How anxiety affects kids' brains

A study shows how anxiety can affect children's brains.

Children with anxiety problems actually have a bigger "fear center" in their brain, researchers report.

The study included 76 children aged 7 to 9, which is when anxiety-related traits and symptoms can first be reliably detected, according to the Stanford University School of Medicine researchers.

The parents provided information about their youngsters' anxiety levels, and the children also underwent MRI scans of their brain structure and function.

The investigators focused on an area of the brain called the amygdala, which is a person's "fear center," and found that kids with high anxiety levels had a larger amygdala compared to children with low anxiety levels. This part of the brain, the researchers noted, had more connections to other brain regions involved in attention, emotion perception and regulation.

The researchers also developed a way to predict children's anxiety levels based on brain scan measurements of amygdala size and its level of connection to other brain areas, according to the study in the June issue of the journal Biological Psychiatry.

"It is a bit surprising that alterations to the structure and connectivity of the amygdala were so significant in children with higher levels of anxiety, given both the young age of the children and the fact that their anxiety levels were too low to be observed clinically," first author Dr. Shaozheng Qin said in a journal news release.

The study is an important advance in identifying young children at risk for anxiety disorders and improves understanding of how anxiety develops in people, according to Qin.

While the study found an association between reported levels of anxiety and the structure and connectivity of the amygdala in kids, it did not prove a cause-and-effect relationship.

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Irregular bedtime can mean behavioral problems in children

Irregular bedtimes in children can lead to sleep deprivation which can harm a child's brain and cause children to have behavioral issues.

Researchers from UCL have found that children with irregular bedtimes are more likely to have behavioral difficulties.

The study, which is published in the journal Pediatrics, found that irregular bedtimes could disrupt natural body rhythms and cause sleep deprivation, undermining brain maturation and the ability to regulate certain behaviours.

Professor Yvonne Kelly (UCL Epidemiology & Public Health), said: "Not having fixed bedtimes, accompanied by a constant sense of flux, induces a state of body and mind akin to jet lag and this matters for healthy development and daily functioning."

"We know that early child development has profound influences on health and wellbeing across the life course. It follows that disruptions to sleep, especially if they occur at key times in development, could have important lifelong impacts on health."

Analysing data from more than 10,000 children in the UK Millennium Cohort Study, the team collected bedtime data at three, five and seven years, as well as incorporating reports from the children's mothers and teachers on behavioral problems.

The study found a clear clinical and statistically significant link between bedtimes and behavior as irregular bedtimes affected children's behavior by disrupting circadian rhythms, leading to sleep deprivation that affects the developing brain.

As children progressed through early childhood without a regular bedtime, their behavioural scores -- which included hyperactivity, conduct problems, problems with peers and emotional difficulties -- worsened. However, children who switched to a more regular bedtime had clear improvements in their behaviour.

Professor Kelly said: "What we've shown is that these effects build up incrementally over childhood, so that children who always had irregular bedtimes were worse off than those children who did have a regular bedtime at one or two of the ages when they were surveyed.

"But our findings suggest the effects are reversible," continued Professor Kelly. "For example, children who change from not having to having regular bedtimes show improvements in their behaviour."

Irregular bedtimes were most common at the age of three, when around one in five children went to bed at varying times. However, by the age of seven, more than half the children went to bed regularly between 7.30 and 8.30 pm. Children whose bedtimes were irregular or who went to bed after 9 pm came from more socially disadvantaged backgrounds, and this was factored into the study findings.

Professor Kelly said: "As it appears the effects of inconsistent bedtimes are reversible, one way to try and prevent this would be for health care providers to check for sleep disruptions as part of routine health care visits. Given the importance of early childhood development on subsequent health, there may be knock-on effects across the life course. Therefore, there are clear opportunities for interventions aimed at supporting family routines that could have important lifelong impacts."

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Common cause for brain tumors in children

A specific signaling pathway was found to be the common cause for many brain tumors in children.

An overactive signaling pathway is a common cause in cases of pilocytic astrocytoma, the most frequent type of brain cancer in children. This was discovered by a network of scientists coordinated by the German Cancer Research Center (as part of the International Cancer Genome Consortium, ICGC). In all 96 cases studied, the researchers found defects in genes involved in a particular pathway. Hence, drugs can be used to help affected children by blocking components of the signaling cascade.

The findings are published in the latest issue of the journal Nature Genetics.

