Stories about: brain development

Real-time contextual information could help doctors interpret children’s brain scans

Radiologists who can tune in to the nuances of brain scans in children are a pretty rarified group. Only about 3 percent of U.S. radiologists, some 800 to 900 physicians, practice in pediatrics. Those specifically trained in pediatric neuroradiology are even scarcer.

To a less trained eye, normal developmental changes in a child’s brain may be misinterpreted as abnormal on MRI. Conversely, a complex brain disorder can sometimes appear normal. That’s especially true when the abnormality affects both sides of the brain equally (see sidebar).

It can be hard to find the cause of a child’s developmental delay without a proper read. “Pediatric brain scans of children under age 4 can be particularly tricky to read because the brain is rapidly developing during this period,” says Sanjay Prabhu, MBBS, a pediatric neuroradiologist at Boston Children’s Hospital. “If you’re looking at adult scans all the time, it’s incredibly difficult to transition to pediatric scans and understand what is considered ‘normal’ and ‘abnormal.’ Clinicians often wonder, ‘Should I repeat the scan? Should I send the patient to a specialist?’”

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‘Hotspots’ for DNA breakage in neurons may promote brain genetic diversity, disease

DNA breakage brain
DNA breaks in certain genes may help brains evolve, but also can cause disease (Constantin Ciprian/Shutterstock)

As organs go, the brain seems to harbor an abundance of somatic mutations — genetic variants that arise after conception and affect only some of our neurons. In a recent study in Science, researchers found about 1,500 variants in each of neurons they sampled.

New research revealing the propensity of DNA to break in certain spots backs up the idea of a genetically diverse brain. Reported in Cell last month, it also suggests a new avenue for thinking about brain development, brain tumors and neurodevelopmental/psychiatric diseases.

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How amniotic and cerebrospinal fluids talk to the developing brain: proteomics

proteomics amniotic fluid cerebrospinal fluid brain development
Counterclockwise, from bottom left: In the earliest stage of nervous system development, the amniotic fluid is rich with proteins, shown as dots, that communicate with neural stem cells. As the neural tube closes and the brain takes shape, the proteins become fewer and less complex. (Hillary Mullan, Boston Children’s Hospital)

When we were developing in the womb, we were immersed in amniotic fluid. As our nervous systems formed, some of this fluid was trapped inside the neural tube, forming the cerebrospinal fluid that bathes our brains.

In the past, these fluids have been seen as a “cushion” or a place to dump waste products. But new research suggests that they actively participate in nervous system development.

Publishing this week in Developmental Cell, researchers led by Maria Lehtinen, PhD, and Kevin Chau in the Department of Pathology at Boston Children’s Hospital show that amniotic fluid and cerebrospinal fluid (CSF) contain rich portfolios of proteins that tell neural stem cells what to do — how to divide and what kinds of cells to make. They also show that the messages change in different phases of development.

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On the clock: Circadian genes may regulate brain plasticity

brain circadian rhythmsFirst in a two-part series on circadian biology and disease. Read part 2.

It’s long been known that a master clock in the hypothalamus, deep in the center of our brain, governs our bodily functions on a 24-hour cycle. It keeps time through the oscillatory activity of timekeeper molecules, much of which is controlled by a gene fittingly named Clock.

It’s also been known that the timekeeper molecules and their regulators live outside this master clock, but what exactly they do there remains mysterious. A new study reveals one surprising function: they appear to regulate the timing of brain plasticity—the ability of the brain to learn from and change in response to experiences.

“We found that a cell-intrinsic Clock may control the normal trajectory of brain development,” says Takao Hensch, PhD, a professor in the Departments of Molecular and Cellular Biology and Neurology at Harvard University and a member of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital.

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Autism-like behaviors, impaired nerve tracts found in institutionalized children

Sad child-shutterstock_92102072 croppedThe sad experience of abandoned children in Romanian orphanages continues to provide stark lessons about the effects of neglect and deprivation of social and emotional interactions. The long-running Bucharest Early Intervention Project (BEIP) has been able to transfer some of these institutionalized children, selected at random, into quality foster care homes—and documented the benefits.

In a review article in the January 29 Lancet, BEIP investigator Charles A. Nelson, PhD, and medical student Anna Berens, MsC, both of Boston Children’s Hospital, make a strong case for global deinstitutionalization—as early in a child’s life as possible. Currently, it’s estimated that at least 8 million children worldwide are growing up in institutional settings.

The BEIP studies have documented a series of problems in institutionalized children, especially those who aren’t placed in foster care or are placed when they are older:

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Mapping mosaicism: Tracing subtle mutations in our brains

brain genetic mosaicism
(Erik Jacobsen, Threestory Studio. Used with permission.)

DNA sequences were once thought to be the same in every cell, but the story is now known to be more complicated than that. The brain is a case in point: Mutations can arise at different times in brain development and affect only a percentage of neurons, forming a mosaic pattern.

Now, thanks to new technology described last week in Neuron, these subtle “somatic” brain mutations can be mapped spatially across the brain and even have their ancestry traced.

Like my family, who lived in Eastern Europe, migrated to lower Manhattan and branched off to Boston, California and elsewhere, brain mutations can be followed from the original mutant cells as they divide and migrate to their various brain destinations, carrying their altered DNA with them.

