A Neuropsychological Profile for Agenesis of the Corpus Callosum?: Cognitive, Academic, Executive, Social, and Behavioral Functioning in School-Age Children

Objectives: Agenesis of the corpus callosum (AgCC), characterized by developmental absence of the corpus callosum, is one of the most common congenital brain malformations. To date, there are limited data on the neuropsychological consequences of AgCC and factors that modulate different outcomes, especially in children. This study aimed to describe general intellectual, academic, executive, social and behavioral functioning in a cohort of school-aged children presenting for clinical services to a hospital and diagnosed with AgCC. The influences of age, social risk and neurological factors were examined. Methods: Twenty-eight school-aged children (8 to 17 years) diagnosed with AgCC completed tests of general intelligence (IQ) and academic functioning. Executive, social and behavioral functioning in daily life, and social risk, were estimated from parent and teacher rated questionnaires. MRI findings reviewed by a pediatric neurologist confirmed diagnosis and identified brain characteristics. Clinical details including the presence of epilepsy and diagnosed genetic condition were obtained from medical records. Results: In our cohort, ~50% of children experienced general intellectual, academic, executive, social and/or behavioral difficulties and ~20% were functioning at a level comparable to typically developing children. Social risk was important for understanding variability in neuropsychological outcomes. Brain anomalies and complete AgCC were associated with lower mathematics performance and poorer executive functioning. Conclusions: This is the first comprehensive report of general intellectual, academic, executive social and behavioral consequences of AgCC in school-aged children. The findings have important clinical implications, suggesting that support to families and targeted intervention could promote positive neuropsychological functioning in children with AgCC who come to clinical attention

Large-scale functional network dynamics in human callosal agenesis:Increased subcortical involvement and preserved laterality

In the human brain, the corpus callosum is the major white-matter commissural tract enabling the transmission of sensory-motor, and higher level cognitive information between homotopic regions of the two cerebral hemispheres. Despite developmental absence (i.e., agenesis) of the corpus callosum (AgCC), functional connectivity is preserved, including interhemispheric connectivity. Subcortical structures have been hypothesised to provide alternative pathways to enable this preservation. To test this hypothesis, we used functional Magnetic Resonance Imaging (fMRI) recordings in children with AgCC and typically developing children, and a time-resolved approach to retrieve temporal characteristics of whole-brain functional networks. We observed an increased engagement of the cerebellum and amygdala/hippocampus networks in children with AgCC compared to typically developing children. There was little evidence that laterality of activation networks was affected in AgCC. Our findings support the hypothesis that subcortical structures play an essential role in the functional reconfiguration of the brain in the absence of a corpus callosum

Revisiting brain rewiring and plasticity in children born without corpus callosum

The corpus callosum is the largest white matter pathway connecting homologous structures of the two cerebral hemispheres. Remarkably, children and adults with developmental absence of the corpus callosum (callosal dysgenesis, CD) show typical interhemispheric integration, which is classically impaired in adult split-brain patients, for whom the corpus callosum is surgically severed. Tovar-Moll and colleagues (2014) proposed alternative neural pathways involved in the preservation of interhemispheric transfer. In a sample of six adults with CD, they revealed two homotopic bundles crossing the midline via the anterior and posterior commissures and connecting parietal cortices, and the microstructural properties of these aberrant bundles were associated with functional connectivity of these regions. The aberrant bundles were specific to CD and not visualised in healthy brains. We extended this study in a developmental cohort of 20 children with CD and 29 typically developing controls (TDC). The two anomalous white-matter bundles were visualised using tractography. Associations between structural properties of these bundles and their regional functional connectivity were explored. The proposed atypical bundles were observed in 30% of our CD cohort crossing via the anterior commissure, and in 30% crossing via the posterior commissure (also observed in 6.9% of TDC). However, the structural property measures of these bundles were not associated with parietal functional connectivity, bringing into question their role and implication for interhemispheric functional connectivity in CD. It is possible that very early disruption of embryological callosal development enhances neuroplasticity and facilitates the formation of these proposed alternative neural pathways, but further evidence is needed

Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual

Anterior and posterior commissures in agenesis of the corpus callosum: alternative pathways for attention processes?

Developmental absence (agenesis) of the corpus callosum (AgCC) is a congenital brain malformation resulting from disruption of corpus callosum formation, a structure that is crucial for the transfer and integration of information, including attention processes, across the brain. This study aimed to investigate previously proposed candidates for alternative inter-hemispheric pathways in AgCC by examining (1) white matter volume and microstructure of the anterior and posterior commissures in children with AgCC compared to typically developing controls (TDC), and (2) in children with AgCC, examine the associations of white matter volume and microstructure of the anterior and posterior commissures and any remaining corpus callosum with attention processes. Participants were 21 children with AgCC (13 complete, 8 partial) recruited from The Royal Children's Hospital, Melbourne, and 30 TDC aged 8–17 years. T1-and diffusion-weighted MR sequences were used to calculate volume and microstructural parameters. Neuropsychological testing assessed attention processes. We found the anterior commissure was significantly larger in volume in children with AgCC than TDC (p = .027), with reduced mean FA (p = .001) associated with increased mean RD (p < .001). In children with AgCC, we found microstructural properties of the anterior commissure associated with attentional processes, specifically, mean FA of the anterior commissure was associated with better divided attention (p = .03), and the association between alerting attention and mean AD and RD was found to be moderated by age (p = .027, p = .008) and the degree of corpus callosum agenesis (p = .025, p = .016). Furthermore, in partial AgCC, larger posterior commissure volume was associated with better orienting attention (p = .035). In conclusion, we provide evidence that the volume and microstructure of the anterior commissure are altered in children with AgCC, and this neuroplastic response might have an influence on attention processes