Brain cancer is the primary cause of cancer mortality in children. Even in cases when the cancer is cured, young patients suffer from the stress of a treatment that can be harmful to the developing brain. In a search for new target structures that would create more gentle treatments, cancer researchers are systematically analyzing all alterations in the genetic material of these tumors. This is the mission of the PedBrain consortium, which was launched in 2010. Led by Professor Stefan Pfister from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), the PedBrain researchers have now published the results of the first 96 genome analyses of pilocytic astrocytomas.

Pilocytic astrocytomas are the most common childhood brain tumors. These tumors usually grow very slowly. However, they are often difficult to access by surgery and cannot be completely removed, which means that they can recur. The disease may thus become chronic and have debilitating effects for affected children.

In previous work, teams of researchers led by Professor Dr. Stefan Pfister and Dr. David Jones had already discovered characteristic mutations in a major proportion of pilocytic astrocytomas. All of the changes involved a key cellular signaling pathway known as the MAPK signaling cascade. MAPK is an abbreviation for "mitogen-activated protein kinase." This signaling pathway comprises a cascade of phosphate group additions (phosphorylation) from one protein to the next -- a universal method used by cells to transfer messages to the nucleus. MAPK signaling regulates numerous basic biological processes such as embryonic development and differentiation and the growth and death of cells.

"A couple of years ago, we had already hypothesized that pilocytic astrocytomas generally arise from a defective activation of MAPK signaling," says David Jones, first author of the publication. "However, in about one fifth of the cases we had not initially discovered these mutations. In a whole-genome analysis of 96 tumors we have now discovered activating defects in three other genes involved in the MAPK signaling pathway that have not previously been described in astrocytoma."

"Aside from MAPK mutations, we do not find any other frequent mutations that could promote cancer growth in the tumors. This is a very clear indication that overactive MAPK signals are necessary for a pilocytic astrocytoma to develop," says study director Stefan Pfister. The disease thus is a prototype for rare cancers that are based on defects in a single biological signaling process.

In total, the genomes of pilocytic astrocytomas contain far fewer mutations than are found, for example, in medulloblastomas, a much more malignant pediatric brain tumor. This finding is in accordance with the more benign growth behavior of astrocytomas. The number of mutations increases with the age of the affected individuals.

About one half of pilocytic astrocytomas develop in the cerebellum, the other 50 percent in various other brain regions. Cerebellar astrocytomas are genetically even more homogenous than other cases of the disease: In 48 out of 49 cases that were studied, the researchers found fusions between the BRAF gene, a central component of the MAPK signaling pathway, and various other fusion partners.

"The most important conclusion from our results," says study director Stefan Pfister, "is that targeted agents for all pilocytic astrocytomas are potentially available to block an overactive MAPK signaling cascade at various points. We might thus in the future be able to also help children whose tumors are difficult to access by surgery."

The International Cancer Genome Consortium (ICGC), a network of scientists from currently 15 countries, aims to obtain a comprehensive description of genomic and epigenomic changes in all significant types of cancer. Germany takes part with the PedBrain Tumor Project to analyze pediatric brain tumors (medulloblastoma, which in Germany affects approximately 100 children each year; and pilocytic astrocytoma, which is diagnosed in approximately 200 children each year). Within the PedBrain Tumor Project, 300 samples of each tumor type will be analyzed, along with the same number of samples of healthy tissue from the same patients, to identify changes that are cancer-specific.

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Infant brain's blood flow is regulated differently than an adult brain

Researchers found the blood flow in a developing infant's brain is not the same as an adult's brain. This has many implications for treating developmental disorders.

A new study by Columbia Engineering researchers finds that the infant brain does not control its blood flow in the same way as the adult brain. The paper, which the scientists say could change the way researchers study brain development in infants and children, is published in the February 18 Early Online edition ofProceedings of the National Academy of Sciences (PNAS).

"The control of blood flow in the brain is very important" says Elizabeth Hillman, associate professor of Biomedical Engineering and of Radiology, who led the research study in her Laboratory for Functional Optical Imaging at Columbia. "Not only are regionally specific increases in blood flow necessary for normal brain function, but these blood-flow increases form the basis of signals measured in fMRI, a critical imaging tool used widely in adults and children to assess brain function. Many prior fMRI studies have overlooked the possibility that the infant brain controls blood flow differently."

"Our results are fascinating" says Mariel Kozberg, a neurobiology MD-PhD candidate who works under Hillman and is the lead author of the PNAS paper. "We found that the immature brain does not generate localized blood-flow increases in response to stimuli. By tracking changes in blood-flow control with increasing age, we observed the brain gradually developing its ability to increase local blood flow and, by adulthood, generate a large blood-flow response."

