Brain Development

The wrong genes mean even moderate drinking in pregnancy can affect a child's IQ

December, 2012

A large study suggests that even a few drinks a week can negatively affect the developing fetus, but only if the woman has specific gene variants.

It’s always difficult in human studies to disentangle the effects of lifestyle factors. Alcohol is a case in point, and in particular the vexed question of whether any alcohol is safe during pregnancy. A new study, however, has avoided the complication of co-occurring lifestyle and environment factors by looking directly at genetic variants.

This study, believed to be the first substantial one of its kind, used genetic variation to investigate the effects of moderate (<6 units of alcohol per week) drinking during pregnancy among a large group of women and their children. Since the individual variations that people have in their DNA are not connected to lifestyle and social factors, the approach removes that potential complication.

The study, involving 4,167 children, found that four genetic variants in alcohol-metabolizing genes were strongly related to lower IQ at age eight. But this effect was only seen among the children of women who were moderate drinkers (heavy drinkers were not included in the study), pointing to the effect requiring exposure to alcohol in the womb.

Ten SNPs from four genes previously implicated in alcohol metabolism, intake, or dependency, were analyzed. Four SNPs (particular variants) were related to children’s scores on the cognitive test (WISC), of which three are rare and one quite common. There was an additive effect, with carriers of multiple ‘bad’ alleles being more affected.

There was some evidence that only drinking one or two drinks a week was not harmful to the fetus, but because the numbers of women were relatively small, and individual variability was high, this can’t be assessed with any great certainty.

The critical factor appears to be metabolism of alcohol, with mothers who are ‘fast' metabolizers being safer for their fetus than mothers who metabolize alcohol more slowly.

Mothers' alcohol intake was based on questionnaires completed when they were 18 weeks and 32 weeks pregnant. ‘Moderate’ was defined as between one and six drinks a week. All participants were of white-European origin.

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Importance of Vitamin C during pregnancy

November, 2012

A guinea pig study demonstrates that low levels of vitamin C during pregnancy have long-lasting effects on the child's hippocampus.

Like us, guinea pigs can’t make vitamin C, but must obtain it from their diet. This makes them a good model for examining the effects of vitamin C deficiency.

In a recent study looking specifically at the effects of prenatal vitamin C deficiency, 80 pregnant guinea pigs were fed a diet that was either high or low in vitamin C. Subsequently, 157 of the newborn pups were randomly allocated to either a low or high vitamin C diet (after weaning), creating four conditions: high/high (controls); high/low (postnatal depletion); low/high (postnatal repletion); low/low (pre/postnatal deficiency). Only males experienced the high/low condition (postnatal depletion).

Only the postnatal depletion group showed any effect on body weight; no group showed an effect on brain weight.

Nevertheless, although the brain as a whole grew normally, those who had experienced a prenatal vitamin C deficiency showed a significantly smaller hippocampus (about 10-15% smaller). This reduction was not reversed by later repletion.

This reduction appeared to be related to a significant reduction in the migration of new neurons into the dentate gyrus. There was no difference in the creation or survival of new neurons in the hippocampus.

This finding suggests that marginal deficiency in vitamin C during pregnancy (a not uncommon occurrence) may have long-term effects on offspring.

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Crucial factors in the evolution of the human brain

September, 2012

Two recent studies comparing gene expression in the brains of human and other animals reveal a key protein for brain size and others for connectivity and regulation.

Genetic comparisons have pinpointed a specific protein as crucial for brain size, both between and within species. Another shows how genetic regulation in the frontal lobes distinguishes the human brain from that of closely related species, and points to two genes in particular as critical.

The protein determining brain size

Comparison of genome sequences from humans and other animals has revealed what may be a crucial protein in the development of the human brain. The analysis found that humans have more than 270 copies of a protein called DUF1220 — more than any other animal studied — and that the number of copies in a species seems to match how close they are to us. Chimpanzees, for example, have 125, and gorillas 99, while marmosets have only 30, and mice just one.

