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  • Review Article
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Agenesis of the corpus callosum: genetic, developmental and functional aspects of connectivity

Nature Reviews Neuroscience volume 8, pages 287–299 (2007)Cite this article

Key Points

  • Agenesis of the corpus callosum (AgCC) occurs in approximately 1:4000 live births and can be diagnosed by neuroimaging. It may be part of a broader developmental syndrome or occur in isolation, in which case it is typically accompanied by colpocephaly and Probst bundles.

  • Animal models have revealed that the following general mechanisms are important for callosal development: neuronal proliferation and specification, axonal outgrowth and pathfinding, development and signalling at the midline, target recognition and activity-dependent enhancement or pruning.

  • AgCC can be caused by a combination of genetic mechanisms. Environmental factors probably also contribute to AgCC. However, most cases of AgCC do not have a known cause at this time.

  • The degree of behavioural and neurological impairment in AgCC is diverse, and preliminary findings suggest that other CNS anatomical changes associated with AgCC help determine outcomes.

  • AgCC patients do not exhibit the disconnection syndrome seen in split-brain patients. AgCC results in limited interhemispheric transfer of primary visual information, but intact hemispheric transfer of simple conceptual information such as letters.

  • Primary AgCC frequently presents with deficient problem solving, impaired linguistic pragmatics and impaired social skills, all of which contribute to difficulty with daily living such as maintaining relationships and a job. Cognitive and social deficits in AgCC may be related to interhemispheric transfer deficits or to other anatomical abnormalities.

  • Many neurodevelopmental and psychiatric conditions have been linked to corpus callosum malformation or malfunctioning, including schizophrenia, autism and attention deficit hyperactivity disorder. As such, AgCC may be a good model for examining how callosal and cortico-cortical transfer contribute to these disorders.

Abstract

Agenesis of the corpus callosum (AgCC), a failure to develop the large bundle of fibres that connect the cerebral hemispheres, occurs in 1:4000 individuals. Genetics, animal models and detailed structural neuroimaging are now providing insights into the developmental and molecular bases of AgCC. Studies using neuropsychological, electroencephalogram and functional MRI approaches are examining the resulting impairments in emotional and social functioning, and have begun to explore the functional neuroanatomy underlying impaired higher-order cognition. The study of AgCC could provide insight into the integrated cerebral functioning of healthy brains, and may offer a model for understanding certain psychiatric illnesses, such as schizophrenia and autism.

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Figure 1: Neuroanatomy of the corpus callosum.
Figure 2: Examples of neuroanatomical findings in AgCC.
Figure 3: Corpus callosum development.
Figure 4: Interhemispheric transfer in AgCC.

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References

  1. Schoenemann, P. T., Sheehan, M. J. & Glotzer, L. D. Prefrontal white matter volume is disproportionately larger in humans than in other primates. Nature Neurosci. 8, 242–252 (2005).

    CAS  PubMed  Google Scholar 

  2. Tomasch, J. Size, distribution, and number of fibres in the human corpus callosum. The Anat. Rec. 119, 119–135 (1954).

    CAS  PubMed  Google Scholar 

  3. Bloom, J. S. The role of the corpus callosum in interhemispheric transfer of information: excitation or inhibition? Neuropsychol. Rev. 15, 59–71 (2005).

    PubMed  Google Scholar 

  4. Sperry, R. W. in The Neurosciences (eds Schmitt, F. O. & Worden, F. G.) 5–19 (MIT Press, Cambridge, Massachusetts, 1974).

    Google Scholar 

  5. Gazzaniga, M. S. Forty-five years of spilt-brain research and still going strong. Nature Rev. Neurosci. 6, 653–659 (2005).

    CAS  Google Scholar 

  6. Lindwall, C., Fothergill, T. & Richards, L. Commissure formation in the mammalian forebrain. Curr. Opin. Neurobiol. 17, 3–14 (2007).

    CAS  PubMed  Google Scholar 

  7. Richards, L. J., Plachez, C. & Ren, T. Mechanisms regulating the development of the corpus callosum and its agenesis in mouse and human. Clin. Genet. 66, 276–289 (2004).

    CAS  PubMed  Google Scholar 

  8. Rash, B. G. & Richards, L. J. A role for cingulate pioneering axons in the development of the corpus callosum. J. Comp. Neurol. 434, 147–157 (2001). Provides evidence supporting the role of pioneer axons from the cingulate cortex in the early development of the rostral part of the corpus callosum.

    CAS  PubMed  Google Scholar 

  9. Ren, T. et al. Imaging, anatomical, and molecular analysis of callosal formation in the developing human fetal brain. Anat. Rec. A Discov. Mol. Cell. Evol. Biol. 288, 191–204 (2006).

    PubMed  Google Scholar 

  10. Livy, D. J. & Wahlsten, D. Retarded formation of the hippocampal commissure in embryos from mouse strains lacking a corpus callosum. Hippocampus 7, 2–14 (1997).

    CAS  PubMed  Google Scholar 

  11. Ozaki, H. S. & Wahlsten, D. Prenatal formation of the normal mouse corpus callosum: a quantitative study with carbocyanine dyes. J. Comp. Neurol. 323, 81–90 (1992).

    CAS  PubMed  Google Scholar 

  12. Shu, T., Puche, A. C. & Richards, L. J. Development of midline glial populations at the corticoseptal boundary. J. Neurobiol. 57, 81–94 (2003).

    PubMed  Google Scholar 

  13. Shu, T. & Richards, L. J. Cortical axon guidance by the glial wedge during the development of the corpus callosum. J. Neurosci. 21, 2749–2758 (2001).

