Intact Bilateral Resting-State Networks in the Absence of the Corpus Callosum

Temporal correlations between different brain regions in the resting-state BOLD signal are thought to reflect intrinsic functional brain connectivity (Biswal et al., 1995; Greicius et al., 2003; Fox et al., 2007). The functional networks identified are typically bilaterally distributed across the cerebral hemispheres, show similarity to known white matter connections (Greicius et al., 2009), and are seen even in anesthetized monkeys (Vincent et al., 2007). Yet it remains unclear how they arise. Here we tested two distinct possibilities: (1) functional networks arise largely from structural connectivity constraints, and generally require direct interactions between functionally coupled regions mediated by white-matter tracts; and (2) functional networks emerge flexibly with the development of normal cognition and behavior and can be realized in multiple structural architectures. We conducted resting-state fMRI in eight adult humans with complete agenesis of the corpus callosum (AgCC) and normal intelligence, and compared their data to those from eight healthy matched controls. We performed three main analyses: anatomical region-of-interest-based correlations to test homotopic functional connectivity, independent component analysis (ICA) to reveal functional networks with a data-driven approach, and ICA-based interhemispheric correlation analysis. Both groups showed equivalently strong homotopic BOLD correlation. Surprisingly, almost all of the group-level independent components identified in controls were observed in AgCC and were predominantly bilaterally symmetric. The results argue that a normal complement of resting-state networks and intact functional coupling between the hemispheres can emerge in the absence of the corpus callosum, favoring the second over the first possibility listed above

Cognitive and psychosocial deficits in agenesis of the corpus callosum with normal intelligence

Cognitive disabilities in agenesis of the corpus callosum (ACC) have been described in scattered reports, but few complete case descriptions are available. Consequent psychosocial disabilities in ACC have received little attention. We expected that ACC would be manifest in deficits specific to complex reasoning, concept formation, and problem solving. We also expected that these cognitive problems would be particularly evident in difficulties interpreting and understanding social situations, and in abnormal self-perception. Methods. Cognitive and psychosocial deficits were studied in two adolescents with ACC and normal IQ using a battery of cognitive and psychological tests. Results. Test results indicated poor interhemispheric integration of complex material. Performance on tests of reasoning, and concept formation were clearly below expectations based on IQ. Significantly poor performance was also found on tests of social insight, proverb interpretation, social logic, self-perception, and interpretation of ambiguous stimuli. Gross behavioural disorder or psychopathology were not found. Conclusions. ACC results in disabilities in social cognition that appear to be secondary to deficits in complex cognitive operations such as reasoning, concept formation, and problem solving. It is suggested that these cognitive deficits may be related to diminished interhemispheric transfer of complex information

Brain Connectivity in Autism: The Significance of Null Findings

Autism spectrum disorder (ASD) has become a case study for illustrating the difficulty in tracing a psychiatric disorder to its underlying causes—psychological, genetic, or neurological. Aside from theories derived from the very criteria used to diagnose ASD, one would be hard-pressed to find a psychological theory that is not hotly disputed. Genetic investigations revealed that very large sample sizes are required to tease out the very small effects of very many genes, or large effects of genes present in only very few cases. Meanwhile, investigators doing work at the neurological level have held out hope that their theories might, finally, serve to provide a compact and reliable explanation of ASD that could best mediate between the genes and the phenotype. A new study by Lefebvre et al. ( 1) in this issue of Biological Psychiatry is beginning to cast some doubt that a simple anatomical story will emerge