“Some mutations may occur on one side of the brain and not the other,” says Christopher Walsh, MD, PhD, chief of Genetics and Genomics at Boston Children’s Hospital and co-senior author on the paper. “Some may be ‘clumped,’ affecting just one gyrus [fold] of the brain, disrupting just a little part of the cortex at a time.”

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Five people, one mutation and the evolution of human language

The Sylvian fissure (via BodyParts3D/Wikimedia Commons)
The Sylvian fissure (via BodyParts3D/Wikimedia Commons)
Five people with an unusual pattern of brain folds have afforded a glimpse into how the human brain may have evolved its language capabilities.

How the human brain develops its hills and valleys—expanding its surface area and computational capacity—has been difficult to study. Mice, the staple of scientific research, lack folds in their brains.

Christopher Walsh, MD, PhD, head of the Division of Genetics and Genomics at Boston Children’s Hospital, runs a brain development and genetics clinic and has spent 25 years studying people in whom the brain formation process goes awry. Some brains are too small (microcephaly). Some have folds, or gyri, that are too broad and thick (pachygyria). Some are smooth, lacking folds altogether (lissencephaly). And some have an abnormally large number of small, thin folds—known as polymicrogyria.

In 2005, studying people with polymicrogyria, Walsh and colleagues identified a mutation in a gene known as GPR56, a clue that this gene helps drive the formation of folds in the cortex of the human brain.

In a study published in today’s issue of Science, Walsh and his colleagues focused on five people whose brain MRIs showed polymicrogyria, but just in one location—near a large, deep furrow known as the Sylvian fissure, which includes the brain’s primary language area.

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Neuronal migration and a well-configured cortex: A neuroscientist looks back

Normal brain and Double Cortex-Courtesy Christopher Walsh(Above: In double cortex syndrome, causing epilepsy and mental retardation, an extra cortex forms just beneath the cerebral cortex [right]. The causative DCX mutation interferes with migration of neurons during the cortex’s early development. Courtesy Walsh Lab)

The journal Neuron, celebrating its 25th anniversary, recently picked one influential neuroscience paper from each year of the publication. In this two-part series, we feature the two Boston Children’s Hospital’s scientists who made the cut. The Q&A below is adapted with kind permission from Cell Press. (See part 1)

Key to well-tuned brain function is the migration of neurons to precise locations as the brain develops. The long journey begins deep inside the brain and ends in the outer cerebral cortex—where our highest cognitive functions lie. Christopher Walsh, MD, PhD, has shown that several genetic mutations causing neurodevelopmental disorders disrupt this neuronal migration, landing neurons in the wrong places. Each gene governs a specific sub-task: one kicks off the migration process; others stop migration when neurons have arrived in the right location.

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Microglia’s role in brain development: A neuroscientist looks back

The journal Neuron, celebrating its 25th anniversary, recently picked one influential neuroscience paper from each year of the publication. In this two-part series, we feature the two Boston Children’s Hospital’s scientists who made the cut. The Q&A below is adapted with kind permission from Cell Press.

Microglial cell with synapses
CAUGHT IN THE ACT: This microglial cell is from the lateral geniculate nucleus, which receives visual input from the eyes. The red and blue are synapses that it has engulfed. (Blue synapses represent inputs from the same-side eye; red, the opposite-side eye.)

In 2012, Beth Stevens, PhD, and colleagues provided a new understanding of how glial cells shape healthy brain development. Glia were once thought to be merely nerve “glue” (the meaning of “glia” from the Greek), serving only to protect and support neurons. “In the field of neuroscience, glia have often been ignored,” Stevens told Vector last year.

No longer. Stevens’s 2012 paper documented that microglia—glial cells best known for their immune function—are no passive bystanders. They get rid of excess connections, or synapses, in the developing brain the same way they’d dispatch an invading pathogen—by eating them.

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Mapping the wiring of the developing brain in 3D

Ed. note: Last week we wrote about Jurriaan Peters, MD’s brain network analysis in children with autism. In the second of our two part series on brain mapping, we talk about ways of mapping the brain’s physical wiring.

(AMagill/Flickr)

At the most basic level, the brain is a collection of wires, albeit a really complex one.

But how during development do nerve fibers thread their way through the growing brain and make the right connections?

The answer to that question could reveal more about the nature of conditions like autism spectrum disorders—which, as we reported about a year and a half ago, seem to have their roots in structurally altered brain pathways.

“We know very little about what’s happening in the developing brain in three dimensions,” says Emi Takahashi, PhD, a researcher in the Fetal-Neonatal Neuroimaging & Developmental Science Center (FNNDSC) at Boston Children’s Hospital. “With histology techniques, we can achieve a two-dimensional view over small areas, but it’s hard to know which fiber bundles are growing in which ways during different stages of development in the whole brain.”

But new MRI-based technologies are quickly closing that knowledge gap, giving us our first high-resolution peek into how the developing brain wires itself up.

Using something called high angular resolution diffusion imaging (HARDI) MRI, Takahashi and her colleagues (including neuroradiologist and FNNDSC director P. Ellen Grant, MD) can trace the three-dimensional pathways within the growing brain via stunning images like these:

Courtesy Cerebral Cortex (Takahashi et al., 2012)

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