Research

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icn bullet large RESEARCH UPDATE


What Research is being done


Research into disorders of the corpus callosum (DCC) has taken off in the last two decades, as brain scanning has become more accessible leading to more people being diagnosed with the condition. The underlying causes and consequences of DCC largely remain unknown, but scientists from around the world have recently formed the International Research Consortium for the Corpus Callosum and Cerebral Connectivity (IRC5 in order to better understand disorders of the corpus callosum and associated disorders of cerebral connectivity. The consortium was established in 2015 and, although a small research community, it is unique in bringing together scientists from different disciplines including genetics and molecular biology, neurology, neuroscience, neuropsychology and psychiatry. Through this collaborative network it is hoped that the field will advance more quickly and ultimately help more people affected by DCC.

For more information on the IRC5 see www.irc5.org

On the 28th June 2018, IRC5 hosted the Cortical Connections Symposium in Costa Mesa, California. This scientific meeting was designed for physicians and clinical professionals who treat individuals with developmental malformations of brain connectivity and researchers studying these conditions. Parents and adults with ACC were also welcome to attend.

The Symposium provided an excellent overview of the current science into ACC and we got to listen to the leading researchers in the field who were all passionate about what they do.

The main questions driving their work include:

  • How does the corpus callosum and other white matter develop?
  • What happens in the brain when the corpus callosum does not form correctly?
  • What genes are involved in callosal development?
  • How does it manifest in brain scans?
  • What are the long-term implications in terms of behaviour and cognition?

Here are some highlights from the Symposium:

Fernanda Tovar-Moll (Adjunct Professor, National Center of Structural Biology and Bioimaging at Federal University of Rio de Janeiro, and co-founder and president of the D’Or Institute for Research and Education, Rio de Janeiro)

Prof Fernanda Tovar-Moll and her colleagues are interested in how the brain reorganises itself following a disruption in early development. Her research team uses sophisticated brain imaging methods and found the two hemispheres of the brain still manage to communicate with each other and transfer information despite the absence of the corpus callosum. This suggests that alternative pathways can be formed that may be compensatory in nature. For example, the bundles of axons normally destined to cross the corpus callosum can become rerouted when the normal developmental process is interrupted. These white matter bundles (e.g., Probst bundles and sigmoid bundles) still play an important role in connecting brain regions and are involved in the "long-range" transfer of information between hemispheres.

Linda Richards (Professor of Neuroscience and Deputy Director, Queensland Brain Institute at the University of Queensland; Patron and Scientific Advisor of AusDoCC, the Australian family support group for Disorders of the Corpus Callosum).

Prof Linda Richards is a leading developmental neuroscientist who has conducted pioneering work in how the brain is normally wired during development and what mechanisms may be involved when this process is disrupted. Traditional views of brain development regard the process as hardwired with genes predetermining how brain structures mature. With more modern research methods available, there is evidence that brain development is an adaptive and flexible process with the on-going interaction between genes and the environment playing a crucial role.

Researching individuals with disorders of the corpus callosum (DCC) provides a unique insight into the underlying mechanisms that control the plasticity of the brain and in particular, the development of the neuronal connections between the hemispheres. Prof Richards and colleagues have found the brain can rewire itself during development and produce long-range projections between different brain areas. They are trying to understand how different patterns of brain wiring may relate to the cognitive profile of the individual with DCC; for example, some connections may be essential, while others could be compensated for and not as essential as previously thought. Understanding the role of different patterns of brain wiring could help explain why individuals with DCC have widely different symptoms and outcomes.

A fascinating line of enquiry into the formation of the corpus callosum is to study the mechanisms that led to the evolution of this structure. Interestingly, not all mammals have a corpus callosum; it is present in placental mammals but did not evolve in marsupials and egg-laying monotremes. Instead, their hemispheres communicate by using a simpler network of nerve fibres.

Being based in Australia, Prof Richards and her laboratory team* are in a prime position to study early brain formation in marsupials. They have extensively studied a tiny species of marsupial called the fat-tailed dunnart. This mouse-like creature is born at a very early stage of brain development, just when the nervous system is beginning to form. As most of its cortical development occurs while the joey is inside the mother’s pouch, rather than the uterus, scientists have easy access to studying and manipulating this process - simply by opening up the pouch!

