Agenesis of the corpus callosum: genetic, developmental and functional aspects of connectivity. Nat Rev Neurosci 8:287-299

California Institute of Technology, MC 228-77 Pasadena, California 91125, USA.
Nature reviews Neuroscience (Impact Factor: 31.43). 05/2007; 8(4):287-99. DOI: 10.1038/nrn2107
Source: PubMed


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.

Download full-text


Available from: Lynn K Paul, Oct 09, 2015
64 Reads
    • "In a critical experiment, we than tested in a second approach, whether this contralaterally induced iM1 suppression is absent in patients with AgCC. AgCC is a rare condition, in which callosal fibers are congenitally completely or partially absent, caused by different genetic or environmental factors during prenatal callosal development [15]. As a consequence AgCC patients usually show prolonged visual interhemispheric transfer times [16] [17] and deficiencies in different higher cognitive abilities, where interhemispheric integration is important [18] [19]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: During unilateral hand movements the activity of the contralateral primary motor cortex (cM1) is increased while the activity of the ipsilateral M1 (iM1) is decreased. A potential explanation for this asymmetric activity pattern is transcallosal cM1-to-iM1 inhibitory control. To test this hypothesis, we examined interhemispheric motor inhibition in acallosal patients. We measured fMRI activity in iM1 and cM1 in acallosal patients during unilateral hand movements and compared their motor activity pattern to that of healthy controls. In controls, fMRI activation in cM1 was significantly higher than in iM1, reflecting a normal differential task-related M1 activity. Additional functional connectivity analysis revealed that iM1 activity was strongly suppressed by cM1. Furthermore, DTI analysis indicated that this contralaterally induced suppression was mediated by microstructural properties of specific callosal fibers interconnecting both M1s. In contrast, acallosal patients did not show a clear differential activity pattern between cM1 and iM1. The more symmetric pattern was due to an elevated task-related iM1 activity in acallosal patients, which was significantly higher than iM1 activity in a subgroup of gender and age-matched controls. Also, interhemispheric motor suppression was completely absent in acallosal patients. These findings suggest that absence of callosal connections reduces inhibitory interhemispheric motor interactions between left and right M1. This effect may reveal novel aspects of mechanisms in communication of two hemispheres and establishment of brain asymmetries in general. Copyright © 2015. Published by Elsevier B.V.
    Behavioural brain research 07/2015; 293. DOI:10.1016/j.bbr.2015.07.016 · 3.03 Impact Factor
  • Source
    • "Many brain malformations are primarily characterized by abnormal axonal path-finding, regarded as axonguidance disorders (Engle, 2010). The prenatal disruption of the normal commissuration can lead to partial or complete agenesis of the corpus callosum (= callosal agenesis, CCA) a common brain malformation with a combined prevalence of 0.02–0.5% (Paul et al., 2007; Jeret et al., 1985) in the population and 2–3% of patients with mental retardation (Jeret et al., 1985). CCA, and a wide range of associated neurodevelopmental abnormalities, can be assessed by ultrasound examination from mid-gestation (Santo et al., 2012; Vergani et al., 1994; Comstock et al., 1985), although fetal diagnostics becomes challenging for the fine-grained description of midline structures, as seen in cases with hypoplastic corpus callosum. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Agenesis of the corpus callosum is a model disease for disrupted connectivity of the human brain, in which the pathological formation of interhemispheric fibers results in subtle to severe cognitive deficits. Postnatal studies suggest that the characteristic abnormal pathways in this pathology are compensatory structures that emerge via neural plasticity. We challenge this hypothesis and assume a globally different network organization of the structural interconnections already in the fetal acallosal brain. Twenty fetuses with isolated corpus callosum agenesis with or without associated malformations were enrolled and fiber connectivity among 90 brain regions was assessed using in utero diffusion tensor imaging and streamline tractography. Macroscopic scale connectomes were compared to 20 gestational age-matched normally developing fetuses with multiple granularity of network analysis. Gradually increasing connectivity strength and tract diffusion anisotropy during gestation were dominant in antero-posteriorly running paramedian and antero-laterally running aberrant pathways, and in short-range connections in the temporoparietal regions. In fetuses with associated abnormalities, more diffuse reduction of cortico-cortical and cortico-subcortical connectivity was observed than in cases with isolated callosal agenesis. The global organization of anatomical networks consisted of less segregated nodes in acallosal brains, and hubs of dense connectivity, such as the thalamus and cingulate cortex, showed reduced network centrality. Acallosal fetal brains show a globally altered connectivity network structure compared to normals. Besides the previously described Probst and sigmoid bundles, we revealed a prenatally differently organized macroconnectome, dominated by increased connectivity. These findings provide evidence that abnormal pathways are already present during at early stages of fetal brain development in the majority of cerebral white matter.
    NeuroImage 02/2015; DOI:10.1016/j.neuroimage.2015.02.038 · 6.36 Impact Factor
  • Source
    • "As with leukoaraiosis, the worst loss of connectivity in multiple sclerosis was to hub regions of the connectome that correspond well to many of the rich club regions identified in our and prior studies (van den Heuvel & Sporns, 2011, van den Heuvel et al., 2012). An investigation of the structural connectome in subjects with agenesis of the corpus callosum, a congenital malformation that results in partial or complete absence of interhemispheric callosal fibers, demonstrated profound alterations of global network metrics as well as fiber pathways within the structural core (Owen et al., 2013c), in agreement with the cognitive dysfunction found in these individuals (Paul et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The structural connectome has emerged as a powerful tool to characterize the network architecture of the human brain and shows great potential for generating important new biomarkers for neurologic and psychiatric disorders. The edges of the cerebral graph traverse white matter to interconnect cortical and subcortical nodes, although the anatomic embedding of these edges is generally overlooked in the literature. Mapping the paths of the connectome edges could elucidate the relative importance of individual white matter tracts to the overall network topology of the brain and also lead to a better understanding of the effect of regionally-specific white matter pathology on cognition and behavior. In this work, we introduce edge density imaging (EDI), which maps the number of network edges that pass through every white matter voxel. Test-retest analysis shows good to excellent reliability for edge density (ED) measurements, with consistent results using different cortical and subcortical parcellation schemes and different diffusion MR imaging acquisition parameters. We also demonstrate that ED yields complementary information to both traditional and emerging voxel-wise metrics of white matter microstructure and connectivity, including fractional anisotropy, track density, fiber orientation dispersion and neurite density. Our results demonstrate spatially ordered variations of ED throughout the white matter, notably including greater ED in posterior than anterior cerebral white matter. The EDI framework is employed to map the white matter regions that are enriched with pathways connecting rich club nodes and also those with high densities of intra-modular and inter-modular edges. We show that periventricular white matter has particularly high ED and high densities of rich club edges, which is significant for diseases in which these areas are selectively affected, ranging from white matter injury of prematurity in infants to leukoaraiosis in the elderly. Using edge betweenness centrality, we identify specific white matter regions involved in a large number of shortest paths, some containing highly connected rich club edges while others are relatively isolated within individual modules. Overall, these findings reveal an intricate relationship between white matter anatomy and the structural connectome, motivating further exploration of EDI for biomarkers of cognition and behavior.
    NeuroImage 01/2015; 5. DOI:10.1016/j.neuroimage.2015.01.007 · 6.36 Impact Factor
Show more