    CAS  PubMed  Google Scholar 

  14. Smith, K. et al. Midline radial glia translocation and corpus callosum formation require FGF signaling. Nature Neurosci. 9, 787–797 (2006). Shows, using cell-type-specific inactivation of the FGFR1 gene, how FGF signalling participates in glial development and corpus callosum formation.

    CAS  PubMed  Google Scholar 

  15. Tole, S., Gutin, G., Bhatnagar, L., Remedios, R. & Hebert, J. M. Development of midline cell types and commissural axon tracts requires Fgfr1 in the cerebrum. Dev. Biol. 289, 141–151 (2006).

    CAS  PubMed  Google Scholar 

  16. Shu, T., Sundaresan, V., McCarthy, M. M. & Richards, L. J. Slit2 guides both precrossing and postcrossing callosal axons at the midline in vivo. J. Neurosci. 23, 8176–8184 (2003).

    CAS  PubMed  Google Scholar 

  17. Andrews, W. et al. Robo1 regulates the development of major axon tracts and interneuron migration in the forebrain. Development 133, 2243–2252 (2006).

    CAS  PubMed  Google Scholar 

  18. Keeble, T. R. & Cooper, H. M. Ryk: a novel Wnt receptor regulating axon pathfinding. Int. J. Biochem. Cell Biol. 38, 2011–2017 (2006).

    CAS  PubMed  Google Scholar 

  19. Silver, J. & Ogawa, M. Y. Postnatally induced formation of the corpus callosum in acallosal mice on glia-coated cellulose bridges. Science 220, 1067–1069 (1983).

    CAS  PubMed  Google Scholar 

  20. Shu, T., Butz, K. G., Plachez, C., Gronostajski, R. M. & Richards, L. J. Abnormal development of forebrain midline glia and commissural projections in Nfia knock-out mice. J. Neurosci. 23, 203–212 (2003).

    CAS  PubMed  Google Scholar 

  21. Steele-Perkins, G. et al. The transcription factor gene Nfib is essential for both lung maturation and brain development. Mol. Cell Biol. 25, 685–698 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Shen, Y., Mani, S., Donovan, S. L., Schwob, J. E. & Meiri, K. F. Growth-associated protein-43 is required for commissural axon guidance in the developing vertebrate nervous system. J. Neurosci. 22, 239–247 (2002).

    CAS  PubMed  Google Scholar 

  23. Shu, T., Li, Y., Keller, A. & Richards, L. J. The glial sling is a migratory population of developing neurons. Development 130, 2929–2937 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Riederer, B. M., Berbel, P. & Innocenti, G. M. Neurons in the corpus callosum of the cat during postnatal development. Eur. J. Neurosci. 19, 2039–2046 (2004).

    PubMed  Google Scholar 

  25. Innocenti, G. M. & Price, D. J. Exuberance in the development of cortical networks. Nature Rev. Neurosci. 6, 955–965 (2005).

    CAS  Google Scholar 

  26. Elberger, A. J. Distribution of transitory corpus callosum axons projecting to developing cat visual cortex revealed by DII. J. Comp. Neurol. 333, 326–342 (1993).

    CAS  PubMed  Google Scholar 

  27. Innocenti, G. M., Manger, P. R., Masiello, I., Colin, I. & Tettoni, L. Architecture and callosal connections of visual areas 17, 18, 19 and 21 in the ferret (Mustela putorius). Cereb. Cortex 12, 411–422 (2002).

    PubMed  Google Scholar 

  28. Olavarria, J. F. & Van Sluyters, R. C. Overall pattern of callosal connections in visual cortex of normal and enucleated cats. J. Comp. Neurol. 363, 161–176 (1995).

    CAS  PubMed  Google Scholar 

  29. Kusek, G. K., Wahlsten, D., Herron, B. J., Bolivar, V. J. & Flaherty, L. Localization of two new X-linked quantitative trait loci controlling corpus callosum size in the mouse. Genes Brain Behav. 7 Aug 2006 (doi: 10.1111/j.1601-183X.2006.00264).

  30. Clapcote, S. & Roder, J. C. Deletion polymorphism of Disc 1 is common to all 129 mouse substrains: implications for gene-targeting studies of brain function. Genetics 173, 2407–2410 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Innocenti, G. M. Schizophrenia, neurodevelopment and corpus callosum. Mol. Psychiatry 8, 261–274 (2003).

    CAS  PubMed  Google Scholar 

  32. Arlotta, P. et al. Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo. Neuron 45, 207–221 (2005).

    CAS  PubMed  Google Scholar 

  33. Bedeschi, M. F. et al. Agenesis of the corpus callosum: clinical and genetic study in 63 young patients. Pediatr. Neurol. 34, 186–193 (2006).

    PubMed  Google Scholar 

  34. Bonneau, D. et al. X-linked lissencephaly with absent corpus callosum and ambiguous genitalia (XLAG): clinical, magnetic resonance imaging, and neuropathological findings. Ann. Neurol. 51, 340–349 (2002).

    PubMed  Google Scholar 

  35. Sherr, E. H. The ARX story (epilepsy, mental retardation, autism, and cerebral malformations): one gene leads to many phenotypes. Curr. Opin. Pediatr. 15, 567–571 (2003).

    PubMed  Google Scholar 

  36. Kitamura, K. et al. Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nature Genet. 32, 359–369 (2002). Demonstrates nicely the extent of CNS deficits in Arx -knockout mice (disorders of neuronal migration, neuroblast proliferation and regional specification) and identifies mutations in the orthologous gene in humans by matching the clinical phenotype.

    CAS  PubMed  Google Scholar 

  37. Demyanenko, G. P., Tsai, A. Y. & Maness, P. F. Abnormalities in neuronal process extension, hippocampal development, and the ventricular system of L1 knockout mice. J. Neurosci. 19, 4907–4920 (1999).