This exciting new scientific approach has allowed researchers to gain crucial insights into the early mechanisms of brain formation as well as genetic and environmental influences. For example, the Satb2 gene, which has been found to contribute to the production of neurons that form the corpus callosum, is also present in the fat-tailed dunnart. This gene may instead have a role in forming other connections such as the anterior commissure in marsupials.

Prof Richards and her laboratory team have also used MRI scans to examine the brains of marsupials and monotremes, and have found that nerve fibres that connect the hemispheres are arranged in a specific pattern, very similar to those found in the corpus callosum. This has led to the conclusion that there are specific ways in which the hemispheres prefer to connect in all mammals, and the principles that guide this formation must originate very early on in mammalian evolution. This provides evidence of a very ancient network, from which the corpus callosum evolved, possibly as a means to expand the existing hemispheric connections, rather than being a structure that evolved independently. These new findings may help our understanding of conditions with abnormal brain connectivity, including DCC.

Prof. Richards’ laboratory members are:

Dr Rodrigo Suarez

Dr Jens Bunt

Dr Laura Fenlon

Dr Peter Kozulin

Dr Ryan Dean

Dr Kok-Siong Chen

Dr Timothy Edwards

Dr Annalisa Paolino

Dr Elizabeth Haines

Dr Caitin Bridges

Ms Ching Moey

Mr Jonathan Lim

Ms Laura Morcom

Mr Tobias Bluett

Ms Yunan Yi

Ms Donna Simon

If you want to know more about who the Laboratory members are, please follow the following link. https://qbi.uq.edu.au/richardsgroup

Elliott Sherr (MD, Professor in Neurology and Pediatrics, Institute of Human Genetics and the Weill Institute of Neurosciences, University of California, San Francisco, UCSF)

Prof Elliott Sherr is a Child Neurologist and co-directs the Comprehensive Center for Brain Development at UCSF. His research team studies the genetic and biological mechanisms of disorders of brain development including epilepsy, autism and agenesis of the corpus callosum. They have found that both inherited and non-inherited (i.e., spontaneous) genetic events play an important role in causing brain malformations.

Prof Sherr described how the field of genetic testing has moved rapidly in the last 15 years. In 2003, the state of the art in genetic testing involved looking at chromosomes under a microscope; however our knowledge of genetic disorders was limited - testing 100 individuals would only result in about 8 receiving a genetic diagnosis. Modern sequencing tools have transformed the way that geneticists have been able to identify specific gene mutations, with around 30 to 45% of individuals with ACC now having an identifiable genetic cause. The likelihood of receiving a diagnosis increases if the individual has several congenital abnormalities, such as heart or vision defects. ACC is well known to have a wide range of outcomes and this variability is likely to be related to the diversity in genetic causes that have been found.

Knowing more about which specific genes influence the development of the corpus callosum allows for a better understanding of ACC and can remove a large amount of uncertainty for families. Receiving a genetic diagnosis can also impact on other areas of family life including future treatment options, social support and family planning. As a case example, Prof Sherr described the recent discovery of the DDX3X gene mutation, which primarily affects girls due to its location on the X-chromosome. It has been identified in about 200 individuals to date and may be the cause of 1 to 3% of all intellectual disabilities in females. The DDX3X gene mutation has also been linked to seizures, autism, low muscle tone, abnormalities of the brain such as a thinner corpus callosum, and slower physical developments. The discovery of this gene mutation has led to the establishment of the DDX3X Foundation, a non-profit organisation, which is dedicated to supporting research, connecting families, and raising awareness.

Paul Lockhart (Associate Professor, Co-Director Department of Genetics, Bruce Lefroy Centre, Murdoch Children’s Research Institute, Royal Children’s Hospital, Victoria, Australia)

As a geneticist, Dr Paul Lockhart outlined revolutionary approaches in technology that has led to identifying the genetic causes of many developmental disorders, including ACC. There are about 6,000 different conditions described in literature, but scientists only know the genetic basis for about half of them. There have been remarkable breakthroughs in methodologies (e.g., high-density microarrays, next-generation sequencing), which have resulted in the "golden-age" of gene discovery. Analyses, which used to take weeks to process, can now take half-an-hour at a much-reduced cost.

