Researchers observe brain development in utero

New investigation methods using functional magnetic resonance tomography (fMRT) offer insights into fetal brain development. These “in vivo” observations will uncover different stages of the brain’s development. A research group at the Computational Imaging Research Lab from the MedUni Vienna has observed that parts of the brain that are later responsible for sight are already active at this stage.

To obtain insights into the development of the human brain in utero, the study group observed 32 fetuses from the 21st to 38th week of pregnancy (an average pregnancy lasts 40 weeks). The architecture of the brain is developed particularly during the middle trimester of pregnancy. Using functional magnetic resonance tomography, it was possible to measure activity and thereby gain information about the most important cortical and sub-cortical structures of the developing brain. During the period of the 26th to 29th week of pregnancy in particular, short-range neuronal connections developed especially actively, while in contrast to this, long-range nerve connections exhibited more linear growth during pregnancy. “It became apparent that the areas responsible for sensory perception are developed first and only then, around four weeks later, do the areas responsible for more complex, cognitive skills come along,” says first author Andras Jakab from the Computational Imaging Research Lab at the MedUni Vienna, explaining the results.

In another study, the study group led by Veronika Schöpf and Georg Langs was able to demonstrate for a correlation of eye movement and areas of the brain which are later responsible to process vision as early as the 30th to the 36th weeks of pregnancy. The fact that newborn babies first have to learn to “process” visual stimuli after birth is already known. It has now been possible to demonstrate that this important development starts even before birth. The research group investigated the relationship between eye movements and brain activity. Even at this stage of development, motor visual movement is linked to the areas in the visual cortex of the brain responsible for processing optical signals. “The relationship between eye movement and the responsible areas of the brain has therefore been demonstrated for the first time in utero”, explains first author Veronika Schöpf.

Study finds link between neural stem cell overgrowth and autism-like behavior in mice

People with autism spectrum disorder often experience a period of accelerated brain growth after birth. No one knows why, or whether the change is linked to any specific behavioral changes.

A new study by UCLA researchers demonstrates how, in pregnant mice, inflammation, a first line defense of the immune system, can trigger an excessive division of neural stem cells that can cause “overgrowth” in the offspring’s brain.

The paper appears Oct. 9 in the online edition of the journal Stem Cell Reports. 

“We have now shown that one way maternal inflammation could result in larger brains and, ultimately, autistic behavior, is through the activation of the neural stem cells that reside in the brain of all developing and adult mammals,” said Dr. Harley Kornblum, the paper’s senior author and a director of the Neural Stem Cell Research Center at UCLA’s Semel Institute for Neuroscience and Human Behavior.

In the study, the researchers mimicked environmental factors that could activate the immune system — such as an infection or an autoimmune disorder — by injecting a pregnant mouse with a very low dose of lipopolysaccharide, a toxin found in E. coli bacteria. The researchers discovered the toxin caused an excessive production of neural stem cells and enlarged the offspring’s’ brains.

Neural stem cells become the major types of cells in the brain, including the neurons that process and transmit information and the glial cells that support and protect them.

Notably, the researchers found that mice with enlarged brains also displayed behaviors like those associated with autism in humans. For example, they were less likely to vocalize when they were separated from their mother as pups, were less likely to show interest in interacting with other mice, showed increased levels of anxiety and were more likely to engage in repetitive behaviors like excessive grooming.

Kornblum, who also is a professor of psychiatry, pharmacology and pediatrics at the David Geffen School of Medicine at UCLA, said there are many environmental factors that can activate a pregnant woman’s immune system.

“Although it’s known that maternal inflammation is a risk factor for some neurodevelopmental disorders such as autism, it’s not thought to directly cause them,” he said. He noted that autism is clearly a highly heritable disorder, but other, non-genetic factors clearly play a role.

The researchers also found evidence that the brain growth triggered by the immune reaction was even greater in mice with a specific genetic mutation — a lack of one copy of a tumor suppressor gene called phosphatase and tensin homolog, or PTEN. The PTEN protein normally helps prevent cells from growing and dividing too rapidly. In humans, having an abnormal version of the PTEN gene leads to very large head size or macrocephaly, a condition that also is associated with a high risk for autism.

“Autism is a complex group of disorders, with a variety of causes,” Kornblum said. “Our study shows a potential way that maternal inflammation could be one of those contributing factors, even if it is not solely responsible, through interactions with known risk factors.”

In addition, the team found that the proliferation of neural stem cell and brain overgrowth was stimulated by the activation of a specific molecular pathway. (A pathway is a series of actions among molecules within a cell that leads to a certain cell function.) This pathway involved the enzyme NADPH oxidase, which the UCLA researchers have previously found to be associated with neural stem cell growth.

“The discovery of these mechanisms has identified new therapeutic targets for common autism-associated risk factors,” said Janel Le Belle, an associate researcher in Kornblum’s lab and the paper’s lead author. “The molecular pathways that are involved in these processes are ones that can be manipulated and possibly even reversed pharmacologically.