    CAS  PubMed  Google Scholar 

  38. Itoh, K. et al. Brain development in mice lacking L1–L1 homophilic adhesion. J. Cell Biol. 165, 145–154 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Dupre, N. et al. Hereditary motor and sensory neuropathy with agenesis of the corpus callosum. Ann. Neurol. 54, 9–18 (2003).

    PubMed  Google Scholar 

  40. Boettger, T., Rust, M. B. & Maier, H. Loss of K-Cl co-transporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold. EMBO J. 22, 5422–5434 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Smith, K. M. et al. Midline radial glia translocation and corpus callosum formation require FGF signaling. Nature Neurosci. 9, 787–797 (2006).

    CAS  PubMed  Google Scholar 

  42. Mowat, D. R., Wilson, M. J. & Goossens, M. Mowat–Wilson syndrome. J. Med. Genet. 40, 305–310 (2003). An excellent review of a recently identified haploinsufficiency syndrome with AgCC and Hirschsprung disease.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Zweier, C. et al. Clinical and mutational spectrum of Mowat–Wilson syndrome. Eur. J. Med. Genet. 48, 97–111 (2005).

    PubMed  Google Scholar 

  44. Dobyns, W. B. Absence makes the search grow longer. Am. J. Hum. Genet. 58, 7–16 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Sherr, E. H. et al. Genomic microarray analysis identifies candidate loci in patients with corpus callosum anomalies. Neurology 65, 1496–1498 (2005).

    CAS  PubMed  Google Scholar 

  46. Schaefer, G. B., Bodensteiner, J. B., Buehler, B. A., Lin, A. & Cole, T. R. The neuroimaging findings in Sotos syndrome. Am. J. Med. Genet. 68, 462–465 (1997).

    CAS  PubMed  Google Scholar 

  47. Hu-Lince, D., Craig, D. W., Huentelman, M. J. & Stephan, D. A. The Autism Genome Project: goals and strategies. Am. J. Pharmacogenomics 5, 233–246 (2005).

    CAS  PubMed  Google Scholar 

  48. Karayiorgou, M. & Gogos, J. A. Schizophrenia genetics: uncovering positional candidate genes. Eur. J. Hum. Genet. 14, 512–519 (2006).

    CAS  PubMed  Google Scholar 

  49. Baron-Cohen, S. The cognitive neuroscience of autism. J. Neurol. Neurosurg. Psychiatry 75, 945–948 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Chinnasamy, D., Rudd, R. & Velakoulis, D. A case of schizophrenia with complete agenesis of the corpus callosum. Australas. Psychiatry 14, 327–330 (2006).

    PubMed  Google Scholar 

  51. Rubert, G. Ethanol exposure during embryogenesis decreases the radial glial progenitor pool and affects the generation of neurons and astrocytes. J. Neurosci. Res. 84, 483–496 (2006).

    CAS  PubMed  Google Scholar 

  52. Evrard, S. G. Altered neuron–glia interactions in a low, chronic prenatal ethanol exposure. Brain Res. Dev. Brain Res. 147, 119–133 (2003).

    CAS  PubMed  Google Scholar 

  53. Guerri, C., Pascual, M. & Renau-PIqueras, J. Glia and fetal alcohol syndrome. Neurotoxicology 22, 593–599 (2001).

    CAS  PubMed  Google Scholar 

  54. Greenberg, D. A. Linking acquired neurodevelopmental disorders to defects in cell adhesion. Proc. Natl Acad. Sci. USA 100, 8043–8044 (2003).

    CAS  PubMed  Google Scholar 

  55. Minana, R. Alcohol exposure alters the expression pattern of neural cell adhesion molecules during brain development. J. Neurochem. 75, 954–964 (2000).

    CAS  PubMed  Google Scholar 

  56. Wilkemeyer, M. F. Differential effects of ethanol antagonism and neuroprotection in peptide fragment NAPVSIPQ prevention of ethanol-induced developmental toxicity. Proc. Natl Acad. Sci. USA 100, 8543–8548 (2003).

    CAS  PubMed  Google Scholar 

  57. Roebuck, T. M., Mattson, S. N. & Riley, E. P. A review of the neuroanatomical findings in children with fetal alcohol syndrome or prenatal exposure to alcohol. Alcohol Clin. Exp. Res. 22, 339–344 (1998).

    CAS  PubMed  Google Scholar 

  58. Münte, T. F., Altenmüller, E. & Jäncke, L. The musician's brain as a model of neuroplasticity. Nature Rev. Neurosci. 3, 473–478 (2002).

    Google Scholar 

  59. Satoh, M., Furukawa, K., Takeda, K. & Kuzuhara, S. Left hemianomia of musical symbols caused by callosal infarction. J. Neurol. Neurosurg. Psychiatry 77, 705–706 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Schlaug, G., Jancke, L., Huang, Y., Staiger, J. & Steinmetz, H. Increased corpus callosum size in musicians. Neuropsychologia 33, 1047–1055 (1995).

    CAS  PubMed  Google Scholar 

  61. Alvarez-Dolado, M. et al. Regulation of the L1 cell adhesion molecule by thyroid hormone in the developing brain. Mol. Cell. Neurosci. 16, 499–514 (2000).

    CAS  PubMed  Google Scholar 

  62. Berbel, P., Guadano-Ferraz, A., Angulo, A. & Ramon Cerezo, J. Role of thyroid hormones in the maturation of interhemispheric connections in rats. Behav. Brain Res. 64, 9–14 (1994).

    CAS  PubMed  Google Scholar 

  63. Innocenti, G. M., Frost, D. O. & Illes, J. Maturation of visual callosal connections in visually deprived kittens: a challenging critical period. J. Neurosci. 5, 255–267 (1985).