There are still many challenges in the field and finding a causative change can be difficult. Detecting an alteration in a single gene is said to be equivalent to finding a single typo in 300 copies of the entire Harry Potter series! There are also natural variations found in everyone’s genes, and most are not related to a condition. In order to confidently state that a particular gene is likely to be the cause, scientists need to match up gene mutations and symptoms across several children to find common features. There are now large population databases available, where thousands of individuals have had their genes sequenced. Multiple comparisons can therefore be made that will add to the certainty of diagnosis. One such study based in the UK, Deciphering Developmental Disorders (DDD), has been extremely successful in advancing clinical genetic practice for children with developmental disorders. Although data collection has ended, analysis from the DDD study is on-going and over 30 new genetic conditions have been identified from analysing samples from over 13,000 families.

Dr Lockhart is confident that understanding the genetic basis of disorders is the key to personalised medicine. It will enable families to have more accurate information on diagnosis and outcome, as well as provide the opportunity to develop targeted treatments in the future.

Warren S. Brown (Professor of Psychology and Director of the Lee Travis Research Institute at the Graduate School of Psychology, Fuller Theological Seminary, Pasadena, California)

Prof Warren S. Brown is involved in experimental neuropsychological research related to the functions of the corpus callosum. Over the last 20 years his laboratory has conducted one of the largest studies so far on the cognitive and social profiles of individuals with agenesis of the corpus callosum. His research team is particularly interested in studying the consequences of ACC in individuals who are functioning

well overall but may have subtle problems in areas such as learning and memory, language, theory of mind, personality and emotion processing.

From a series of experiments conducted over the years, Prof Brown describes the following as the "core syndrome" of ACC: (1) reduced interhemispheric integration of sensory and motor information, (2) reduced cognitive processing speed, and (3) deficits in complex reasoning and novel problem solving. These difficulties are said to stem from the reduced communication between the two hemispheres of the brain and is evident in different domains of functioning such as cognition, behaviour and social contexts.

Prof Brown has found that simple visual and tactile information can be transferred between hemispheres in individuals with ACC, but encounter difficulty with more complex information. For example, adults with ACC could correctly judge whether two letters presented separately in the left and right visual fields were the same or different; however they took longer and made more errors when asked to judge if two patterns were the same or different. It was suggested that only a limited amount of information can be transferred between the two hemispheres in ACC and alternative pathways were likely being used.

Lynn K. Paul (Senior Research Scientist at California Institute of Technology, Director of the Corpus Callosum Research Program, Founding President of the National Organisation of Disorders of the Corpus Callosum, NODCC in 2002)

The research led by Dr Lynn Paul has focused on cognition and social skills in individuals with primary ACC. Dr Paul has worked closely with Prof Warren Brown on defining what they see as the core syndrome of ACC, how this manifests in everyday life and throughout the lifespan.

An important finding is the pattern of strengths and weaknesses often seen in individuals with primary ACC; skills that can be consolidated with practice and overlearning are achieved well, but difficulties arise with more complex, novel, or open-ended tasks. Dr Paul outlined the following as examples:

  • good basic reading skills, but relatively poor reading comprehension
  • good rote learning of simple calculations, but poor mathematical problem solving
  • strong basic language skills, but difficulties understanding the subtleties in language that occur in everyday conversation, such as non-literal expressions and humour

Not being able to appreciate second-level meanings in language can lead to many social vulnerabilities; Dr Paul has found high-functioning individuals with ACC may not reliably determine whether someone is being sincere or sarcastic, with an over-tendency towards thinking someone is being sincere. They also had some problems identifying emotions as conveyed by actors, with particular difficulty with negative emotions such as sadness, anger and fear. Interestingly, a recent study found individuals with ACC did not look at the eye region as much as typically developing controls when asked to judge how someone was feeling from a photograph, and this seemed to contribute to their difficulty in correctly identifying emotions.

Difficulties appreciating the intended meaning behind statements, coupled with misreading emotional information, leads to the suggestion that behaviours seen in individuals with ACC may overlap with those on the autism spectrum. Indeed, in a study of adults with ACC, 31% (8 from 26) presented with an autism spectrum disorder, with others being on the borderline range showing impairments in social interaction and communication.

Dr Paul observed that children with primary ACC who are generally functioning well during early childhood seem to "grow into their difficulties" with behavioural and social problems becoming apparent in later childhood and adolescence. It is thought that as the complexity of social information increases with age, as well as higher expectations, difficulties become more visible. However there are few studies that track early development and these problems may be apparent in younger children with ACC, but have not yet been systematically studied.

