Disorders that Appear in Childhood 2007

January, 2007

Among several significant studies involving childhood in 2006, scientists pinpointed specific areas of the brain that contribute to enlarged brain size, which commonly occurs in autism spectrum disorder. Researchers also gained new insights into some of the neuroanatomical and biochemical differences that appear to be responsible for the cognitive difficulties experienced by children with attention-deficit/hyperactivity disorder, and more evidence emerged regarding the role of viral infections in developmental disorders such as cerebral palsy.

Brain Abnormalities in Autism

Autism spectrum disorder (ASD), a grouping that includes autism and disorders similar to it, is a pervasive developmental disorder manifested primarily in greatly diminished social interaction and communication skills. No one knows exactly what causes ASD, but scientists have identified many neurological abnormalities that might contribute to the social and cognitive deficits typically observed in ASD.

Abnormal activity in specific brain regions has been associated with ASD. For example, a part of the brain called the inferior frontal gyrus was markedly less active in children with ASD during the performance of certain tasks related to social interaction, according to a research team led by Marco Iacoboni, a neuroscientist at the University of California, Los Angeles.1

In a study reported in Nature Neuroscience, Iacoboni’s team used functional magnetic resonance imaging to investigate neural activity of 10 high-functioning children with ASD and 10 normally developing children as the children observed and imitated facial emotional expressions. The degree of reduced activity correlated with the severity of their symptoms.

The inferior frontal gyrus is believed to be part of the so-called mirror neuron system, which plays an important role in the perception and expression of emotions and enables individuals to experience empathy. The findings indicate that a dysfunctional mirror neuron system may underlie the social deficits observed in autism.

Abnormalities in brain size also have been associated with ASD. In a study published in the American Journal of Psychiatry, a group of researchers led by Antonio Hardan, a Stanford University psychiatrist, used magnetic resonance imaging scans to compare the size of the cortex (the outer layer of the brain) between 17 children with autism and 14 children without the disorder.2 Cortical thickness is a sensitive index of normal brain development.  

Although the meaning of cortical thickness at the level of individual cells is unknown, the researchers believe it may indicate the degree of "arborization," the branching of brain cell connections. During normal brain development, a massive overproduction of cells and these connections (synapses) to other brain cells occurs. A competitive elimination, or "pruning," of neurons and these connections follows. The scientists hypothesize that this pruning results in cortical thinning.

When the investigators analyzed the brain images, they found increased cortical thickness in the brain’s temporal and parietal lobes of children with autism. They suggest that these anatomical differences are partly responsible for the increased brain size in ASD.

These findings will lead the scientists to look at what normally controls the thinning of the cortex—including genetic influences. They plan to investigate the different genes that are involved in this process, with the hope of finding an association that will help them better understand what causes thicker brain structures in autism, which might lead to new treatments.

An enlarged amygdala also appears to contribute to the increased brain size observed in autism, according to a study published in Archives of General Psychiatry.3 The amygdala is a part of the brain that plays an important role in socio-emotional functioning. In this study, researchers led by Stephen Dager of the University of Washington used magnetic resonance imaging to measure amygdala size in 45 children with ASD between the ages of 3 and 4.

The investigators found that an enlarged amygdala—particularly its right side—was associated with symptom severity in these children. Moreover, when the researchers tested the same children about 3 years later, they found that the children with a greater degree of right amygdala enlargement had poorer development of language and social skills.

Stephen Dager viewing a brain scan 

﻿Investigating autism: Researcher Stephen Dager, foreground, checks a brain scan as he and Dennis Shaw conduct research to measure amygdala size in children with autism spectrum disorder. (Photograph courtesy of Stephen Dager)

These results strongly implicate amygdala abnormalities in the behavioral impairments found in autism, and they also suggest that the size of the right amygdala might be used to predict the clinical course of the disease.

In a more recent paper, published in Neurology, researchers from the same laboratory reported that the disabilities found in children with autism, compared to children with developmental delay, may be attributable to increased "transverse relaxation" of brain cells (gray matter) in the brain.4 Transverse relaxation, as measured by magnetic resonance imaging (MRI), is a measure of how tightly bound brain cells are, as measured by the extent to which they displace water in the brain. This technique is used to measure brain maturation over time.

The investigators compared 60 children with autism to 16 with developmental delay and 10 who were developing normally. All of the children were between 2 and 4 years old. They found that cells were significantly more tightly bound in normally developing children, compared with children with autism. Children with developmental delay fell between the normally developing children and those with autism in terms of how tightly the cells were bound.
Autism remains a mysterious disease. These imaging studies suggest developmental abnormalities in the formation of neuronal structures, perhaps early in gestation.