Moreover, comparison of humans with microcephaly and macrocephaly reveals that those with microcephaly (“small brain”) have lower numbers of this protein than normal for humans, and those with macrocephaly (“large brain”) have higher numbers. Copy numbers of the protein were also correlated with gray matter volume in humans without these brain disorders.

In other words, evidence from three lines of inquiry converge on DUF1220 copy number being associated with brain size.

Differences in gene expression and connectivity

But the development of the human brain is not only about size. The human brain is more complex, more connected, than the brains of most other animals. Another genetic analysis has been comparing gene activity in humans, chimpanzees and rhesus macaques, using post-mortem brain tissue of three regions in particular – the frontal cortex, hippocampus and striatum.

Gene expression in the frontal lobe of humans showed a striking increase in molecular complexity, with much more elaborate regulation and connection. The biggest differences occurred in the expression of human genes involved in plasticity.

One gene in particular stood out as behaving differently in the human brain. This gene — called CLOCK, for obvious reasons — is thought to be the master regulator of our body’s clocks. The finding suggests it has influence beyond this role. Interestingly, this gene is often disrupted in mood disorders such as depression and bipolar syndrome.

A second important distinction was how many more connections there were in human brains among networks that included the language genes FOXP1 and FOXP2.

In comparison to all this, gene expression in the caudate nucleus was very similar across all three species.

The findings point to the role of learning (the genes involved in plasticity) and language in driving human brain evolution. They also highlight the need to find out more about the CLOCK gene.

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C-sections don’t trigger key protein in brain

September, 2012

A mouse study finds that a vital protein is triggered by natural birth, and its reduction in those delivered by C-section correlates with poorer memory and greater anxiety in adulthood.

In the light of a general increase in caesarean sections, it’s somewhat alarming to read about a mouse study that found that vaginal birth triggers the expression of a protein in the brains of newborns that improves brain development, and this protein expression is impaired in the brains of those delivered by C-section.

The protein in question —mitochondrial uncoupling protein 2 (UCP2) — is important for the development of neurons and circuits in the hippocampus. Indeed, it has a wide role, being involved in regulation of fuel utilization, mitochondrial bioenergetics, cell proliferation, neuroprotection and synaptogenesis. UCP2 is induced by cellular stress.

Among the mice, natural birth triggered UCP2 expression in the hippocampus (presumably because of the stress of the birth), which was reduced in those who were born by C-section. Not only were levels of UCP2 lower in C-section newborns, they continued to be lower through to adulthood.

Cell cultures revealed that inhibiting UCP2 led to decreased number of neurons, neuron size, number of dendrites, and number of presynaptic clusters. Mice with (chemically or genetically) inhibited UCP2 also showed behavioral differences indicative of greater levels of anxiety. They explored less, and they showed poorer spatial memory.

The effects of reduced UCP2 on neural growth means that factors that encourage the growth of new synapses, such as physical exercise, are likely to be much less useful (if useful at all). Could this explain why exercise seems to have no cognitive benefits for a small minority? (I’m speculating here.)

Although the researchers don’t touch on this (naturally enough, since this was a laboratory study), I would also speculate that, if the crucial factor is stress during the birth, this finding applies only to planned C-sections, not to those which become necessary during the course of labor.

UCP2 is also a critical factor in fatty acid utilization, which has a flow-on effect for the creation of new synapses. One important characteristic of breast milk is its high content of long chain fatty acids. It’s suggested that the triggering of UCP2 by natural birth may help the transition to breastfeeding. This in turn has its own benefits for brain development.

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Brain continues to develop well into our 20s

October, 2011

A new study shows that the wiring that connects the frontal lobes to other parts of the cerebral cortex continues to develop well into young adulthood — except for a small minority that show degradation.