The study results suggest that fMRI experiments in infants and children should be carefully designed to ensure that maturation of blood-flow control can be delineated from changes in neuronal development. "On the other hand," says Hillman, "our findings also suggest that vascular development may be an important new factor to consider in normal and abnormal brain development, so our findings could represent new markers of normal and abnormal brain development that could potentially be related to a range of neurological or even psychological conditions."

Functional magnetic resonance imaging, or fMRI, is one of several brain-imaging methods that measure changes in blood flow to detect the presence and location of neuronal activity. In adults, blood-flow increases occur in specific regions of the brain during a particular task like moving your hand or reacting to a stimulus. FMRI relies upon measuring decreases in deoxygenated hemoglobin resulting from this blood-flow increase to understand which parts of the brain are responsible for different actions and emotions. FMRI and other brain-imaging methods are currently being widely used to explore brain development, and to understand disorders in infants and children including autism and ADHD.

"Until now, we had been studying blood flow in the adult brain," Hillman notes, "but we became interested in several studies that reported odd, sometimes negative, blood-flow responses in newborn and premature infants and decided to carefully explore what was different about the immature brain compared to the adult. Initially, I saw these studies as a way to watch how the adult system assembled itself during development. Then we realized how important our findings were to those using brain imaging to study child development and developmental disorders."

The team used a unique multispectral optical intrinsic signal imaging system (MS-OISI) built in Hillman's lab to perform the research. MS-OISI is a high-speed, high-resolution imaging approach that takes advantage of the different absorption spectra of deoxygenated and oxygenated hemoglobin in order to determine changes in the concentrations of each. The researchers found that, with increasing age, there was a gradual development of a localized increase in blood flow, while a strong, delayed decrease in flow was consistently present. Only by adulthood was the positive increase able to balance the decrease in flow.

"Our results suggest that the infant brain might not be able to generate localized blood- flow increases, even if there is neuronal activity occurring, and that the development of blood- flow control occurs in parallel with early neuronal development," says Kozberg. "This could suggest that fMRI studies of infants and children may be detecting changes in both vascular and neuronal development -- in fact, vascular development may be an important new factor to consider in normal and abnormal brain development."

The team also found that the younger age groups were highly sensitive to blood pressure increases in response to stimulation and that these increases can cause large increases in blood flow across the brain. "This finding indicates that the newborn brain is also unable to regulate its overall blood-flow levels," Kozberg explains. "This could explain earlier fMRI results in infants and children that were sometimes positive and sometimes negative, because it is difficult to tell whether blood pressure increases are occurring in infants and children. This result suggests that great care should be taken in setting stimulus thresholds in young subjects."

The researchers add that, since the newborn brain appears to be able to sustain itself without tightly controlled blood flow, their findings suggest that the infant brain may be intrinsically more resistant to damage due to a lack of oxygen than the adult brain. "This could be an important property to understand, both in terms of understanding how best to treat blood-flow problems in the newborn infant brain, which can cause lifelong problems such as cerebral palsy, and to potentially better understand how to treat the adult brain in conditions such as stroke," Hillman observes.

"Our lab operates at the intersection of neuroscience and engineering," continues Hillman." Not only do we develop the imaging systems that let us investigate the living brain in new ways, but like all engineers, we're fascinated with figuring out 'how things work,' and the brain is no exception."

Next steps for Hillman and her team include further defining the cellular mechanisms underlying the developing hemodynamic response at a cellular and microvascular level, using methods such as high-speed and multi-plane in-vivo two-photon microscopy, another technique developed in the lab. They're particularly interested in tracking changes in neuronal activity, microvascular architecture and connectivity, and the distribution and activity of other cellular populations thought to be associated with neurovascular coupling as a function of development.

"This will help us understand how the neonatal brain is different, and better understand how mature blood-flow control mechanisms in the adult brain work," says Kozberg. Adds Hillman, "We are also keen to take this research into the clinic and explore whether our findings could improve diagnosis and monitoring of newborn infants. Our findings so far feel like just the tip of the iceberg. There is so much more for us to do now to understand why the infant brain is so different, and how we can use our findings to improve understanding of a wealth of devastating childhood and developmental conditions."

This research was supported by grants and student fellowships from the National Institute of Neurological Disorders and Stroke, the National Eye Institute, the National Science Foundation, the National Defense Science and Engineering Graduate Fellowship, the Medical Scientist Training Program, and the Human Frontier Science Program. Hillman is also a member of the Columbia University graduate program in Neurobiology and Behavior and the Kavli Institute for Brain Sciences.

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