Proverb comprehension in individuals with agenesis of the corpus callosum

Comprehension of non-literal language involves multiple neural systems likely involving callosal connections. We describe proverb comprehension impairments in individuals with isolated agenesis of the corpus callosum (AgCC) and normal-range general intelligence. Experiment 1 compared Gorham Proverb Test (Gorham, 1956) performance in 19 adults with AgCC and 33 neurotypical control participants of similar age, sex, and intelligence. Experiment 2 used the Proverbs subtest of the Delis-Kaplan Executive Function System (D-KEFS, 2001) to compare 19 adults with AgCC and 17 control participants with similar age, sex, and intelligence. Gorham Proverbs performance was impaired in the AgCC group for both the free-response and multiple-choice tasks. On the D-KEFS proverbs test, the AgCC group performed significantly worse on the free-response task (and all derivative scores) despite normal levels of performance on the multiple-choice task. Covarying verbal intelligence did not alter these outcomes. However, covarying a measure of non-literal language comprehension considerably reduced group differences in proverb comprehension on the Gorham test, but had little effect on the D-KEFS group differences. The difference between groups seemed to be greatest when participants had to generate their own interpretation (free response), or in the multiple choice format when the test included many proverbs that were likely to be less familiar. Taken together, the results of this study clearly show that proverb comprehension is diminished in individuals with AgCC compared to their peers

Verbal learning and memory in agenesis of the corpus callosum

The role of interhemispheric interactions in the encoding, retention, and retrieval of verbal memory can be clarified by assessing individuals with complete or partial agenesis of the corpus callosum (AgCC), but who have normal intelligence. This study assessed verbal learning and memory in AgCC using the California Verbal Learning Test—Second Edition (CVLT-II). Twenty-six individuals with AgCC were compared to 24 matched controls on CVLT-II measures, as well as Donders׳ four CVLT-II factors (i.e., Attention Span, Learning Efficiency, Delayed Memory, and Inaccurate Memory). Individuals with AgCC performed significantly below healthy controls on the Delayed Memory factor, confirmed by significant deficits in short and long delayed free recall and cued recall. They also performed less well in original learning. Deficient performance by individuals with AgCC during learning trials, as well as deficits in all forms of delayed memory, suggest that the corpus callosum facilitates interhemispheric elaboration and encoding of verbal information

Does bilateral damage to the human amygdala produce autistic symptoms?

A leading neurological hypothesis for autism postulates amygdala dysfunction. This hypothesis has considerable support from anatomical and neuroimaging studies. Individuals with bilateral amygdala lesions show impairments in some aspects of social cognition. These impairments bear intriguing similarity to those reported in people with autism, such as impaired recognition of emotion in faces, impaired theory of mind abilities, failure to fixate eyes in faces, and difficulties in regulating personal space distance to others. Yet such neurological cases have never before been assessed directly to see if they meet criteria for autism spectrum disorders (ASD). Here we undertook such an investigation in two rare participants with developmental-onset bilateral amygdala lesions. We administered a comprehensive clinical examination, as well as the Autism Diagnostic Observation Schedule (ADOS), the Social Responsiveness Scale (SRS), together with several other standardized questionnaires. Results from the two individuals with amygdala lesions were compared with published norms from both healthy populations as well as from people with ASD. Neither participant with amygdala lesions showed any evidence of autism across the array of different measures. The findings demonstrate that amygdala lesions in isolation are not sufficient for producing autistic symptoms. We suggest instead that it may be abnormal connectivity between the amygdala and other structures that contributes to autistic symptoms at a network level

