The corpus callosum is the major axon tract that connects and integrates neural activity between the two cerebral hemispheres. Although ∼1:4,000 children are born with developmental absence of the corpus callosum, the primary etiology of this condition remains unknown. Here, we demonstrate that midline crossing of callosal axons is dependent upon the prior remodeling and degradation of the intervening interhemispheric fissure. This remodeling event is initiated by astroglia on either side of the interhemispheric fissure, which intercalate with one another and degrade the intervening leptomeninges. Callosal axons then preferentially extend over these specialized astroglial cells to cross the midline. A key regulatory step in interhemispheric remodeling is the differentiation of these astroglia from radial glia, which is initiated by Fgf8 signaling to downstream Nfi transcription factors. Crucially, our findings from human neuroimaging studies reveal that developmental defects in interhemispheric remodeling are likely to be a primary etiology underlying human callosal agenesis.

Structural magnetic resonance (MR) connectomics holds promise for the diagnosis, outcome prediction, and treatment monitoring of many common neurodevelopmental, psychiatric, and neurodegenerative disorders for which there is currently no clinical utility for MR imaging (MRI). Before computational network metrics from the human connectome can be applied in a clinical setting, their precision and their normative intersubject variation must be understood to guide the study design and the interpretation of longitudinal data. In this work, the reproducibility of commonly used graph theoretic measures is investigated, as applied to the structural connectome of healthy adult volunteers. Two datasets are examined, one consisting of 10 subjects scanned twice at one MRI facility and one consisting of five subjects scanned once each at two different facilities using the same imaging platform. Global graph metrics are calculated for unweighed and weighed connectomes, and two levels of granularity of the connectome are evaluated: one based on the 82-node cortical and subcortical parcellation from FreeSurfer and one based on an atlas-free parcellation of the gray-white matter boundary consisting of 1000 cortical nodes. The consistency of the unweighed and weighed edges and the module assignments are also computed for the 82-node connectomes. Overall, the results demonstrate good-to-excellent test-retest reliability for the entire connectome-processing pipeline, including the graph analytics, in both the intrasite and intersite datasets. These findings indicate that measurements of computational network metrics derived from the structural connectome have sufficient precision to be tested as potential biomarkers for diagnosis, prognosis, and monitoring of interventions in neurological and psychiatric diseases.

The corpus callosum is the largest white matter fiber bundle connecting the two cerebral hemispheres. In this work, we investigate the effect of callosal dysgenesis on functional magnetic resonance imaging (fMRI) resting-state networks and the functional connectome. Since alternate commissural routes between the cerebral hemispheres exist, we hypothesize that bilateral cortical networks can still be maintained in partial or even complete agenesis of the corpus callosum (AgCC). However, since these commissural routes are frequently indirect, requiring polysynaptic pathways, we hypothesize that quantitative measurements of interhemispheric functional connectivity in bilateral networks will be reduced in AgCC compared with matched controls, especially in the most highly interconnected cortical regions that are the hubs of the connectome. Seventeen resting-state networks were extracted from fMRI of 11 subjects with partial or complete AgCC and 11 matched controls. The results show that the qualitative organization of resting-state networks is very similar between controls and AgCC. However, interhemispheric functional connectivity of precuneus, posterior cingulate cortex, and insular-opercular regions was significantly reduced in AgCC. The preserved network organization was confirmed with a connectomic analysis of the resting-state fMRI data, showing five functional modules that are largely consistent across the control and AgCC groups. Hence, the reduction or even complete absence of callosal connectivity does not affect the qualitative organization of bilateral resting-state networks or the modular organization of the functional connectome, although quantitatively reduced functional connectivity can be demonstrated by measurements within bilateral cortical hubs, supporting the hypothesis that indirect polysynaptic pathways are utilized to preserve interhemispheric temporal synchrony.

The development of hemispheric lateralization for language is poorly understood. In one hypothesis, early asymmetric gene expression assigns language to the left hemisphere. In an alternate view, language is represented a priori in both hemispheres and lateralization emerges via cross-hemispheric communication through the corpus callosum. To address this second hypothesis, we capitalized on the high temporal and spatial resolution of magnetoencephalographic imaging to measure cortical activity during language processing, speech preparation, and speech execution in 25 participants with agenesis of the corpus callosum (AgCC) and 21 matched neurotypical individuals. In contrast to strongly lateralized left hemisphere activations for language in neurotypical controls, participants with complete or partial AgCC exhibited bilateral hemispheric activations in both auditory or visually driven language tasks, with complete AgCC participants showing significantly more right hemisphere activations than controls or than individuals with partial AgCC. In AgCC individuals, language laterality positively correlated with verbal IQ. These findings suggest that the corpus callosum helps to drive language lateralization.