    CAS  PubMed  Google Scholar 

  64. d'Ercole, C. et al. Prenatal diagnosis of fetal corpus callosum agenesis by ultrasonography and magnetic resonance imaging. Prenat. Diagn. 18, 247–253 (1998).

    CAS  PubMed  Google Scholar 

  65. Shevell, M. I. Clinical and diagnostic profile of agenesis of the corpus callosum. J. Child Neurol. 17, 896–900 (2002).

    PubMed  Google Scholar 

  66. Goodyear, P. W., Bannister, C. M., Russell, S. & Rimmer, S. Outcome in prenatally diagnosed fetal agenesis of the corpus callosum. Fetal Diagn. Ther. 16, 139–145 (2001).

    CAS  PubMed  Google Scholar 

  67. Moutard, M. L. et al. Agenesis of corpus callosum: prenatal diagnosis and prognosis. Childs Nerv. Syst. 19, 471–476 (2003). Through prenatal ultrasound identification and postnatal follow-up, this research shows that most individuals with AgCC either have early developmental delay or demonstrate learning deficits in school years, suggesting that asymptomatic AgCC individuals are probably rare.

    PubMed  Google Scholar 

  68. Brown, W. S., Jeeves, M. A., Dietrich, R. & Burnison, D. S. Bilateral field advantage and evoked potential interhemispheric transmission in commissurotomy and callosal agenesis. Neuropsychologia 37, 1165–1180 (1999). Compares IHT between individuals with AgCC, a person with a split-brain and controls, using both evoked potentials and bilateral field matching tasks. It demonstrates the limitations of interhemispheric transfer caused by corpus callosum absence.

    CAS  PubMed  Google Scholar 

  69. Brown, W. S., Thrasher, E. D. & Paul, L. K. Interhemispheric Stroop effects in partial and complete agenesis of the corpus callosum. J. Int. Neuropsychol. Soc. 7, 302–311 (2001).

    CAS  PubMed  Google Scholar 

  70. Jeeves, M. A. in Structure and Function of the Cerebral Commissures (eds Russell, I., Hof, M. v. & Berlucchi, G.) 449–474 (Macmillian, New York, 1979).

    Google Scholar 

  71. Meerwaldt, J. D. Disturbances of spatial perception in a patient with agenesis of the corpus callosum. Neuropsychologia 21, 161–165 (1983).

    CAS  PubMed  Google Scholar 

  72. Sauerwein, H. C. & Lassonde, M. Intra- and inter-hemispheric processing of visual information in callosal agenesis. Neuropsychologia 21, 167–171 (1983).

    CAS  PubMed  Google Scholar 

  73. Lassonde, M. & Bryden, M. P. Dichotic listening, callosal agenesis and cerebral laterality. Brain Lang. 39, 475–481 (1990).

    Google Scholar 

  74. Lassonde, M., Bryden, M. P. & Demers, P. The corpus callosum and cerebral speech lateralization. Brain Lang. 38, 195–206 (1990).

    CAS  PubMed  Google Scholar 

  75. Kessler, J., Huber, M., Pawlik, G., Heiss, W. D. & Markowitsch, H. J. Complex sensory cross integration deficits in a case of corpus callosum agenesis with bilateral language representation: Positron-Emission-Tomography and neuropsychological findings. Int. J. Neurosci. 58, 275–282 (1991).

    CAS  PubMed  Google Scholar 

  76. McAndrews, M. B. Language representation and sensory-motor mapping absent a corpus callosum. Neuroimage 13, S816 (2001).

    Google Scholar 

  77. Chiarello, C. A house divided? Cognitive functioning with callosal agenesis. Brain Lang. 11, 128–158 (1980). Chiarello provides a summary of cognitive data from multiple published case studies and a meta-analysis of the psychology literature on AgCC as of 1980.

    CAS  PubMed  Google Scholar 

  78. Sauerwein, H. C., Nolin, P. & Lassonde, M. in Callosal Agenesis: A Natural Split Brain? (eds Lassonde, M. & Jeeves, M. A.) 221–233 (Plenum, New York, 1994). Includes a meta-analysis of basic cognitive skills in AgCC, as well as seven fairly high-functioning individuals with AgCC (borderline to low average IQ). Neurocognitive patterns were examined and deficits in more subtle cognitive tasks were found.

    Google Scholar 

  79. Brown, L. N. & Sainsbury, R. S. Hemispheric equivalence and age-related differences in judgments of simultaneity to somatosensory stimuli. J. Clin. Exp. Neuropsychol. 22, 587–598 (2000).

    CAS  PubMed  Google Scholar 

  80. David, A. S., Wacharasindhu, A. & Lishman, W. A. Severe psychiatric disturbance and abnormalities of the corpus callosum: Review and case series. J. Neurol. Neurosurg. Psychiatr. 56, 85–93 (1993).

    CAS  Google Scholar 

  81. Aalto, S. et al. Neuroanatomical substrata of amusement and sadness: a PET activation study using film stimuli. Neuroreport 13, 67–73 (2002).

    CAS  PubMed  Google Scholar 

  82. Fischer, M., Ryan, S. B. & Dobyns, W. B. Mechanisms of interhemispheric transfer and patterns of cognitive function in acallosal patients of normal intelligence. Arch. Neurol. 49, 271–277 (1992).

    CAS  PubMed  Google Scholar 

  83. Imamura, T., Yamadori, A., Shiga, Y., Sahara, M. & Abiko, H. Is disturbed transfer of learning in callosal agenesis due to a disconnection syndrome? Behav. Neurol. 7, 43–48 (1994).