New Insights into ADHD

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder with consequences that diminish academic and occupational achievement and increase the risk of depression, substance abuse, and accidental injury or even death. ADHD is characterized by restlessness and distractibility, believed to be caused by an impaired ability to inhibit certain impulses inside the brain.

ADHD can, in most cases, be successfully treated with medications that increase the availability of an inhibiting neurotransmitter, called dopamine, inside the brain. Scientists have long suspected that having too little dopamine might produce ADHD. Recent evidence suggests that this is the case and points to defects in “dopamine transporters” in the brain as the main culprit: the transporters take up too much dopamine before it can be passed from one brain cell to another.

A research team led by Donald Gilbert, a pediatric neurologist at Cincinnati Children's Hospital Medical Center, tested how the brain’s motor cortex inhibits movement in 16 children and adolescents with ADHD, both before and after they were given medications that increase the availability of dopamine inside the brain.5

The resultant increased amounts of dopamine inhibited motor cortex activity in all children tested, but the medicine had a much greater effect in children with a genetic variation called DAT1, which ordinarily causes too much dopamine transporter activity. The result is too little inhibitory dopamine. This research implicates genetically altered dopamine transporters in ADHD.

In a related development, Katya Rubia of the Institute of Psychiatry at King's College in London and colleagues found similar deficiencies in brain regions responsible for motor inhibition  and switching of behavior in a group of 19 boys with ADHD who had never taken any medication for the disorder.6 This is significant, the researchers point out, because previous research has been undertaken in children who had been taking ADHD medications, which might have confounded the results.

Using functional magnetic resonance imaging, Rubia's team found abnormal brain activation in these "medication-naive" children and adolescents with ADHD during tasks that involved motor inhibition and task switching (which requires cognitive flexibility). The finding suggests that under activation in this patient group is unrelated to long-term stimulant exposure. Under activation was evident during both tasks in prefrontal brain regions, as well as in temporal and parietal regions, which in the past have not been implicated in ADHD.

3-D image of two children 
﻿Brain activation in ADHD: Children with attention-deficit/hyperactivity disorder showed reduced brain activation in the medial prefrontal cortex when they had to inhibit a motor response, left, and in frontotemporal brain regions when they had to switch tasks, right.  (Image courtesy of Katya Rubia) 

Brain thickness as an indicator of brain development has been studied in ADHD, just as it has been studied in autism. National Institute of Mental Health researchers led by Philip Shaw measured cortical thickness in a group of 166 children with ADHD.7 The researchers obtained magnetic resonance images approximately every two years in these children and compared them with scans of healthy children.

An analysis of the images revealed that children with ADHD had a thinner cortex in parts of the brain that are important for the control of attention. Subsequent scans of these children revealed that those with worse clinical outcomes had a particularly thin cortex at the front of the brain, near a region that controls aspects of attention, such as inhibiting inappropriate behaviors.

Moreover, the children with ADHD who had better clinical outcomes showed a distinctive pattern of cortical change in the right parietal cortex, which controls some of the most fundamental aspects of attention. Here, by late adolescence, the cortex reached the same thickness in these children as in healthy children. However, this "normalization" did not occur in the children with worse clinical outcomes. These results were unaffected by whether the children had been taking medication for ADHD.

This work gives a very detailed picture of the cortex in children with ADHD and highlights brain changes that may reflect, or even drive, recovery from the disorder, the researchers suggest.
As in autism, imaging studies are suggesting what is going wrong in brain functions in ADHD. These types of studies may be useful in both diagnosis and treatment.

Cerebral Palsy: The Role of Infections

Researchers uncovered more evidence in 2006 that highlights the importance of infections in developmental disorders such as cerebral palsy. Cerebral palsy is a permanent and often serious brain disorder, detectable from early childhood, which causes abnormal control of body movement or posture. The causes of cerebral palsy are largely unknown, and currently it cannot be prevented.

In a paper published in the British Medical Journal, Catherine Gibson at the University of Adelaide, Australia, and her team reported investigations into whether certain viral infections might be associated with cerebral palsy.8 The researchers tested neonatal dried blood samples from 443 babies with the disorder and 883 babies without it for herpes viruses, a group of viruses that includes those responsible for chicken pox and cold sores.

The results showed that significantly more of the babies with cerebral palsy were exposed to herpes viruses during their mother’s pregnancy than those without it, suggesting that these viruses may be involved in development of the disorder during pregnancy. These studies will need to be confirmed with other populations.