Excessive cerebral spinal fluid and enlarged brain size in infancy are potential biomarkers for autism

Children who were later diagnosed with autism spectrum disorder had excessive cerebrospinal fluid and enlarged brains in infancy, a study by a multidisciplinary team of researchers with the UC Davis MIND Institute has found, raising the possibility that those brain anomalies may serve as potential biomarkers for the early identification of the neurodevelopmental disorder.

The study is the first to follow the brain-growth trajectories from infancy in children who later develop autism and the first to associate excessive cerebrospinal fluid during infancy with autism. “Early Brain Development and Elevated Extra-Axial Fluid in Infants who Develop Autism Spectrum Disorder,” is published online today in the neurology journal Brain, published by Oxford University Press.

"This is the first report of an infant brain anomaly associated with autism that is detectable by using conventional structural MRI,” said MIND Institute Director of Research David Amaral, who co-led the study.

"This study raises the potential of developing a very early method of detecting autism spectrum disorder. Early detection is critical, because early intervention can decrease the cognitive and behavioral impairments associated with autism and may result in more positive long-term outcomes for the child,” Amaral said.

The study was conducted in 55 infants between 6 and 36 months of age, 33 of whom had an older sibling with autism. Twenty-two infants were children with no family history of the condition.

The researchers reported that the brain anomaly was detected significantly more often in the high-risk infants who were later diagnosed with autism between 24 and 36 months. Prior research by Sally Ozonoff, the vice chair for research and professor in the Department of Psychiatry and Behavioral Sciences, who co-led the study, has shown that the risk of autism is nearly 20 times greater in siblings of children with autism than in the general population. The U. S. Centers for Disease Control and Prevention puts the overall incidence of autism at 1 in 88.

The excessive cerebrospinal fluid and enlarged brain volume were detected by periodically measuring the infants’ brain growth and development using magnetic resonance imaging (MRI), and by regularly assessing their cognitive, social, communication and motor development. Both the high- and low-risk infants underwent their first MRI scans at 6 to 9 months. The second MRI scans occurred when they were 12 to 15 months old. The third was conducted between 18 and 24 months. The MRIs were conducted while the infants were sleeping naturally, without the need for sedation or anesthesia.

At 6 months, the researchers began intensive behavioral assessments of the infants’ development. Their parents also periodically completed questionnaires about their babies’ behaviors. These tests were conducted until the infants were 24 to 36 months old, when each child was evaluated as having autism spectrum disorder, other developmental delays, or typical development.

In addition to the 10 children diagnosed with autism, 24 percent of the high-risk and 13.5 percent of the low-risk infants were classified as having other developmental delays. Some 45.5 percent of high-risk and over 86 percent of low-risk babies were found to be developing normally.

The researchers found that by 6 to 9 months of age, the children who developed autism had elevated cerebrospinal fluid levels in the “extra-axial” space above and surrounding the brain, and that those fluid levels remained abnormally elevated between 18 to 24 months of age. The more fluid during early infancy, the more severe were the child’s autism symptoms when diagnosed, the study found.

In the infants who would go on to be diagnosed with autism, the ”extra-axial” fluid volume was, on average, 33 percent greater at 12 to 15 months and 22 percent greater at 18 to 24 months, when compared with typically developing infants. At 6 to 9 months, the extra-axial fluid volume was 20 percent greater, when compared with typically developing infants.
The study also provided the first MRI evidence of brain enlargement in autism prior to 24 months. The infants in the study diagnosed with autism had, on average, 7 percent larger brain volumes at 12 months, compared with the typically developing infants.

The excessive extra-axial fluid and enlarged brain volume were detected by brain imaging before behavioral signs of autism were evident. “The cause of the increased extra-axial fluid and enlarged brain size is currently unknown”, Amaral said.

Early diagnosis may be of particular benefit to infants whose older siblings have been diagnosed with autism, but the researchers caution that this finding must be replicated before it could aid in the early diagnosis of ASD. The MIND Institute is currently collaborating with other research institutions to replicate these findings and to evaluate how well the potential biomarker can accurately predict a later diagnosis of ASD.

“It is critical to understand how often this brain finding is present in children who do not develop autism, as well,” said Ozonoff. “For a biomarker to be useful in predicting autism outcomes, we want to be sure it does not produce an unacceptable level of false positives.”
“If this finding of elevated extra-axial fluid is replicated in a larger sample of infants who develop autism, and it accurately distinguishes between infants who do not develop autism, it has the potential of becoming a noninvasive biomarker that would aid in early detection, and ultimately improve the long-term outcomes of these children through early intervention,” said Mark Shen, UC Davis graduate student and the study’s lead author.

Migraine and Depression Together May Be Linked with Brain Size

Older people with a history of migraines and depression may have smaller brain tissue volumes than people with only one or neither of the conditions, according to a new study in the May 22, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“Studies show that people with migraine have double the risk of depression compared to people without migraine,” said study author Larus S. Gudmundsson, PhD, with the National Institute on Aging and the Uniformed Services University of the Health Sciences, in Bethesda, Md. Gudmundsson is also a member of the American Academy of Neurology. “We wanted to find out whether having both conditions together possibly affected brain size.”