    CAS  PubMed  Google Scholar 

  84. Solursh, L. P., Margulies, A. I., Ashem, B. & Stasiak, E. A. The relationships of agenesis of the corpus callosum to perception and learning. J. Nerv. Ment. Dis. 141, 180–189 (1965).

    CAS  PubMed  Google Scholar 

  85. Liederman, J., Merola, J. & Martinez, S. Interhemispheric collaboration in response to simultaneous bilateral input. Neuropsychologia 23, 673–683 (1985).

    CAS  PubMed  Google Scholar 

  86. Temple, C. M., Jeeves, M. A. & Vilarroya, O. Ten pen men: rhyming skills in two children with callosal agenesis. Brain Lang. 37, 548–564 (1989).

    CAS  PubMed  Google Scholar 

  87. Temple, C. M., Jeeves, M. A. & Vilarroya, O. Reading in callosal agenesis. Brain Lang. 39, 235–253 (1990).

    CAS  PubMed  Google Scholar 

  88. Banich, M. T. & Brown, W. S. A life-span perspective on interaction between the cerebral hemispheres. Dev. Neuropsychol. 18, 1–10 (2000).

    CAS  PubMed  Google Scholar 

  89. Sanders, R. J. Sentence comprehension following agenesis of the corpus callosum. Brain Lang. 37, 59–72 (1989).

    CAS  PubMed  Google Scholar 

  90. Temple, C. M. & Ilsley, J. Phonemic discrimination in callosal agenesis. Cortex 29, 341–348 (1993).

    CAS  PubMed  Google Scholar 

  91. Brown, W. S., Symington, M., Van Lancker-Sidtis, D., Dietrich, R. & Paul, L. K. Paralinguistic processing in children with callosal agenesis: emergence of neurolinguistic deficits. Brain Lang. 93, 135–139 (2005).

    PubMed  Google Scholar 

  92. Paul, L. K., Van Lancker-Sidtis, D., Schieffer, B., Dietrich, R. & Brown, W. S. Communicative deficits in agenesis of the corpus callosum: nonliteral language and affective prosody. Brain Lang. 85, 313–324 (2003). This was the first publication to examine social cognition in a relatively large sample (n = 7) of individuals with primary AgCC. It revealed a deficit in comprehension of second-order meanings in verbal communication.

    PubMed  Google Scholar 

  93. Brown, W. S., Paul, L. K., Symington, M. & Dietrich, R. Comprehension of humor in primary agenesis of the corpus callosum. Neuropsychologia 43, 906–916 (2005).

    PubMed  Google Scholar 

  94. Huber-Okrainec, J., Blaser, S. E. & Dennis, M. Idiom comprehension deficits in relation to corpus callosum agenesis and hypoplasia in children with spina bifida meningomylocele. Brain Lang. 93, 349–368 (2005).

    PubMed  Google Scholar 

  95. Buchanan, D. C., Waterhouse, G. J. & West, S. C. Jr. A proposed neurophysiological basis of alexithymia. Psychother. Psychosom. 34, 248–255 (1980).

    CAS  PubMed  Google Scholar 

  96. O'Brien, G. in Callosal Agenesis: A Natural Split Brain? (eds Lassonde, M. & Jeeves, M. A.) 235–246 (Plenum, New York, 1994).

    Google Scholar 

  97. Eckstein, K. & Friederici, A. D. It's early: event-related potential evidence for initial interaction of syntax and prosody in speech comprehension. J. Cogn Neurosci. 18, 1696–1711 (2006).

    PubMed  Google Scholar 

  98. Eckstein, K. & Friederici, A. D. Late interaction of syntactic and prosodic processes in sentence comprehension as revealed by ERPs. Cogn. Brain Res. 25, 130–143 (2005).

    Google Scholar 

  99. Friederici, A. D. & Alter, K. Lateralization of auditory language functions: a dynamic dual pathway model. Brain Lang. 89, 267–276 (2004).

    PubMed  Google Scholar 

  100. Borod, J. C., Bloom, R. L., Brickman, A. M., Nakhutina, L. & Curko, E. A. Emotional processing deficits in individuals with unilateral brain damage. Appl. Neuropsychol. 9, 23–36 (2002).

    PubMed  Google Scholar 

  101. Josse, G. & Tzourio-Mazoyer, N. Hemispheric specialization for language. Brain Res. Rev. 44, 1–12 (2004).

    PubMed  Google Scholar 

  102. Tabibnia, G. & Zaidel, E. Alexithymia, interhemispheric transfer, and right hemispheric specialization: a critical review. Psychother. Psychosom. 74, 81–92 (2005).

    PubMed  Google Scholar 

  103. Badaruddin, D. H. et al. Social and behavioral problems of children with agenesis of the corpus callosum. Child Psychiatry and Hum. Dev. (in the press).

  104. Brown, W. S. & Paul, L. K. Cognitive and psychosocial deficits in agenesis of the corpus callosum with normal intelligence. Cogn. Neuropsychiatr. 5, 135–157 (2000). This two-case study examined IHT, general cognition and social cognition in AgCC and outlines a theory linking the social deficits back to the anatomically-based deficits in IHT. This theory is foundational to current neuropsychological studies of AgCC.

    Google Scholar 

  105. Stickles, J. L., Schilmoeller, G. L. & Schilmoeller, K. J. A 23-year review of communication development in an individual with agenesis of the corpus callosum. Int. J. Disabil. Dev. Educ. 49, 367–383 (2002).

    Google Scholar 

  106. Paul, L. K., Schieffer, B. & Brown, W. S. Social processing deficits in agenesis of the corpus callosum: Narratives from the Thematic Apperception Test. Arch. Clin. Neuropsychol. 19, 215–225 (2004).