Significance statement

The role that corpus callosum development has on the hemispheric specialization of language is poorly understood. Here, we used magnetoencephalographic imaging during linguistic tests (verb generation, picture naming) to test for hemispheric dominance in patients with agenesis of the corpus callosum (AgCC) and found reduced laterality (i.e., greater likelihood of bilaterality or right hemisphere dominance) in this cohort compared with controls, especially in patients with complete agenesis. Laterality was positively correlated with behavioral measures of verbal intelligence. These findings provide support for the hypothesis that the callosum aids in functional specialization throughout neural development and that the loss of this mechanism correlates with impairments in verbal performance.

Sensorimotor deficits are prevalent in many neurodevelopmental disorders like autism, including one of its common genetic etiologies, a 600 kb reciprocal deletion/duplication at 16p11.2. We have previously shown that copy number variations of 16p11.2 impact regional brain volume, white matter integrity, and early sensory responses in auditory cortex. Here, we test the hypothesis that abnormal cortical neurophysiology is present when genes in the 16p11.2 region are haploinsufficient, and in humans that this in turn may account for behavioral deficits specific to deletion carriers. We examine sensorimotor cortical network activity in males and females with 16p11.2 deletions compared with both typically developing individuals, and those with duplications of 16p11.2, using magnetoencephalographic imaging during preparation of overt speech or hand movements in tasks designed to be easy for all participants. In deletion carriers, modulation of beta oscillations (12-30 Hz) were increased during both movement types over effector-specific regions of motor cortices compared with typically developing individuals or duplication carriers, with no task-related performance differences between cohorts, even when corrected for their own cognitive and sensorimotor deficits. Reduced left hemispheric language specialization was observed in deletion carriers but not in duplication carriers. Neural activity over sensorimotor cortices in deletion carriers was linearly related to clinical measures of speech and motor impairment. These findings link insufficient copy number repeats at 16p11.2 to excessive neural activity (e.g., increased beta oscillations) in motor cortical networks for speech and hand motor control. These results have significant implications for understanding the neural basis of autism and related neurodevelopmental disorders.SIGNIFICANCE STATEMENT The recurrent ∼600 kb deletion at 16p11.2 (BP4-BP5) is one of the most common genetic etiologies of ASD and, more generally, of neurodevelopmental disorders. Here, we use high-resolution magnetoencephalographic imaging (MEG-I) to define with millisecond precision the underlying neurophysiological signature of motor impairments for individuals with 16p11.2 deletions. We identify significant increases in beta (12-30 Hz) suppression in sensorimotor cortices related to performance during speech and hand movement tasks. These findings not only provide a neurophysiological phenotype for the clinical presentation of this genetic deletion, but also guide our understanding of how genetic variation encodes for neural oscillatory dynamics.

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.

Copy number variants (CNVs) of the chromosomal locus 16p11.2, consisting of either deletions or duplications, have been implicated in autism, schizophrenia, epilepsy, and other neuropsychiatric disorders. Since abnormal white matter microstructure can be seen in these more broadly defined clinical disorders, we used diffusion magnetic resonance imaging and tract-based spatial statistics to investigate white matter microstructural integrity in human children with 16p11.2 deletions. We show that deletion carriers, compared with typically developing matched controls, have increased axial diffusivity (AD) in many major central white matter tracts, including the anterior corpus callosum as well as bilateral internal and external capsules. Higher AD correlated with lower nonverbal IQ in the deletion carriers, but not controls. Increases in fractional anisotropy and mean diffusivity were also found in some of the same tracts with elevated AD. Closer examination with neurite orientation dispersion and density imaging revealed that fiber orientation dispersion was decreased in some central white matter tracts. Notably, these alterations of white matter are unlike microstructural differences reported for any other neurodevelopmental disorders, including autism spectrum disorders that have phenotypic overlap with the deletion carriers. These findings suggest that deletion of the 16p11.2 locus is associated with a unique widespread pattern of aberrant white matter microstructure that may underlie the impaired cognition characteristic of this CNV.

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.

Copy number variants at the 16p11.2 chromosomal locus are associated with several neuropsychiatric disorders, including autism, schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder, and speech and language disorders. A gene dosage dependence has been suggested, with 16p11.2 deletion carriers demonstrating higher body mass index and head circumference, and 16p11.2 duplication carriers demonstrating lower body mass index and head circumference. Here, we use diffusion tensor imaging to elucidate this reciprocal relationship in white matter organization, showing widespread increases of fractional anisotropy throughout the supratentorial white matter in pediatric deletion carriers and, in contrast, extensive decreases of white matter fractional anisotropy in pediatric and adult duplication carriers. We find associations of these white matter alterations with cognitive and behavioral impairments. We further demonstrate the value of imaging metrics for characterizing the copy number variant phenotype by employing linear discriminant analysis to predict the gene dosage status of the study subjects. These results show an effect of 16p11.2 gene dosage on white matter microstructure, and further suggest that opposite changes in diffusion tensor imaging metrics can lead to similar cognitive and behavioral deficits. Given the large effect sizes found in this study, our results support the view that specific genetic variations are more strongly associated with specific brain alterations than are shared neuropsychiatric diagnoses. Hum Brain Mapp 37:2833-2848, 2016. © 2016 Wiley Periodicals, Inc.