In response to this Dr Paul is conducting a longitudinal study of infants with ACC along with Prof Jed Elison (Institute of Child Development and Department of Pediatrics, University of Minnesota). This is the first study looking at the behavioural impact of disorders of the corpus callosum from birth into early childhood. Information is being collected from families through online questionnaires with the aim to better understand how ACC influences behaviour and neurological development during this critical period. Knowing these factors will help in the development of more effective intervention methods and support children and adults with ACC.

For more information about this study and how to enrol go to: http://emotion.caltech.edu/?page_id=11851


icn bullet large Recent Published Research


Title: Structural and functional brain rewiring clarifies preserved interhemispheric transfer in humans born without the corpus callosum Authors: Tovar-Moll F., Monteiro M., Andrade J., Bramati IE., Vianna-Barbosa R., Marins T., Rodrigues E., Dantas N., Behrens TEJ., de Oliveira-Souza R., Moll J., & Lent R. Journal: Proceedings of the National Academy of Sciences, 111 (21), 7843–7848 Published: 2014

Despite the absence of the major pathway that connects the two hemispheres of the brain, individuals born without the corpus callosum still show some degree of transfer of information between the hemispheres. This finding has perplexed scientists and demonstrates how information is processed in the brain in individuals with ACC is very different to when the corpus callosum has been surgically removed; for example, to alleviate symptoms of severe epilepsy. Following this surgical procedure the classic "disconnection syndrome" is often seen whereby the two hemispheres function independently.

In order to study the nature of this preserved interhemispheric transfer of information in ACC, scientists from D’Or Institute for Research and Education (Rio de Janeiro, Brazil) assessed six individuals with ACC (aged 6 to 33 years) using detailed brain imaging techniques and neuropsychological tests. The individuals with ACC were able to show intact interhemispheric transfer on behavioural measures (e.g., recognising an object by touch without the aid of vision). The brain imaging results showed evidence of functional connectivity between different areas of the brain; that is, some degree of synchrony of activity across brain regions was seen while the individual was resting in the brain scanner. The authors suggest that this connectivity indicates that alternative pathways are formed in the absence of the corpus callosum, which may be compensatory in nature. For example, the bundles of axons normally destined to cross the corpus callosum that become rerouted when the developmental process is interrupted. These white matter bundles (e.g., Probst bundles and sigmoid bundles) still play an important role in connecting brain regions and can explain the cross-transfer of information between hemispheres. The authors conclude by stating that ACC is associated with extensive brain rewiring, and through the plasticity of the brain during prenatal and postnatal development, new circuits are established which allow the integration of information between brain regions.

Title: Corpus callosum abnormalities: neuroradiological and clinical correlations. Authors: Al-Hashim A. H., Blaser, S., Raybaud, C., & MacGregor, D. Journal: Developmental Medicine and Child Neurology, 58, 427-436. Published: 2015

The authors reviewed hospital records (from the Hospital for Sick Children, Toronto) of patients who had an MRI scan because concerns had been raised during the prenatal scan or there had been concerns about early development. In total 125 patients (aged 1 to 18 years) were identified who had abnormalities of the corpus callosum from scans conducted between 1999 and 2012.

In a typically developing brain, different regions of the corpus callosum are thought to be responsible for connecting distinct areas of the brain. The authors were interested in whether certain problems could be predicted by the part of the corpus callosum that was absent; for example, whether those without the front (anterior) region had problems with motors skills and those without the end (posterior) region had problems with vision. They were also interested in whether the presence of other brain malformations influenced outcome.

Most of the sample had complete agenesis of the corpus callosum, with no connecting fibres present (52%). A small proportion (2%) had the front regions (rostrum, genu, and body) absent, while it was more common (30%) to have the end regions (isthmus and splenium) absent when the diagnosis was partial agenesis of the corpus callosum. The remainder of the sample (16%) had an unusually thin corpus callosum (hypoplasia).

Their main finding was that cardiac anomalies were more common in the group with complete agenesis (25% of this group); however grouping patients by the type of agenesis was not associated with any particular outcome. For example, visual impairment occurred in 40% of the sample but was not more common in those with posterior agenesis as predicted. The authors suggest that perhaps more sophisticated measures of vision may detect differences.

Overall the sample had a high level of associated problems: developmental delay (77%), gross motor delay (74%), speech delay (74%), social delay (66%) and behavioural issues (49%). Epilepsy was diagnosed in 36% of patients and dysmorphic features were found in 61%. It should be noted that the sample had been referred to a tertiary healthcare centre and therefore would be expected to have more complex medical problems.

