The structural connectome of the human brain in agenesis of the corpus callosum

Abstract

Adopting a network perspective, the structural connectome reveals the large-scale white matter connectivity of the human brain, yielding insights into cerebral organization otherwise inaccessible to researchers and clinicians. Connectomics has great potential for elucidating abnormal connectivity in congenital brain malformations, especially axonal pathfinding disorders. Agenesis of the corpus callosum (AgCC) is one of the most common brain malformations and can also be considered a prototypical genetic disorder of axonal guidance in humans. In this exploratory study, the structural connectome of AgCC is mapped and compared to that of the normal human brain. Multiple levels of granularity of the AgCC connectome are investigated, including summary network metrics, modularity analysis, and network consistency measures, with comparison to the normal structural connectome after simulated removal of all callosal connections (“virtual callostomy”). These investigations reveal four major findings. First, global connectivity is abnormally reduced in AgCC, but local connectivity is increased. Second, the network topology of AgCC is more variable than that of the normal human connectome, contradicting the predictions of the virtual callosotomy model. Third, modularity analysis reveals that many of the tracts that comprise the structural core of the cerebral cortex have relatively weak connectivity in AgCC, especially the cingulate bundles bilaterally. Finally, virtual lesions of the Probst bundles in the AgCC connectome demonstrate that there is consistency across subjects in many of the connections generated by these ectopic white matter tracts, and that they are a mixture of cortical and subcortical fibers. These results go beyond prior diffusion tractography studies to provide a systems-level perspective on anomalous connectivity in AgCC. Furthermore, this work offers a proof of principle for the utility of the connectome framework in neurodevelopmental disorders.

Structural and functional brain rewiring clarifies preserved interhemispheric transfer in humans born without the corpus callosum

“…We hypothesize, along with Owen et al (19), that the reported abnormal tracts, and perhaps additional ones yet to be described in the white matter of CD patients, result from abnormal molecular mechanisms taking place in the natural course of events in ontogenesis, leading to an anomalous network of connections in these subjects.…”

“…Together, the longtime known Probst bundle (10), the more recently described sigmoid bundle (11), and the two novel aberrant midbrain and ventral forebrain tracts here reported make up the fundamental brain circuitry of CD subjects (12,19). We focused on the abnormal commissural interhemispheric bundles and showed that they link structurally and functionally the two homotopically synchronized posterior parietal areas (primarily BA39), cortical sectors involved in tactile object recognition (17,18,20).…”

Resting-State Networks and the Functional Connectome of the Human Brain in Agenesis of the Corpus Callosum

“…Overall, the findings may result from indirect commissural pathways maintaining bilateral resting-state networks in the absence of direct callosal routes, although with reduced interhemispheric functional connectivity in highly connected hub regions, and possibly also a mechanism involving a common external impetus such as the thalamus enforcing bihemispheric temporal synchrony. The strength of inter-regional functional connectivity was also strikingly more variable across AgCC subjects than controls, which may in part reflect the less consistent organization of their anatomic connectivity, as shown in a recent study of the AgCC structural connectome (Owen et al, 2013a). These initial observations demonstrate the great potential of resting-state fMRI to reveal abnormal function in the malformed brain and thereby also help elucidate the function of the normal human brain.…”

“…Hypothesis-driven analyses of structural connectivity of partial AgCC using fiber tractography (Tovar-Moll et al, 2007;Wahl et al, 2009) have shown that some of these individuals have novel heterotopic callosal connections such as sigmoid bundles not seen in the control population. These patterns of connectivity were not seen in all pAgCC subjects, which implies that the aberrant anatomic connectivity of AgCC is individualized, thereby contributing to the relatively variable topology observed across subjects in their structural connectomes (Owen et al, 2013a). The inconsistent organization of the structural connectome in AgCC could provide a basis for the larger inter-subject variation that we observe in the functional connectivity of these subjects versus normal volunteers (Tables 3 and Supplementary Table S2).…”

“…In a recent paper (Owen et al, 2013a), the structural connectome of complete AgCC subjects was investigated using diffusion MRI and tractography. This work found that the modular organization in cAgCC is profoundly reorganized.…”