“In agreement with past clinical findings, these data add to the significant evidence that autism-associated brain alterations begin prenatally and continue to evolve after birth,” she said.

Kornblum added that the findings that neural stem cell hyper-proliferation can contribute to autism-associated features may be somewhat surprising. “Autism neuropathology is primarily thought of as a dysregulation of neuronal connectivity, although the molecular and cellular means by which this occurs is not known,” he said. “Therefore, our hypothesis — that one potential means by which autism may develop is through an overproduction of cells in the brain, which then results in altered connectivity — is a new way of thinking about autism etiology.”

The next step, the researchers say, is to determine if and how the changes they observed lead to changes in the connections between brain cells, and if those effects can be altered after they have happened.

Venturing inside the teenage brain

If you’ve ever tried to warn teenagers of the consequences of risky behavior — only to have them sigh and roll their eyes — don’t blame them.

Blame their brain anatomy.

Sociologists and psychologists have long known that teen brains are predisposed to downplay risk, act impulsively and be undaunted by the threat of punishment. But now scientists are beginning to understand why.

"I think teenage behavior is probably the most misunderstood of any age group — not only by parents but by teenagers themselves," says Pradeep Bhide, a Florida State University College of Medicine neuroscientist and director of the Center for Brain Repair.

"It’s a critical time in life, and a very stressful one, when they are going through so many changes at the same time that their brains are changing. The teen years are actually a very busy time for brain development."

During the past year, Bhide brought together some of the world’s foremost brain researchers in a quest to explain why teenagers — and male teens in particular — often behave erratically. He and two Cornell University colleagues examined 20 of the leading research projects from brain experts around the world and recently published their findings in a special volume of the scientific journal Developmental Neuroscience.

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Sleep twitches light up the brain

A University of Iowa study has found twitches made during sleep activate the brains of mammals differently than movements made while awake.

Researchers say the findings show twitches during rapid eye movement (REM) sleep comprise a different class of movement and provide further evidence that sleep twitches activate circuits throughout the developing brain. In this way, twitches teach newborns about their limbs and what they can do with them.

“Every time we move while awake, there is a mechanism in our brain that allows us to understand that it is we who made the movement,” says Alexandre Tiriac, a fifth-year graduate student in psychology at the UI and first author of the study, which appeared this month in the journal Current Biology. “But twitches seem to be different in that the brain is unaware that they are self-generated. And this difference between sleep and wake movements may be critical for how twitches, which are most frequent in early infancy, contribute to brain development.”

Mark Blumberg, a psychology professor at the UI and senior author of the study, says this latest discovery is further evidence that sleep twitches— whether in dogs, cats or humans—are connected to brain development, not dreams.

“Because twitches are so different from wake movements,” he says, “these data put another nail in the coffin of the ‘chasing rabbits’ interpretation of twitches.”

For this study, Blumberg, Tiriac and fellow graduate student Carlos Del Rio-Bermudez studied the brain activity of unanesthetized rats between 8 and 10 days of age. They measured the brain activity while the animals were awake and moving and again while the rats were in REM sleep and twitching.

What they discovered was puzzling, at first.

“We noticed there was a lot of brain activity during sleep movements but not when these animals were awake and moving,” Tiriac says.

The researchers theorized that sensations coming back from twitching limbs during REM sleep were being processed differently in the brain than awake movements because they lacked what is known as “corollary discharge.”

First introduced by researchers in 1950, corollary discharge is a split-second message sent to the brain that allows animals—including rats, crickets, humans and more—to recognize and filter out sensations generated from their own actions. This filtering of sensations is what allows animals to distinguish between sensations arising from their own movements and those from stimuli in the outside world.

So, when the UI researchers noticed an increase in brain activity while the newborn rats were twitching during REM sleep but not when the animals were awake and moving, they conducted several follow-up experiments to determine whether sleep twitching is a unique self-generated movement that is processed as if it lacks corollary discharge.

The experiments were consistent in supporting the idea that sensations arising from twitches are not filtered: And without the filtering provided by corollary discharge, the sensations generated by twitching limbs are free to activate the brain and teach the newborn brain about the structure and function of the limbs.

“If twitches were like wake movements, the signals arising from twitching limbs would be filtered out,” Blumberg says. “That they are not filtered out suggests again that twitches are special—perhaps special because they are needed to activate developing brain circuits.”

The UI researchers were initially surprised to find the filtering system functioning so early in development.

“But what surprised us even more,” Blumberg says, “was that corollary discharge appears to be suspended during sleep in association with twitching, a possibility that – to our knowledge – has never before been entertained.”

Brain Development in Schizophrenia Strays from the Normal Path

Schizophrenia is generally considered to be a disorder of brain development and it shares many risk factors, both genetic and environmental, with other neurodevelopmental disorders such as autism and intellectual disability.

The normal path for brain development is determined by the combined effects of a complex network of genes and a wide range of environmental factors.