    PubMed  Google Scholar 

  107. Paul, L. K. et al. Emotional arousal in agenesis of the corpus callosum. Int. J. Psychophysiol. 61, 47–56 (2006).

    PubMed  Google Scholar 

  108. Happe, F. Time to give up on a single explanation for autism. Nature Neurosci. 9, 1218–1220 (2006).

    CAS  PubMed  Google Scholar 

  109. Motomura, N. H. Monozygotic twin cases of the agenesis of the corpus callosum with schizophrenic disorder. Psychiatry Clin. Neurosci. 56, 199–202 (2002).

    PubMed  Google Scholar 

  110. Hardan, A. Y., Minshew, N. J. & Keshavan, M. S. Corpus callosum size in autism. Neurology 55, 1033–1036 (2000).

    CAS  PubMed  Google Scholar 

  111. Vidal, C. N. et al. Mapping corpus callosum deficits in autism: an index of aberrant cortical connectivity. Biol. Psychiatry 60, 218–225 (2006).

    PubMed  Google Scholar 

  112. Doherty, D., Tu, S., Schilmoeller, K. & Schilmoeller, G. Health-related issues in individuals with agenesis of the corpus callosum. Child Care Health Dev. 32, 333–342 (2006).

    CAS  PubMed  Google Scholar 

  113. Plessen, K. J. et al. Reduced white matter connectivity in the corpus callosum of children with Tourette syndrome. J. Child Psychol. Psychiatry 47, 1013–1122 (2006).

    PubMed  PubMed Central  Google Scholar 

  114. Seidman, L. J., Valera, E. M. & Makris, N. Structural brain imaging of attention-deficit/hyperactivity disorder. Biol. Psychiatry 57, 1263–1272 (2005).

    PubMed  Google Scholar 

  115. Roessner, V., Banaschewski, T., Uebel, H., Becker, A. & Rothenberger, A. Neuronal network models of ADHD — lateralization with respect to interhemispheric connectivity reconsidered. Eur. Child Adolesc. Psychiatry 13, I71–I79 (2004).

    PubMed  Google Scholar 

  116. Meyer, J. Rare variants of the gene encoding the potassium chloride co-transporter 3 are associated with bipolar disorder. Int. J. Psychopharmacol. 8, 495–504 (2005).

    CAS  Google Scholar 

  117. Le Bihan, D. Looking into the functional architecture of the brain with diffusion MRI. Nature Rev. Neurosci. 4, 469–480 (2003).

    CAS  Google Scholar 

  118. Buchmann, J. et al. Modulation of transcallosally mediated motor inhibition in children with attention deficits hyperactivity disorder (ADHD) by medication with methylphenidate (MPH). Neurosci. Lett. 405, 14–18 (2006).

    CAS  PubMed  Google Scholar 

  119. Barbaresi, W. J. Autism — A review of the state of the science for pediatric primary health care clinicians. Arch. Pediatr. Adolesc. Med. 160, 1167–1175 (2006).

    PubMed  Google Scholar 

  120. Gottesman, I. I. & Gould, T. D. The endophenotype concept in psychiatry: etymology and strategic intentions. Am. J. Psychiatry 160, 636–645 (2003).

    PubMed  Google Scholar 

  121. Bogen, J. E. in Clinical Neuropsychology (eds Heilman, K. M. & Valenstein, E.) 308–359 (Oxford Univ. Press, New York, 1979).

    Google Scholar 

  122. Bogen, J. E. in Handbook of Clinical Neurology (ed. Frederiks, J. A. M.) 99–106 (Elsevier, Amsterdam, 1985).

    Google Scholar 

  123. Zaidel, D. & Sperry, R. W. Some long-term motor effects of cerebral commissurotomy in man. Neuropsychologia 15, 193–204 (1977).

    CAS  PubMed  Google Scholar 

  124. Zaidel, D. & Sperry, R. W. Memory impairment after commissurotomy in man. Brain 97, 263–272 (1974).

    CAS  PubMed  Google Scholar 

  125. Hoppe, K. D. & Bogen, J. E. Alexithymia in twelve commissurotomized patients. Psychother. Psychosom. 28, 148–155 (1977).

    CAS  PubMed  Google Scholar 

  126. Jeeves, M. A., Silver, P. H. & Milne, A. B. Role of the corpus callosum in the development of a bimanual skills. Dev. Neuropsychol. 4, 305–323 (1988).

    Google Scholar 

  127. Lassonde, M., Sauerwein, H., Chicoine, A. J. & Geoffroy, G. Absence of disconnexion syndrome in callosal agenesis and early callosotomy: brain reorganization or lack of structural specificity during ontogeny? Neuropsychologia 29, 481–495 (1991). Examines the impact of plasticity and development of compensatory mechanisms for individuals with AgCC and children who have commissurotomy. The findings suggest that childhood patients with commissurotomy compensate for callosal disconnection much more effectively than adult patients with commissurotomy.

    CAS  PubMed  Google Scholar 

  128. Njiokiktjien, C. in Pediatric behavioural neurology: The child's corpus callosum (eds Ramaekers, G. & Njiokiktjien, C.) 235–250 (Suyi Publicaties, Amsterdam, 1991).

    Google Scholar 

  129. Guillem, P., Fabre, B., Cans, C., Robert-Gnansia, E. & Jouk, P. S. Trends in elective terminations of pregnancy between 1989 and 2000 in a French county (the Isere). Prenat. Diagn. 23, 877–883 (2003).

    CAS  PubMed  Google Scholar 

  130. Wang, L. W., Huang, C. C. & Yeh, T. F. Major brain lesions detected on sonographic screening of apparently normal term neonates. Neuroradiology 46, 368–373 (2004).

    CAS  PubMed  Google Scholar 

  131. Bodensteiner, J., Schaefer, G. B., Breeding, L. & Cowan, L. Hypoplasia of the corpus callosum: a study of 445 consecutive MRI scans. J. Child Neurol. 9, 47–49 (1994).