For the study, 4,296 people with an average age of 51 were tested for migraine headache from 1967 to 1991; they were later assessed from 2002 to 2006 at an average age of 76 for a history of major depressive disorder (depression). Participants also underwent MRI, from which brain tissue volumes were estimated. A total of 37 participants had a history of both migraine and depression, while 2,753 had neither condition.

The study found that people with both migraine and depression had total brain tissue volumes an average of 19.2 milliliters smaller than those without either condition. There was no difference in the total brain volume when comparing people with only one of the conditions to people with neither condition.

“It is important to note that participants in this study were imaged using MRI once, so we cannot say that migraine and depression resulted in brain atrophy. In future studies, we need to examine at what age participants develop both migraine and depression and measure their brain volume changes over time in order to determine what comes first,” said Gudmundsson.

Gudmundsson noted that some of the factors leading to a joint effect of migraine and depression on brain volume may include pain, brain inflammation, genetics and differences in a combination of social and economic factors. “Our study suggests that people with both migraine and depression may represent a unique group from those with only one of these conditions and may also require different strategies for long-term treatment.”

The Shrinking of the Hobbit’s Brain

Where do Hobbits come from? No, not the little humanoids in the J. R. R. Tolkien books, but Homo floresiensis, the 1-meter-tall human with the chimp-sized brain that lived on the Indonesian island of Flores between 90,000 and 13,000 years ago. There are two main hypotheses: either the creature downsized from H. erectus, a human ancestor that lived in Africa and Asia and that is known to have made it to Flores about 800,000 years ago and may have shrunk when it got there—a case of so-called “insular dwarfism” often seen in other animals that get small when they take up residence on islands. Or it evolved from an even earlier, smaller-brained ancestor, such as the early human H. habilis or an australopithecine like Lucy, that somehow made it to Flores from Africa. The insular dwarfism hypothesis had fallen out of favor recently, however, because many researchers thought that the Hobbit’s brain, often estimated at 400 cubic centimeters in volume, was too small to have evolved from the larger H. erectus brain, which was at least twice as big. But a new study, published online today in the Proceedings of the Royal Society B, finds from CT scans of the Hobbit’s brain that it was actually about 426 cubic centimeters in volume. The team calculates that this is big enough to make the island dwarfism hypothesis considerably more plausible once the body size differences between the Hobbit and H. erectus—which was nearly twice as tall—are adjusted for.

Brain Size Didn’t Drive Evolution, Research Suggests

Brain organization, not overall size, may be the key evolutionary difference between primate brains, and the key to what gives humans their smarts, new research suggests.

In the study, researchers looked at 17 species that span 40 million years of evolutionary time, finding changes in the relative size of specific brain regions, rather than changes in brain size, accounted for three-quarters of brain evolution over that time. The study, published today (March 26) in the Proceedings of the Royal Society B, also revealed that massive increases in the brain’s prefrontal cortex played a critical role in great ape evolution.

"For the first time, we can really identify what is so special about great ape brain organization," said study co-author Jeroen Smaers, an evolutionary biologist at the University College London.

Is bigger better?

Traditionally, scientists have thought humans’ superior intelligence derived mostly from the fact that our brains are three times bigger than our nearest living relatives, chimpanzees.

But bigger isn’t always better. Bigger brains take much more energy to power, so scientists have hypothesized that brain reorganization could be a smarter strategy to evolve mental abilities.

To see how brain organization evolved throughout primates, Smaers and his colleague Christophe Soligo analyzed post-mortem slices of brains from 17 different primates, then mapped changes in brain size onto an evolutionary tree.

Over evolutionary time, several key brain regions increased in size relative to other regions. Great apes (especially humans) saw a rise in white matter in the prefrontal cortex, which contributes to social cognition, moral judgments, introspection and goal-directed planning.

"The prefrontal cortex is a little bit like the CEO of the brain," Smaers told LiveScience. "It takes information from other brain areas and it synthesizes them."

When great apes diverged from old-world monkeys about 20 million years ago, brain regions tied to motor planning also increased in relative size. That could have helped them orchestrate the complex movements needed to manipulate tools — possibly to get at different food sources, Smaers said.

Gibbons and howler monkeys showed a different pattern. Even though their bodies and their brains got smaller over time, the hippocampus, which plays a role in spatial tasks, tended to increase in size in relation to the rest of the brain. That may have allowed these monkeys to be spatially adept and inhabit a more diverse range of environments.

Prefrontal cortex

The study shows that specific parts of the brain can selectively scale up to meet the demands of new environments, said Chet Sherwood, an anthropologist at George Washington University, who was not involved in the study.

The finding also drives home the importance of the prefrontal cortex, he said.

"It’s very suggestive that connectivity of prefrontal cortex has been a particularly strong driving force in ape and human brains," Sherwood told LiveScience.

Is Athleticism Linked to Brain Size?

To find out, researchers at the University of California, Riverside performed laboratory experiments on house mice and found that mice that have been bred for dozens of generations to be more exercise-loving have larger midbrains than those that have not been selectively bred this way.