However, longitudinal brain imaging studies in both healthy and patient populations are required in order to map the disturbances in brain structures as they emerge, i.e., the disturbed trajectories of brain development.

A new study by an international, collaborative group of researchers has measured neurodevelopment in schizophrenia, by studying brain development during childhood and adolescence in people with and without this disorder. With access to new statistical approaches and long-term follow-up with participants, in some cases over more than a decade, the researchers were able to describe brain development patterns associated with schizophrenia.

"Specifically, this paper shows that parts of the brain’s cortex develop differently in people with schizophrenia," said first author Dr. Aaron F. Alexander-Bloch, from the National Institute of Mental Health.

"The mapping of the path that the brain follows in deviating from normal development provides important clues to the underlying causes of the disorder," said Dr. John Krystal, Editor of Biological Psychiatry.

The findings were derived by investigating the trajectory of cortical thickness growth curves in 106 patients with childhood-onset schizophrenia and a comparison group of 102 healthy volunteers.

Each participant, ranging from 7–32 years of age, had repeated imaging scans over the course of several years. Then, using over 80,000 vertices across the cortex, the researchers modeled the effect of schizophrenia on the growth curve of cortical thickness.

This revealed differences that occur within a specific group of highly-connected brain regions that mature in synchrony during typical development, but follow altered trajectories of growth in schizophrenia.

"These findings show a relationship between the hypothesis that schizophrenia is a neurodevelopmental disorder and the longstanding hypothesis – first articulated by the German anatomist Karl Wernicke in the late 19th century – that it is a disease of altered connectivity between regions of the brain," added Alexander-Bloch.

This theoretical consistency is important, as it allows researchers to better focus future studies of brain connectivity in schizophrenia, by targeting the brain regions known to be affected.

Socioeconomic status and structural brain development

Recent advances in neuroimaging methods have made accessible new ways of disentangling the complex interplay between genetic and environmental factors that influence structural brain development. In recent years, research investigating associations between socioeconomic status (SES) and brain development have found significant links between SES and changes in brain structure, especially in areas related to memory, executive control, and emotion. This review focuses on studies examining links between structural brain development and SES disparities of the magnitude typically found in developing countries. We highlight how highly correlated measures of SES are differentially related to structural changes within the brain.

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A long childhood feeds the hungry human brain

A five-year old’s brain is an energy monster. It uses twice as much glucose (the energy that fuels the brain) as that of a full-grown adult, a new study led by Northwestern University anthropologists has found.

The study helps to solve the long-standing mystery of why human children grow so slowly compared with our closest animal relatives.

It shows that energy funneled to the brain dominates the human body’s metabolism early in life and is likely the reason why humans grow at a pace more typical of a reptile than a mammal during childhood.

Results of the study will be published the week of Aug. 25 in the journal Proceedings of the National Academy of Sciences.

"Our findings suggest that our bodies can’t afford to grow faster during the toddler and childhood years because a huge quantity of resources is required to fuel the developing human brain," said Christopher Kuzawa, first author of the study and a professor of anthropology at Northwestern’s Weinberg College of Arts and Sciences. "As humans we have so much to learn, and that learning requires a complex and energy-hungry brain."

Kuzawa also is a faculty fellow at the Institute for Policy Research at Northwestern.

The study is the first to pool existing PET and MRI brain scan data — which measure glucose uptake and brain volume, respectively — to show that the ages when the brain gobbles the most resources are also the ages when body growth is slowest. At 4 years of age, when this “brain drain” is at its peak and body growth slows to its minimum, the brain burns through resources at a rate equivalent to 66 percent of what the entire body uses at rest.

The findings support a long-standing hypothesis in anthropology that children grow so slowly, and are dependent for so long, because the human body needs to shunt a huge fraction of its resources to the brain during childhood, leaving little to be devoted to body growth. It also helps explain some common observations that many parents may have.

"After a certain age it becomes difficult to guess a toddler or young child’s age by their size," Kuzawa said. "Instead you have to listen to their speech and watch their behavior. Our study suggests that this is no accident. Body growth grinds nearly to a halt at the ages when brain development is happening at a lightning pace, because the brain is sapping up the available resources."

It was previously believed that the brain’s resource burden on the body was largest at birth, when the size of the brain relative to the body is greatest. The researchers found instead that the brain maxes out its glucose use at age 5. At age 4 the brain consumes glucose at a rate comparable to 66 percent of the body’s resting metabolic rate (or more than 40 percent of the body’s total energy expenditure).

"The mid-childhood peak in brain costs has to do with the fact that synapses, connections in the brain, max out at this age, when we learn so many of the things we need to know to be successful humans," Kuzawa said.

"At its peak in childhood, the brain burns through two-thirds of the calories the entire body uses at rest, much more than other primate species," said William Leonard, co-author of the study. "To compensate for these heavy energy demands of our big brains, children grow more slowly and are less physically active during this age range. Our findings strongly suggest that humans evolved to grow slowly during this time in order to free up fuel for our expensive, busy childhood brains."