Probst bundles describe the fibres that fail to cross the midline between the two hemispheres and get rerouted. These were noted in 60% of the sample and often occurred alongside colpocephaly (enlargement of ventricles in the brain). Interestingly the presence of Probst bundles was associated with better adaptive and social functioning and may signify the important role of Probst bundles as compensatory fibres.

It was reported that 37% of the sample had an identifiable genetic cause of the corpus callosum abnormality such as a single gene disorder, copy number variants, or a recognisable syndrome. Interestingly, patients who had complex form of corpus callosum abnormalities (i.e., additional brain malformations) were no more likely to have an underlying genetic diagnosis (i.e., a positive result on a chromosomal microarray) than those with isolated forms. Additional brain abnormalities were fairly common (46% of the sample) and were associated with a higher risk of epilepsy, and delays in gross motor skills and speech.

The authors recommend that cardiac evaluations should be part of routine screens, in addition to the standard visual and auditory tests that are taken. Furthermore they stress the importance of genetic testing in all individuals with corpus callosum malformations, as it may not necessarily be the case that a high risk of chromosomal abnormalities is confined to complex forms of ACC.

Title: Neurodevelopmental outcome in prenatally diagnosed isolated agenesis of the corpus callosum Authors: Folliot-Le Doussal, L., Chadie, A., Basseur-Daudruy, M., Verspyck, E., Saugier-Veber, P., Marret, S., & the Perinatal Network of Haute-Normandie Journal: Early Human Development Published: 2018

This French study (based in Normandy) was a long-term follow-up of 25 children who were diagnosed with isolated ACC before they were born (previously reported in Chadie et al., 2008; see below). Children were on average 8 years when assessed at follow-up, but ranged between 2 and 16 years. Neurodevelopmental outcome, as defined by general intelligence, motor and cognitive abilities, was considered to be normal in 9 children (36%), which included 6 with complete ACC. Thirteen children (52%, 8 with complete ACC) were reported to have mild disabilities, such as language disorders, attention deficit disorder and anxiety. Three children (12%, all with complete ACC) had moderate/severe disabilities (intellectual disability, speech impairments, significant delay in motor skills). One child classified as having

moderate/severe disabilities was found to have additional cerebral abnormalities in a MRI scan that were not detected in their prenatal scan.

Measures of intellectual functioning were taken from 15 children, with the majority showing intact skills (40% had an IQ score above 85, 80% had an IQ score above 70). However some discrepancies were noted with relative weaknesses in verbal comprehension, social judgement and executive functions. The rate of children with normal development was lower than in their earlier follow-up study (36% vs. 55%), with six children who had been classified as having normal development now showing mild disabilities at an older age. The authors emphasise the importance of ongoing monitoring of children with ACC and that problems may occur beyond school age.

Title: Isolated corpus callosum agenesis: A ten-year follow-up after prenatal diagnosis (How are the children without corpus callosum at 10 years of age?) Authors: Moutard, M.-L., Kieffer, V., Feingold, J., Lewin, F., Baron, J.-M., Adamsbaum, C., Gélot, A., Isapof, A., Kieffer, F., & De Villemeur, T.B. Journal: Prenatal Diagnosis, 32(3), 277-283 Published: 2012

This French study is a follow-up of the 17 children diagnosed with ‘apparently isolated ACC’ previously reported in the Moutard et al. (2003) study (see below). As five children were not able to return for testing, the paper reports the outcome of 12 children at 10 years of age. One child was given a late diagnosis of fetal alcohol syndrome (FAS) with ACC considered to be associated with this syndrome; his assessment results were still included in their analysis.

Most children showed good outcome with intelligence levels within the normal range (i.e., above 80) for 67% of the group (8 from 12). However, mild learning difficulties were often reported which included slowness (58%), lack of concentration/attention (33%) and emotional immaturity (42%). All children attended a mainstream school, with approximately half needing some special adaptations in the classroom to support their learning. Outcome was not related to whether the child had complete or partial ACC, was male or female, or experienced febrile seizures.

The number of children classified with borderline intelligence (i.e. below 80) was higher than the earlier follow-up study of these children at 6 years of age (33% vs.

22%). The authors suggest that cognitive impairments may emerge as children grow older and continued monitoring, especially of behavioural and psychological problems, is needed beyond 10 years. Although prenatal diagnosis of isolated ACC is reliable, the authors caution there is a small risk that associated factors may be missed during prenatal screening.