Agenesis of the corpus callosum and autism: a comprehensive comparison

The corpus callosum, with its ∼200 million axons, remains enigmatic in its contribution to cognition and behaviour. Agenesis of the corpus callosum is a congenital condition in which the corpus callosum fails to develop; such individuals exhibit localized deficits in non-literal language comprehension, humour, theory of mind and social reasoning. These findings together with parent reports suggest that behavioural and cognitive impairments in subjects with callosal agenesis may overlap with the profile of autism spectrum disorders, particularly with respect to impairments in social interaction and communication. To provide a comprehensive test of this hypothesis, we directly compared a group of 26 adults with callosal agenesis to a group of 28 adults with a diagnosis of autism spectrum disorder but no neurological abnormality. All participants had full-scale intelligence quotient scores >78 and groups were matched on age, handedness, and gender ratio. Using the Autism Diagnostic Observation Schedule together with current clinical presentation to assess autistic symptomatology, we found that 8/26 (about a third) of agenesis subjects presented with autism. However, more formal diagnosis additionally involving recollective parent-report measures regarding childhood behaviour showed that only 3/22 met complete formal criteria for an autism spectrum disorder (parent reports were unavailable for four subjects). We found no relationship between intelligence quotient and autism symptomatology in callosal agenesis, nor evidence that the presence of any residual corpus callosum differentiated those who exhibited current autism spectrum symptoms from those who did not. Relative to the autism spectrum comparison group, parent ratings of childhood behaviour indicated children with agenesis were less likely to meet diagnostic criteria for autism, even for those who met autism spectrum criteria as adults, and even though there was no group difference in parent report of current behaviours. The findings suggest two broad conclusions. First, they support the hypothesis that congenital disruption of the corpus callosum constitutes a major risk factor for developing autism. Second, they quantify specific features that distinguish autistic behaviour associated with callosal agenesis from autism more generally. Taken together, these two findings also leverage specific questions for future investigation: what are the distal causes (genetic and environmental) determining both callosal agenesis and its autistic features, and what are the proximal mechanisms by which absence of the callosum might generate autistic symptomatology

Learning and memory in individuals with agenesis of the corpus callosum

Damage to long white matter pathways in the cerebral cortex is known to affect memory capacity. However, the specific contribution of interhemispheric connectivity in memory functioning is only beginning to become understood. The present study examined verbal and visual memory processing in individuals with agenesis of the corpus callosum (AgCC) using the Wechsler Memory Scale-Third Edition (WMS-III; Wechsler, 1997b). Thirty participants with AgCC (FSIQ >78) were compared against 30 healthy age and IQ matched controls on auditory/verbal (Logical Memory, Verbal Paired Associates) and visual (Visual Reproduction, Faces) memory subtests. Performance was worse in AgCC than controls on immediate and delayed verbal recall for rote word pairs and on delayed recall of faces, as well as on percent recall for these tasks. Immediate recall for thematic information from stories was also worse in AgCC, but groups did not differ on memory for details from narratives or on recall for thematic information following a time delay. Groups also did not differ on memory for abstract figures or immediate recall of faces. On all subtests, individuals with AgCC had greater frequency of clinically significant impairments than predicted by the normal distribution. Results suggest less efficient overall verbal and visual learning and memory with relative weaknesses processing verbal pairs and delayed recall for faces. These findings suggest that the corpus callosum facilitates more efficient learning and recall for both verbal and visual information, that individuals with AgCC may benefit from receiving verbal information within semantic context, and that known deficits in facial processing in individuals with AgCC may contribute to their impairments in recall for faces

Cognitive and psychosocial deficits in agenesis of the corpus callosum with normal intelligence

Cognitive disabilities in agenesis of the corpus callosum (ACC) have been described in scattered reports, but few complete case descriptions are available. Consequent psychosocial disabilities in ACC have received little attention. We expected that ACC would be manifest in deficits specific to complex reasoning, concept formation, and problem solving. We also expected that these cognitive problems would be particularly evident in difficulties interpreting and understanding social situations, and in abnormal self-perception. Methods. Cognitive and psychosocial deficits were studied in two adolescents with ACC and normal IQ using a battery of cognitive and psychological tests. Results. Test results indicated poor interhemispheric integration of complex material. Performance on tests of reasoning, and concept formation were clearly below expectations based on IQ. Significantly poor performance was also found on tests of social insight, proverb interpretation, social logic, self-perception, and interpretation of ambiguous stimuli. Gross behavioural disorder or psychopathology were not found. Conclusions. ACC results in disabilities in social cognition that appear to be secondary to deficits in complex cognitive operations such as reasoning, concept formation, and problem solving. It is suggested that these cognitive deficits may be related to diminished interhemispheric transfer of complex information