Investigating the lateralisation and disconnection model of social functioning in Agenesis of the Corpus Callosum using cognitive neuroscience techniques

© 2013 Dr. Alissandra May McIlroyRecent research has begun to characterise the nature of social dysfunction in individuals with agenesis of the corpus callosum (ACC). Typical lateralisation of function coupled with disrupted interhemispheric transfer between the cerebral hemispheres has been proposed to account for the difficulties observed on various socio-emotional tasks in ACC, ranging from basic emotion perception through to higher-level nonliteral language comprehension and social reasoning. It has also been speculated that this laterality and disconnection model applies to social difficulties experienced in everyday life. The key underlying assumptions of the model have not been directly addressed, however. Specifically, the cerebral lateralisation of socio-emotional functions has not been investigated in individuals with ACC, and whilst it is known that interhemispheric transfer capacities are limited by task complexity, transfer of socially relevant information between the left and right hemispheres has not been assessed to date. The present thesis investigated the lateralisation of emotional and non-emotional face processing and language in individuals with ACC as well as the interhemispheric transfer and integration of emotional information. The impact of other factors (extent of ACC, comorbid brain malformations and handedness) on laterality and interhemispheric transfer were also considered. Twenty-two participants with ACC (50% male; 47% right-handed) aged between 8.33 and 22.67 years (M= 12.13 years, SD= 3.28 years) and 16 typically developing controls (50% male; 75% right-handed) aged between 8.00 and 22.50 years (M= 12.64 years, SD= 3.63 years) were recruited through the Royal Children’s Hospital, Melbourne. Participants completed three out-of-scanner computerised tasks (chimeric faces, face matching and face-word matching tasks) and two in-scanner functional magnetic resonance imaging tasks (explicit emotion processing and noun-verb generation tasks). There was convergent evidence for a higher rate of atypical lateralisation of socially relevant functions in ACC. In addition, there was evidence for a reduction (but not elimination) of the capacity for interhemispheric transfer and integration of facial expressions and affective labels in ACC. Only individuals in the partial ACC group were able to match bilaterally presented facial expressions at above chance levels, suggesting some capacity for interhemispheric transfer of facial emotion information in this group, but elimination of this capacity in the complete ACC group. Whilst the results of the interhemispheric transfer experiments largely fit with the propositions of the laterality and disconnection model, the evidence for atypical lateralisation in ACC indicates that the model does not provide a sufficient explanation for social dysfunction in this population. Alternative models that account for individual variability in ACC will be discussed

Inhibitory control in children with agenesis of the corpus callosum compared with typically developing children

OBJECTIVES: The developmental absence (agenesis) of the corpus callosum (AgCC) is a congenital brain malformation associated with risk for a range of neuropsychological difficulties. Inhibitory control outcomes, including interference control and response inhibition, in children with AgCC are unclear. This study examined interference control and response inhibition: 1) in children with AgCC compared with typically developing (TD) children, 2) in children with different anatomical features of AgCC (complete vs. partial, isolated vs. complex), and 3) associations with white matter volume and microstructure of the anterior (AC) and posterior commissures (PC) and any remnant corpus callosum (CC). METHODS: Participants were 27 children with AgCC and 32 TD children 8-16 years who completed inhibitory control assessments and brain MRI to define AgCC anatomical features and measure white matter volume and microstructure. RESULTS: The AgCC cohort had poorer performance and higher rates of below average performance on inhibitory control measures than TD children. Children with complex AgCC had poorer response inhibition performance than children with isolated AgCC. While not statistically significant, there were select medium to large effect sizes for better inhibitory control associated with greater volume and microstructure of the AC and PC, and with reduced volume and microstructure of the remnant CC in partial AgCC. CONCLUSIONS: This study provides evidence of inhibitory control difficulties in children with AgCC. While the sample was small, the study found preliminary evidence that the AC ( f 2=.18) and PC ( f 2=.30) may play a compensatory role for inhibitory control outcomes in the absence of the CC

Structural neuroplastic responses preserve functional connectivity and neurobehavioural outcomes in children born without corpus callosum

The corpus callosum is the largest white matter pathway in the brain connecting the two hemispheres. In the context of developmental absence (agenesis) of the corpus callosum (AgCC), a proposed candidate for neuroplastic response is strengthening of intrahemispheric pathways. To test this hypothesis, we assessed structural and functional connectivity in a uniquely large cohort of children with AgCC (n&thinsp;=&thinsp;20) compared with typically developing controls (TDC, n&thinsp;=&thinsp;29), and then examined associations with neurobehavioral outcomes using a multivariate data-driven approach (partial least squares correlation, PLSC). For structural connectivity, children with AgCC showed a significant increase in intrahemispheric connectivity in addition to a significant decrease in interhemispheric connectivity compared with TDC, in line with the aforementioned hypothesis. In contrast, for functional connectivity, children with AgCC and TDC showed a similar pattern of intrahemispheric and interhemispheric connectivity. In conclusion, we observed structural strengthening of intrahemispheric pathways in children born without corpus callosum, which seems to allow for functional connectivity comparable to a typically developing brain, and were relevant to explain neurobehavioral outcomes in this population. This neuroplasticity might be relevant to other disorders of axonal guidance, and developmental disorders in which corpus callosum alteration is observed</div