Published Research currently on Corpal Website (from 2008)

Title: Social and behavioral problems of children with agenesis of the corpus callosum Authors: Badaruddin, D., Andrews, G., Bolte, S., Schilmoeller, K., Paul, L.K., Brown, W.S. Journal: Child Psychiatry and Human Development, 38, 287-302. Published: 2007

The researchers summarise the range of behaviour problems in children with ACC who are relatively high functioning and typically developing (i.e., no reported delays in early motor milestones of sitting and walking) as reported by a parental questionnaire (the Child Behavior Checklist). Parents of 33 children with ACC (aged 6 to 11 years) reported considerable problems in areas of attention (e.g., daydreaming, staring, being confused, inability to sit still, failing to finish tasks, wandering away), unusual thoughts, social interactions, physical complaints and aggressive behaviour. Fewer problems were reported by parents of 28 younger children with ACC (aged 2 to 5 years), with sleep difficulties being the primary problem reported. Some children with ACC had traits that related to diagnosis of autism; for example difficulties initiating and sustaining conversation, establishing friendships, showing social and emotional give-and-take, using and understanding nonverbal communication. The typical repetitive and restricted behaviours seen in autism were not so apparent in children with ACC.

Title: Neurodevelopmental outcome in prenatally diagnosed isolated agenesis of the corpus callosum Authors: Chadie, A., Radi, S., Trestard, L., Charollais, A., Eurin, D., Verspyck, E., Marret, S. Journal: Acta Paediatrica, 97, 420-424 Published: 2008

This French study looked at the outcome of 20 children who were diagnosed with isolated ACC before they were born. Children were generally younger than 6 years when assessed, but ranged between 3 and 16 years. Neurodevelopmental outcome, as defined by general intelligence, motor and cognitive abilities, was considered to be normal in 11 children (55%), which included eight with complete ACC. Five children (25%) were considered to have moderate disabilities (speech delay, comprehension difficulties, attention disorders), and four children (20%) had severe disabilities (intellectual disability, speech impairments, cerebral palsy). In three of the four severely disabled children, a follow-up MRI scan showed additional major cerebral abnormalities that were not detected in their prenatal scan.

Title: Agenesis of the corpus callosum: prenatal diagnosis and prognosis Authors: Moutard., M., Kieffer, V., Feingold, J., Kieffer, F., Lewin, F., Adamsbaum., C., Gelot, A., Campistal I Plana, J., van Bogaert, P., Andre, M., Ponst, G. Journal: Child's Nervous System, 19, 471-476 Published: 2003

This French study reports on the long-term outcome of children diagnosed with isolated ACC before they were born. A group of 17 children were assessed at ages 2, 4, and 6, although the drop-off rate was high and only seven children were seen at 6 years of age. Most children showed good outcome, with motor skills developing at the expected ages. Intellectual ability was generally within the normal range, although scores varied over time for some children. When the children were of school age subtle cognitive and behaviour problems emerged, particularly in reasoning, slowness, and paying attention. Outcome was not related to whether the child had complete or partial ACC, was male or female, or experienced febrile seizures.

Title: Agenesis of the corpus callosum: genetic, developmental and functional aspects of connectivity Authors: Paul, L.K., Brown, W.S, Adolphs, R., Tyszka, J.M., Richards, L.J., Mukherjee, P., Sherr, E.H. Journal: Nature Reviews Neuroscience, 8, 287-299. Published: 2007

This paper provides a comprehensive review of the research into ACC that has been done to date. The way the corpus callosum develops is described; this involves a complex series of multiple steps, where disruption at any stage can lead to ACC. A

review of genetic factors that cause ACC is provided along with possible environmental factors. The authors conclude that most cases of ACC do not have a known cause at this time. The wide-ranging consequence of ACC on behaviour and cognition is discussed. It is suggested that by grouping together individuals with similar brain anatomy we may be more successful at determining outcome. Individuals with primary ACC and good general cognitive ability often show a pattern of deficits in problem solving, social skills, processing emotion, and in the practical use of language and communication. These difficulties may be due to problems transferring information between hemispheres or to other abnormalities in the brain. Many neurodevelopmental and psychiatric conditions have been linked to corpus callosum malformation or malfunctioning, including schizophrenia, autism and attention deficit hyperactivity disorder. The study of ACC may therefore provide insight on how altered brain connectivity may contribute to these disorders, as well as how information is transferred in the typically developing brain.