    CAS  PubMed  Google Scholar 

  132. Jeret, J. S., Serur, D., Wisniewski, K. & Fisch, C. Frequency of agenesis of the corpus callosum in the developmentally disabled population as determined by computerized tomography. Pediatr. Neurosci. 12, 101–103 (1985).

    PubMed  Google Scholar 

  133. Conover, P. & Roessmann, U. Malformational complex in an infant with intrauterine influenza viral-infection. Arch. Pathol. Lab. Med. 114, 535–538 (1990).

    CAS  PubMed  Google Scholar 

  134. Mehta, N. & Hartnoll, G. Congenital CMV with callosal lipoma and agenesis. Pediatr. Neurol. 24, 222–224 (2001).

    CAS  PubMed  Google Scholar 

  135. Wang, X., Jakobs, C. & Bawle, E. V. D-2-Hydroxyglutaric aciduria with absence of corpus callosum and neonatal intracranial haemorrhage. J. Inherit. Metab. Dis. 26, 92–94 (2003).

    CAS  PubMed  Google Scholar 

  136. Hetts, S. W., Sherr, E. H., Gobuty, S., Chao, S. & Barkovich, A. J. Anomalies of the corpus callosum: MR analysis of the phenotypic spectrum. Am. J. Roentgenol. 187, 1343–1348 (2006).

    Google Scholar 

  137. Rauch, R. A. & Jinkins, J. R. in Callosal Agenesis: A Natural Split Brain? (eds Lassonde, M. & Jeeves, M. A.) 83–95 (Plenum, New York, 1994).

    Google Scholar 

  138. Baker, L. L. & Barkovich, A. J. The large temporal horn: MR analysis in developmental brain anomalies versus hydrocephalus. Am. J. Neuroradiol. 13, 115–122 (1992).

    CAS  PubMed  Google Scholar 

  139. Mori, K. Giant interhemispheric cysts associated with agenesis of the corpus callosum. J. Neurosurg. 76, 224–230 (1992).

    CAS  PubMed  Google Scholar 

  140. Tovar-Moll, F. et al. Neuroplasticity in Human Callosal Dysgenesis: A diffusion tensor imaging study. Cereb. Cortex 17, 531–541 (2006).

    PubMed  Google Scholar 

  141. Parrish, M. L., Roessmann, U. & Levinsohn, M. W. Agenesis of the corpus callosum: a study of the frequency of associated malformations. Ann. Neurol. 6, 349–354 (1979).

    CAS  PubMed  Google Scholar 

  142. Fazeli, A. et al. Phenotype of mice lacking functional Deleted in colorectal cancer (Dcc) gene. Nature 386, 796–804 (1997).

    CAS  PubMed  Google Scholar 

  143. Richards, L. J. Surrounded by Slit — how forebrain commissural axons can be led astray. Neuron 33, 153–155 (2002).

    CAS  PubMed  Google Scholar 

  144. Hofer, S. & Frahm, J. Topography of the human corpus callosum revisited — comprehensive fiber tractography using diffusion tensor magnetic resonance imaging. Neuroimage 32, 989–994 (2006).

    PubMed  Google Scholar 

  145. Jellison, B. J. et al. Diffusion tensor imaging of cerebral white matter: a pictorial review of physics, fiber tract anatomy, and tumor imaging patterns. Am. J. Neuroradiol. 25, 356–369 (2004).

    PubMed  Google Scholar 

  146. Schmahmann, J. D. & Pandya, D. N. Fiber Pathways of the Brain (Oxford Univ. Press, 2006).

    Google Scholar 

  147. Brown, W. S. & Jeeves, M. A. Bilateral visual field processing and evoked potential interhemispheric transmission time. Neuropsychologia 31, 1267–1282 (1993).

    CAS  PubMed  Google Scholar 

  148. APA. Diagnostic and Statistical Manual of Mental Disorders 4th edn (American Psychiatric Association, Washington DC, 1994).

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Acknowledgements

We would like to thank the Sherr, Brown and Adolphs labs for helpful suggestions. We would also like to thank the Pfeiffer Foundation for supporting the 2006 AgCC interdisciplinary research symposium.

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Authors and Affiliations

  1. California Institute of Technology, MC 228-77, Pasadena, 91125, California, USA

    Lynn K. Paul, Ralph Adolphs & J. Michael Tyszka

  2. Travis Research Institute, 180 N. Oakland Ave., Pasadena, 91101, California, USA

    Lynn K. Paul & Warren S. Brown

  3. Department of Anatomy and Developmental Biology, University of Queensland, Otto Hirschfeld Building #81, St Lucia, 4072, Queensland, Australia

    Linda J. Richards

  4. Department of Neurology, University of California San Francisco, 350 Parnassus Ave, Suite 609, California, 94143-0137, USA

    Pratik Mukherjee & Elliott H. Sherr

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DATABASES

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schizophrenia

FURTHER INFORMATION

Corpus callosum research program

UCSF Department of Neurology Brain Development Research Program

National Organization for Disorders of the Corpus Callosum

Glossary

Interhemispheric transfer

(IHT). Transmission of information between the cerebral hemispheres, typically assessed with laterally presented stimuli.

Diffusion MRI

(dMRI). This broad term covers both diffusion-weighted MRI data acquisition and image analysis of this data, including diffusion tensor imaging. The MRI signal is weighted by the amount of water diffusion within tissues. The weighting can vary with direction, allowing diffusion anisotropy arising from microscopic restrictions in biological tissues to be observed.

Pioneer axons

These are axons that innervate targets early in development and form a substrate for the guidance of later developing axons.