Brain imaging data from 103 healthy people aged 5-32, each of whom was scanned at least twice, has demonstrated that wiring to the frontal lobe continues to develop after adolescence.

The brain scans focused on 10 major white matter tracts. Significant changes in white matter tracts occurred in the vast majority of children and early adolescents, and these changes were mostly complete by late adolescence for projection and commissural tracts (projection tracts project from the cortex to non-cortical areas, such as the senses and the muscles, or from the thalamus to the cortex; commissural tracts cross from one hemisphere to the other). But association tracts (which connect regions within the same hemisphere) kept developing after adolescence.

This was particularly so for the inferior and superior longitudinal and fronto-occipital fascicule (the inferior longitudinal fasciculus connects the temporal and occipital lobes; the superior longitudinal fasciculus connects the frontal lobe to the occipital lobe and parts of the temporal and parietal lobes). These frontal connections are needed for complex cognitive tasks such as inhibition, executive functioning, and attention.

The researchers speculated that this continuing development may be due to the many life experiences in young adulthood, such as pursing post-secondary education, starting a career, independence and developing new social and family relationships.

But this continuing development wasn’t seen in everyone. Indeed, in some people, there was evidence of reductions, rather than growth, in white matter integrity. It may be that this is connected with the development of psychiatric disorders that typically develop in adolescence or young adulthood — perhaps directly, or because such degradation increases vulnerability to other factors (e.g., to drug use). This is speculative at the moment, but it opens up a new avenue to research.

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[2528] Lebel, C., & Beaulieu C.
(2011).  Longitudinal Development of Human Brain Wiring Continues from Childhood into Adulthood.
The Journal of Neuroscience. 31(30), 10937 - 10947.

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Large brains in mammals first evolved for better sense of smell

July, 2011

High-tech X-ray scans of ancient fossil skulls have revealed that the increase in brain size that began with the first mammals was driven by improvements in smell and touch.

190-million-year-old fossil skulls of Morganucodon and Hadrocodium, two of the earliest known mammal species, has revealed that even at this early stage of mammalian evolution, mammals had larger brains than would be expected for their body size. High-resolution CT scans of the skulls have now shown that this increase in brain size can be attributed to an increase in those regions dealing with smell and touch (mammals have a uniquely well developed ability to sense touch through their fur).

Comparison of these fossils with seven fossils of early reptiles (close relatives of the first mammals), 27 other primitive mammals, and 270 living mammals, has further revealed that the size of the mammalian brain evolved in three major stages. First, an initial increase in the olfactory bulb and related areas (including the cerebellum) by 190 million years ago; then another jump in the size of these regions shortly after that time; and finally an increase in those regions that control neuromuscular coordination by integrating different senses by 65 million years ago.

It’s speculated that the initial increase in smell and touch was driven by early mammals being nocturnal — dinosaurs being active during the day.

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[2301] Rowe, T. B., Macrini T. E., & Luo Z-X.
(2011).  Fossil Evidence on Origin of the Mammalian Brain.
Science. 332(6032), 955 - 957.

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Common insecticide associated with delayed mental development of young children

March, 2011

The insecticide which has largely replaced those phased out because of their effects on children’s development has now been found to also be associated with delayed mental development.

A study involving 725 black and Dominican pregnant women living in New York and, later, their 3-year-old children, has found that children who were more highly exposed to PBO in personal air samples taken during the third trimester of pregnancy scored 3.9 points lower on the Bayley Mental Developmental Index than those with lower exposures. This is a similar effect size to that of lead exposure.

PBO is a marker for the insecticide permethrin, which is one of the most common pyrethroid insecticides used in U.S. homes since the EPA phased out the widespread residential use of organophosphorus insecticides in 2000-2001 because of risks to child neurodevelopment.

PBO was detected in the majority of personal air samples (75%).

As this is the first study of these compounds, the results should be considered preliminary.

