several neurons of the striate cortex of case 2 are swollen and chromatolytic, and some others are shrunk and stained darkly (Fig. 5C); these degenerative changes are found in various layers and over extensive regions of the cerebral cortex including OBg (Fig. 5D), so they may be attributable to other pathologic conditions, such as hypoxia caused by severe anemia, than the absence of the corpus callosum. In either case, layer VI is well developed and contains densely arranged medium sized neurons (Fig. 3B and C). OBg of both brains shows no marked alterations in the cortical lamination except that OBg of case 2 is much thinner than normal and that in both cases the limits of layer 111 are less sharply defined than normal (Fig. 3B and C). The thickness (or the relative thickness in case 2) of each lamina is not so definitely changed. In both brains, the most conspicuous structural alterations are observed in layer III. This layer contains mostly smaller neurons (4-7 #m) than normal which are comparable to layer l lI neurons of the striate cortex in their size, and the characteristic large pyramidal cells are scarsely detectable (Fig. 5B and D). By contrast, in the brain of a 3-month-old normal infant, layer llI of OBg contains several large pyramidal cells (7-10/~m, Fig. 4D) and is indicative of their proper growth and maturation into the giant pyramidal cells as seen in OBg of the normal adult brain (Fig. 4B). Furthermore, even in the microencephalic brain of a newborn infant with normal corpus callosum, layer IIl of OBg contains apparently larger neurons (3-4/~m, Fig. 4F) than those of the striate cortex (2-3/,m, Fig. 4E), although the size of neurons is considerably small. Thus, we cannot detect any definite sign of the characteristic neuronal development in layer i I I of OBg of the brains with absence of the corpus callosum. In both cases, other layers of OBg reveal less marked changes. Layers II and IV are filled with many small neurons. There are many medium-sized neurons in layer V, but no definite changes are detectable. Layer VI is as well developed as that of the striate cortex and contains largest neurons among each layer. In Well-stained sections, fibers of the optic (visual) radiations are sufficiently stained and can be traced into the internal granular layer of the striate cortex, whereas the callcsal radiations .6 are not apparent. The anterior limit of area 19 which is another callosal zone of the visual cortex has not been clearly defined in cytoarchitecture 17. This region of the cerebral cortex does not exhibit such an outstanding feature as seen in OBg. In the present study, the anterior limit of area 19 could not be sufficiently identified. Therefore, this region of the cerebral cortex was not referred for detailed analysis. Lastly, bilateral cerebral pedunculi of case 1 are severely atrophic and this fits with the observation that the precentral gyri of both hemispheres are lacking in the characteristic giant pyramids of layer V and contain mostly a reduced number of smaller neurons. Again, layer Ill of this region of the cerebral cortex is filled with small neurons.
250 DISCUSSION
The findings obtained by us through anterograde degeneration studies (see Introduction) and by other authors 4,9,11,1s,19 in monkeys indicate that OBg is a specialized zone of the cortex which sends and receives callosal fibers. In viewing the general concept that each field of the cerebral cortex is a sector possessing certain cytoarchitectonic characteristics by which it is defined, and that the cytoarchitectonic differences describe the differences in neuronal connections, the following question arises. What kind of structural variant of the cortex is responsible for callosal connections of areas 17, 18 and 19 being so highly heterogeneous, and restricted to the narrow cortical zones of OBg and the anterior limit of area 19? The callosal OBg differs from the rest of area 18 in that it contains outstanding large pyramidal cells in layer 1112,6. From the present observations in human corpus callosum agenesis, it is suggested that large layer Ill pyramids of OBg may be much related to callosal connections. This receives strong support from the recent study of Glickstein and Whitteridge 7, who found that OBg large pyramids of macaque monkeys were shrunk and reduced in number following section of the corpus callosum. In the normal brain, there also exist small- to medium-sized neurons in layer Ill of OBg (Fig. 4B and D). However, these neurons seem less seriously affected by the absence of the corpus callosum, since in the present brain a moderate population of them with approximately normal appearance is detectable in layer III of OBg (Fig. 5B). An important comment upon the present study has been provided by Van Valkenburg 16. He described that in agenesis of the corpus callosum, there are generally other developmental disturbances in the brain which make it very difficult to arrive at definite conclusions. Two brains examined in this study are microencephalic and there are several abnormal running of the cerebral sulci and gyri. In gross appearance, the smallness of these brains seems to be caused largely by foreshortening of the frontal and parietal cortices, and the occipital cortex seems less seriously disturbed except that in case 2 the parieto-occipital sulcus does not meet with the calcarine sulcus. Furthermore, the laminar structure and neurons of the 'acallosal' striate cortex show no specific changes. In addition, the extent and location of the striate cortex which was reconstructed using serial N issl sections appear within normal limits; this was examined with reference to the study of Polyak 12. Despite these