The corpus callosum is hypothesized to play a fundamental role in integrating information and mediating complex behaviors. Here, we demonstrate that lack of normal callosal development can lead to deficits in functional connectivity that are related to impairments in specific cognitive domains. We examined resting-state functional connectivity in individuals with agenesis of the corpus callosum (AgCC) and matched controls using magnetoencephalographic imaging (MEG-I) of coherence in the alpha (8–12 Hz), beta (12–30 Hz) and gamma (30–55 Hz) bands. Global connectivity (GC) was defined as synchronization between a region and the rest of the brain. In AgCC individuals, alpha band GC was significantly reduced in the dorsolateral pre-frontal (DLPFC), posterior parietal (PPC) and parieto-occipital cortices (PO). No significant differences in GC were seen in either the beta or gamma bands. We also explored the hypothesis that, in AgCC, this regional reduction in functional connectivity is explained primarily by a specific reduction in interhemispheric connectivity. However, our data suggest that reduced connectivity in these regions is driven by faulty coupling in both inter- and intrahemispheric connectivity. We also assessed whether the degree of connectivity correlated with behavioral performance, focusing on cognitive measures known to be impaired in AgCC individuals. Neuropsychological measures of verbal processing speed were significantly correlated with resting-state functional connectivity of the left medial and superior temporal lobe in AgCC participants. Connectivity of DLPFC correlated strongly with performance on the Tower of London in the AgCC cohort. These findings indicate that the abnormal callosal development produces salient but selective (alpha band only) resting-state functional connectivity disruptions that correlate with cognitive impairment. Understanding the relationship between impoverished functional connectivity and cognition is a key step in identifying the neural mechanisms of language and executive dysfunction in common neurodevelopmental and psychiatric disorders where disruptions of callosal development are consistently identified.

BACKGROUND AND PURPOSE:Little is known about the anatomic connectivity of callosal axons in individuals with partial agenesis of the corpus callosum (pAgCC). We used tractography based on both diffusion tensor imaging (DTI) and high angular resolution diffusion imaging (HARDI) to investigate interhemispheric white matter connectivity in pAgCC.

Autism spectrum disorders (ASD) have numerous etiologies, including structural brain malformations such as agenesis of the corpus callosum (AgCC). We sought to directly measure the occurrence of autism traits in a cohort of individuals with AgCC and to investigate the neural underpinnings of this association. We screened a large AgCC cohort (n = 106) with the Autism Spectrum Quotient (AQ) and found that 45% of children, 35% of adolescents, and 18% of adults exceeded the predetermined autism-screening cut-off. Interestingly, performance on the AQ’s imagination domain was inversely correlated with magnetoencephalography measures of resting-state functional connectivity in the right superior temporal gyrus. Individuals with AgCC should be screened for ASD and disorders of the corpus callosum should be considered in autism diagnostic evaluations as well.

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.

Agenesis of the corpus callosum (AgCC) is a congenital brain malformation that occurs in approximately 1:1,000–1:6,000 births. Several syndromes associated with AgCC have been traced to single gene mutations; however, the majority of AgCC causes remain unidentified. We investigated a mother and two children who all shared complete AgCC and a chromosomal deletion at 1q42. We fine mapped this deletion and show that it includes Disrupted-in-Schizophrenia 1 (DISC1), a gene implicated in schizophrenia and other psychiatric disorders. Furthermore, we report a de novo chromosomal deletion at 1q42.13 to q44, which includes DISC1, in another individual with AgCC. We resequenced DISC1 in a cohort of 144 well-characterized AgCC individuals and identified 20 sequence changes, of which 4 are rare potentially pathogenic variants. Two of these variants were undetected in 768 control chromosomes. One of these is a splice site mutation at the 5’ boundary of exon 11 that dramatically reduces full-length mRNA expression of DISC1, but not of shorter forms. We investigated the developmental expression of mouse DISC1 and find that it is highly expressed in the embryonic corpus callosum at a critical time for callosal formation. Taken together our results suggest a significant role for DISC1 in corpus callosum development.