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Why bigger brains developed

December, 2010

More support for the theory that bigger brains were a response to living in social groups comes from a wide-ranging comparison of 511 mammalian species, but a comparison of wasp brains over time points to the importance of parasitism.

A comparison of the brain and body size of over 500 species of living and fossilised mammals has found that the brains of monkeys grew the most over 60 million years, followed by horses, dolphins, camels and dogs. Those with relatively bigger brains tend to live in stable social groups. The brains of more solitary mammals, such as cats, deer and rhino, grew much more slowly during the same period.

On the other hand, a new study comparing wasp brains over time has revealed that the mushroom bodies (neural clusters responsible for processing and remembering smells and sights) of parasitic wasps are consistently larger and more complex than those of nonparasitic wasps, which represent the very oldest form of wasp.

Previously, findings that social insects tend to have larger mushroom bodies than solitary ones have lead researchers to believe that the transition from solitary to social living was behind the larger brain regions. These new findings suggest that it is parasitism (which evolved 90 million years before social insects appear) that is behind the growth in size. That may be because well-developed mushroom bodies help parasitic wasps better locate hosts for their larvae.

Of course, this doesn’t rule out the possibility that sociality lead to another boost in size and complexity, and indeed the researchers suggest that these neurological developments may have been a crucial precursor for central place foraging. This behavior is widespread in this group of insects (the Aculeata), requires extensive spatial learning, and may have contributed to the various developments of social behavior. A comparison of the brains of social worker bees and those of parasitic wasps would be helpful.

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Big brains attributed to mother's care

October, 2010

Comparison of marsupial and placental mammal brains reveals that maternal investment is a critical factor in evolving a large brain, and primates benefit from two approaches.

Analysis of the brain sizes of 197 marsupial and 457 placental mammals has found that marsupial mammals (e.g. kangaroos, possums), had relative brain sizes that are at least as big as placental mammals. Previous belief that marsupials have relatively smaller brains appears to be produced by the inclusion of the one outlier group — primates. In both placental and marsupial groups, big brains were correlated to length of maternal care (i.e. lactation). Basal metabolic rate (the energy an animal expends at rest), although correlated with brain size in placental mammals, did not correlate with marsupial brain size. Because brain tissue uses so much energy, it has been assumed that a high metabolism was a prerequisite for a big brain.

The new findings indicate that maternal investment is a more critical factor than metabolic rate. It may also be that primates have been especially advantaged by combining both methods of increasing brain size: fast growth in the womb with the help of the mother’s high metabolic rate (placental method), and slower but lengthy growth after birth with the help of extended lactation (marsupial method).

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[1895] Weisbecker, V., & Goswami A.
(2010).  Brain size, life history, and metabolism at the marsupial/placental dichotomy.
Proceedings of the National Academy of Sciences. 107(37), 16216 - 16221.

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New ways of assessing connectivity establish a "brain age" measure of child development

September, 2010

A new way of analyzing brain scans reveals exactly what changes in the brain, in terms of connectivity, as it matures.

Last year I reported on a study involving 210 subjects aged 7 to 31 that found that in contrast to the adult brain, most of the tightest connections in a child's brain are between brain regions that are physically close to each other. As the child grows to adulthood, the brain switches from an organization based on local networks based on physical proximity to long-distance networks based on functionality. Now the same researchers, using five-minute scans from 238 people aged 7 to 30, have looked at nearly 13,000 functional (rather than structural) connections and identified 200 key ones. On the basis of these 200 connections, the brains could be identified as belonging to a child (7-11) or an adult (25-30) with 92% accuracy, and adolescents or adults with 75% accuracy. Moreover, the most important factor in predicting development (accounting for about 68%) was the trimming of the vast number of childhood connections.

Apart from emphasizing the importance of pruning connections in brain development, the main value of this research is in establishing an effective analytic method and baseline measurements for normal development. It is hoped that this will eventually help researchers work out indicators for various developmental disorders.

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