observations, one may make a comment that the brain of case 2 is considerably small, and the striate and OBg cortices are much thinner than normal indicating diffuse retardation of neuronal development. This is true; however, the following observations should be emphasized. When the corpus catlosum is normally developed, even though the brain is microencephalic, layer Ill of OBg contains apparently larger neurons than those of the striate cortex although their size is considerably small. Van Valkenburg TM further described that when no other disturbances are present, the difficulty remains as to whether the corpus callosum was actually absent, or whether it had not reached the opposite hemisphere. The anterior commissure has been shown relevant to interhemispheric transmission of the visual information (,see review by Doty et al.Z). There are several anatomical evidences indicating that the
251 cortical projections of the anterior commissure of monkeys are limited to the temporal regions of the cerebral cortex 2°. Furthermore, in the previous study 14, we could not detect any degenerated fibers in the anterior commissure following unilateral large ablation of areas 17, 18 and 19 o f the cat. Therefore, it is very probable that the anterior commissure contribution to visual function is largely by connecting the temporal visual region o f either side rather than 'direct' interhemispheric connections of areas 17, 18 and 19. However, in several cases of corpus callosum agenesis, hypertrophy of the anterior commissure has been notedL q~he hypertrophic anterior commissure may describe the possibility that some aberrant callosal fibers from areas 17, 18 and 19 arrive at the oppesite hemisphere via the anterior commissure. In the present cases, this seems unlikely because the anterior commissure shows approximately normal appearance. Because of the reasons discussed above, we consider that the absence of large layer III pyramids from OBg of the brains presented in this account may be largely attributable to the absence of the corpus callosum. Unfortunately, the brains examined in this study are those o f infants and it seems necessary to evaluate the present observations further in adult cases of corpus callosum agenesis. In addition, Akert et al. 1 found in the biolzsied postcentral cortex of a 26-year-old woman, who had been proved lacking in the corpus callcsum by pneumoencephalography, that layer II1 was considerably reduced in width and pyramidal cells of this layer were smaller than normal, while other layers revealed less marked changes. ACKNOWLEDGEMENTS The authors are grateful to Profs. A. Ojima, I. H i r o n o and Dr. I. Sasaoka, Department of Pathology, Gifu University School of Medicine, and Dr. A. Aoki, Laboratory of Pathology, Gifu Prefectural Hospital for their kind allowance to examine the brains presented in this report.
REFERENCES I AKERT, K., PULETT1, F., AND ERICKSON, T. C., Abnormalities of the cerebral cortex associated with agenesis of corpus callosum and focal cortical seizures, Trans. Amer. neurol. Ass., 79 (1954) 151 153. 2 BON1N,G. vorq, The striate area of primates, J. comp. NeuroL, 77 (1942) 405-429. 3 BRODMANN,K., Beitrfi,ge zur histologischen Lokalisation der Grosshirnrinde. Dritte Mitteilung. Die Rindenfclder der niederen Affen, J. Psychol. Neurol. (Lpz.), 4 (1905) 177 226. 4 CRAGG, B. G., The topography of the afferent projections in the circumstriate visual cortex of the monkey studied by the Nauta method, Vision Res., 9 (1969) 733-747. 5 DOTY, R. W., NEGRO,O, N., AND PAULO,S., Forebrain commissures and vision. In R. JUNG(Ed.), Handbook o f Sensory Physiology, Vol. VII/3B, Springer, Berlin, 1973, pp. 543-582. 6 ECONOMO,C. YON,Ze[laufbau der Grosshirnrinde des Menschen, Springer, Berlin, 1927, pp. 84 95. 7 GLICKSTEIN, M., AND WHITTERIDGE, D., Degeneration of layer III pyramidal cells in area 18 following destruction of callosal input, Anat. Rec., 178 (1974) 362 363. 8 ITO, M., YASHIKI,K., AND HIRATA, T., Agenesis of the corpus callosum in man, Acta anat. nippon, 47 0972) 391-402.
252 9 KAROL, E. A., AND PANDYA, D. N., The distribution of the corpus callosum in the rhesus monkey, Brain, 94 (1971l 471-486. 10 LOESER,J. D., AND ALVORD,E. C., JR., Agenesis of the corpus callosum, Brain, 91 0968) 553 ~570. 11 MYERS,R. E., Commissural connections between occipital lobes of the monkey, J. comp. Neurol., 118 (1962) 1-16. 12 POLYAK,S., The Vertebrate Visual System, Univ. Chicago Press, Chicago, Ill., 1957, pp. 446-539: 13 PROaST, M., Ueber den Bau des vollst~.ndig balkenlosen Grosshirnes, sowie fiber Mikrogyrie und Heterotopie der grauen Substanz, Arch. Psychiat. Nervenkr., 34 0901) 709--786. 14 SHOtJMURA, K., An attempt to relate the origin and distribution of commissural fibers to the presence of large and medium pyramids in layer III in the cat's visual cortex, Brain Research, 67 0974) 13-25. 15 SLAGER, U. T., KELLY, A. B., AND WAGNER, J. A., Congenital absence of the corpus callosum; report of a case and review of the literature, New Engl. J. Med., 256 (1957) 1171-1176. 16 VAN VALKENBURG,C. T., Experimental and pathologico-anatomical researches on the corpus callosum, Brain, 36 (1913) 119-165. 17 ZEK1, S. M., The secondary visual areas of the monkey, Brain Research, 13 (1969) 197-226. 18 ZEKI, S. M., Interhemispheric connections of prestriate cortex in monkey, Brain Research, 19 (1970) 63-75. 19 ZEKI, S. M., Cortical projections from two prestriate areas in the monkey, Brain Research, 34 (1971) 19-35. 20 ZEK~, S. M., Comparison of the cortical degeneration in the visual regions of the temporal lobe of the monkey following section of the anterior commissure and the splenium, J. comp. Neurot., 148 (1973) 167-176.