Commissurotomy

Surgical procedure that involves severing the corpus callosum as well as the anterior commissures (can also include severing of posterior and hippocampal commissures). This is the original 'split-brain' procedure as reported by Roger Sperry.

Callosotomy

Surgical procedure that involves severing only the corpus callosum, either in part or in its entirety, leaving other commissures intact. This has also been described by some as a 'split-brain' procedure.

Alexithymia

Impairment in the expression of one's feelings and mood states. A dominant hypothesis is that alexithymia arises from compromised connection between the language processing in the left hemisphere and affect processing in the right.

Mendelian

A trait resulting from changes in a single gene that has a significant effect on the phenotype and is inherited in a simple pattern that is similar or identical to those described by Gregor Mendel. Also referred to as monogenic.

Retrospective chart reviews

A retrospective analysis of medical records of a group of individuals with a particular condition or disease, typically used to study rare diseases for which prospective identification and follow up are difficult.

X-inactivation

Early embryonic inactivation of the genes in each cell on one of a female's X chromosomes (may also occur in males with Klinefelter syndrome who have more than one X chromosome). The result is that dosage of X-chromosomal gene products is equivalent to those in typical males (who ony have one X chromosome).

Meckel–Gruber syndrome, type 3

(MKS3). Patients typically have renal cysts, CNS malformations, hepatic ductal dysplasia/cysts and polydactyly. MKS3 is caused by mutations in the gene meckelin (also known as TMEM67).

Encephaloceles

A neural tube defect (NTD) that results in a sac-like protrusion of brain tissue and overlying meninges. These NTDs are frequently associated with other brain or craniofacial malformations, and clinically with broad-ranging neurological problems.

Polydactyly

The anatomical variant of having more than the normal number of digits on the hands or feet. This is observed in approximately 1:500 births and is usually inherited as an autosomal dominant trait with variable penetrance.

Hirschsprung disease

A developmental disorder of the enteric nervous system resulting in absence of the neuronal ganglion cells in the distal colon, which in turn results in a functional obstruction of the colon. Can present with a dramatically distended colon (megacolon) or with bowel perforation. It is a cardinal feature of Mowat–Wilson syndrome.

Haploinsufficiency

A clinically evident symptom arising when one of the two copies of a gene is mutated, leaving a single functional copy and a presumed reduction in the level of the encoded protein.

Klinefelter syndrome

A genetic syndrome defined as a 47, XXY karyotype in a phenotypic male. Patients frequently have small testes, minimal sperm production, breast enlargement in puberty and psychosocial problems.

Chorioretinal lacunae

Punched out lesions in the pigmented layer of the retina that cluster around the optic disc that are pathognomonic for Aicardi syndrome.

Microarray-based comparative genomic hybridization

(CGH). A method that compares the quantity of DNA across the whole genome between two individuals. Two DNA samples are labelled red and green, respectively, and are both hybridized to a slide that has an array of many thousands of spots containing DNA from unique places in the genome. The colour ratio at each spot determines the relative amount of DNA present between the two samples.

Sotos syndrome

Also known as cerebral gigantism, this is a genetic disorder that results in early physical overgrowth and cognitive impairment. Most cases are caused by haploinsufficiency of the gene NSD1, which is a coregulator for steroid receptors.

Heterotopia

In general, this term refers to the displacement of neuronal cell bodies into the white matter.

Tachistoscopic

Presentation of visual stimuli more rapidly than the eyes can move. Tachistoscopic presentation thus results in a visual stimulus being perceived in only one hemisphere; representation of the image in the opposite hemisphere will require interhemispheric transfer of information.

Stroop interference effect

A measure of reaction time when identifying one feature of a stimulus, while inhibiting a dominant tendency to identify it according to an interfering feature (for example, the normally increased reaction time when naming the ink colour of the word “red” printed in green ink).

Bilateral field advantage

The normal decrease in reaction time when comparing two stimuli presented in opposite visual hemifields, compared with presentation of both within one hemifield. The reason for this advantage is dual processing, that is, each hemisphere only has to process one stimulus. Without efficient interhemispheric transfer, there cannot be such an advantage.

Anterior commissure

A small band of approximately 50,000 axons that connects the cerebral hemispheres. The anterior commissure connects the temporal lobes and is located at the base of the fornix.

Dichotic listening

A research method testing language lateralization by simultaneously presenting different auditory input to each ear. The degree to which individuals preferentially recall information from one ear or the other is an indication of which hemisphere is dominant in language processing.

Syntax

Grammatical arrangement of words and phrases in a sentence, which affects relationships of meaning. For example, changing the placement of a word or phrase can change the meaning.

Linguistic pragmatics

The processes that allow one to go beyond the literal meaning of language and actually interpret the speaker's intended meaning. This may involve utilizing second-order meanings, body language, vocal inflection, context and other factors.

Valence

A continuous scale from pleasant to aversive.

Diffusion tensor imaging

(DTI). Anisotropic diffusion within tissues is modelled as a second-rank tensor, which can be calculated from diffusion-weighted MRI acquired in six or more non-collinear directions. The tensor at each point in the image can be visualized as an oriented and scaled ellipsoid. More simply, quantities such as the mean diffusivity and fractional anisotropy can be calculated from the tensor and visualized as conventional images. The tensor contains information about likely axonal fibre direction and can be used to create virtual fibre tracts through the DTI, reflecting structural connectivity in white matter.

Endophenotype

A characteristic that is a subset of a particular condition and may be shared by individuals who do not have the full disorder.

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Paul, L., Brown, W., Adolphs, R. et al. Agenesis of the corpus callosum: genetic, developmental and functional aspects of connectivity. Nat Rev Neurosci 8, 287–299 (2007). https://doi.org/10.1038/nrn2107

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