Theodore Garland’s lab measured the brain mass of these uniquely athletic house mice, bred for high voluntary wheel-running, and analyzed their high-resolution brain images. The researchers found that the volume of the midbrain — a small region of the brain that relays information for the visual, auditory, and motor systems — in the bred-for-athleticism mice was nearly 13 percent larger than the midbrain volume in the control or “regular” mice.

“To our knowledge, this is the first example in which selection for a particular mammalian behavior — high voluntary wheel running in house mice in our set of experiments — has been shown to result in a change in size of a specific brain region,” said Garland, a professor of biology and the principal investigator of the research project.

Study results appeared online Jan. 16 in The Journal of Experimental Biology

A Key Gene for Brain Development

About one in ten thousand babies is born with an abnormally small head. The cause for this disorder – which is known as microcephaly – is a defect in the develoment of the embryonic brain. Children with microcephaly are severely retarded and their life expectancy is low. Certain cases of autism and schizophrenia are also associated with the dysregulation of brain size.

The causes underlying impaired brain development can be environmental stress (such as alcohol abuse or radiation) or viral infections (such as rubella) during pregnancy. In many cases, however, a mutant gene causes the problem.

David Keays, a group leader at the IMP, has now found a new gene which is responsible for Microcephaly. Together with his PhD-student Martin Breuss, he was able to identify TUBB5 as the culprit. The gene is responsible for making tubulins, the building blocks of the cell’s internal skeleton. Whenever a cell moves or divides, it relies on guidance from this internal structure, acting like a scaffold.

The IMP-researchers, together with collaborators at Monash University (Victoria, Australia), were able to interfere with the function of the TUBB5 in the brains of unborn mice. This led to massive disturbances in the stem cell population and impaired the migration of nerve cells. Both, the generation of large numbers of neurons from the stem cell reservoir and their correct positioning in the cortex, are essential for the development of the mammalian brain.

To determine whether the findings are also relevant in humans, David Keays collaborates with clinicians from the Paris-Sorbonne University. The French team led by Jamel Chelly, examined 120 patients with pathological brain structures and severe disabilities. Three of the children were found to have a mutated TUBB5-gene.

This information will prove vital to doctors treating children with brain disease. It will allow the development of new genetic tests which will form the basis of genetic counseling, helping parents plan for the future. By understanding how different genes cause brain disorders, it is hoped that one day scientists will be able to create new drugs and therapies to treat them.

The new findings by the IMP-researchers are published in the current issue of the journal “Cell Reports”. For David Keays, understanding the function of TUBB5 is the key to understanding brain development. “Our project shows how research in the lab can help improve lives in the clinic”, he adds.

The paper “Mutations in the β-tubulin Gene TUBB5 Cause Microcephaly with Structural Brain Abnormalities” is published on December 13, 2012, in the online Journal Cell Reports.

Raw Food Not Enough to Feed Big Brains

Eating a raw food diet is a recipe for disaster if you’re trying to boost your species’ brainpower. That’s because humans would have to spend more than 9 hours a day eating to get enough energy from unprocessed raw food alone to support our large brains, according to a new study that calculates the energetic costs of growing a bigger brain or body in primates. But our ancestors managed to get enough energy to grow brains that have three times as many neurons as those in apes such as gorillas, chimpanzees, and orangutans. How did they do it? They got cooking, according to a study published online today in the Proceedings of the National Academy of Sciences.

"If you eat only raw food, there are not enough hours in the day to get enough calories to build such a large brain," says Suzana Herculano-Houzel, a neuroscientist at the Federal University of Rio de Janeiro in Brazil who is co-author of the report. "We can afford more neurons, thanks to cooking."

Humans have more brain neurons than any other primate—about 86 billion, on average, compared with about 33 billion neurons in gorillas and 28 billion in chimpanzees. While these extra neurons endow us with many benefits, they come at a price—our brains consume 20% of our body’s energy when resting, compared with 9% in other primates. So a long-standing riddle has been where did our ancestors get that extra energy to expand their minds as they evolved from animals with brains and bodies the size of chimpanzees?

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Evolution Mostly Driven by Brawn, Not Brains, Analysis Finds

The most common measure of intelligence in animals, brain size relative to body size, may not be as dependent on evolutionary selection on the brain as previously thought, according to a new analysis by scientists.

Brain size relative to body size has been used by generations of scientists to predict an animal’s intelligence. For example, although the human brain is not the largest in the animal kingdom in terms of volume or mass, it is exceptionally large considering our moderate body mass.

Now, a study by a team of scientists at UCL, the University of Konstanz, and the Max Planck Institute of Ornithology has found that the relationship between the two traits is driven by different evolutionary mechanisms in different animals.

Crucially, researchers have found that the most significant factor in determining relative brain size is often evolutionary pressure on body size, and not brain size. For example, the evolutionary history of bats reveals they decreased body size much faster than brain size, leading to an increase in relative brain size. As a result, small bats were able to evolve improved flying maneuvrability while maintaining the brainpower to handle foraging in cluttered environments.

This shows that relative brain size can not be used unequivocally as evidence of selection for intelligence. The study is published in the Proceedings of the National Academy of Sciences.