Brain-Disease Drug Targets Genes Inherited From Dad

Anyone who’s passed basic biology knows that we get one copy of a gene from our mother, a second from our father. But few people realize that not all of these genes end up being treated equally. Imprinted genes are expressed from only the maternal or paternal allele, rather than both. And, when this process goes wrong, it can actually lead to diseases. Now, researchers have identified a possible way to treat imprinting errors. In the brain, Ube3a is an imprinted gene; only the maternal allele is expressed, even if it is mutated and the paternal allele is normal. This is the case in Angelman syndrome, a severe neurodevelopmental disorder caused by mutation or deletion of the maternal allele of Ube3a. Ube3a is imprinted only in the brain, though; in other tissues, the paternal allele is expressed along with the maternal one.
This led Benjamin Philpot and his colleagues at UNC Chapel Hill to wonder: wouldn’t it be great if we could get the normal, paternal version of Ube3a to work in the brain — to unsilence it? Maybe this could help kids with Angelman syndrome.

To find a drug that might allow the paternal copy of Ube3a to be expressed, they first made mice in which only the paternal copy of the gene was linked to the gene for yellow fluorescent protein. They then isolated cortical neurons from these mice and exposed the neurons to a variety of chemicals. If any of these chemicals caused the cells to glow yellow, that meant that they allowed expression of the paternal UBE-3A-yellow fluorescent protein hybrid.
The scientists screened 2,306 different compounds, four times each. Most of the compounds have already been approved for use in humans, so if the researchers found anything promising, clinical trials would be expedited. They concentrated on agents known to be active in the central nervous system and those that are known to interfere in epigenetic regulation (like the methylation often used in imprinting). Unfortunately, none of these activated the paternal UBE-3A-yellow fluorescent protein hybrid.
But there was one compound that unsilenced the gene: topotecan, a drug that is part of a class called topoisomerase inhibitors. Topoisomerases are enzymes that alleviate the stress on a DNA double helix that occurs when the two strands are pulled apart, as they are when a gene is expressed.
Once topotecan was identified, the researchers went on to show that other topoisomerase-inhibiting drugs, both those structurally similar to topotecan and those with different structures, could unsilence paternal Ube3a. They then injected topotecan into mouse brains to demonstrate that it could work in vivo, and not just in tissue culture dishes. They found that paternal Ube3a expression persisted in spinal cord neurons for up to 12 weeks after drug treatment; this long lasting effect is significant because genetic imprinting is thought to be established during specific points in embryonic development and then maintained for life.
Paternal Ube3a is normally silenced by what’s called an antisense transcript—a piece of RNA that covers up the gene to prevent its expression. (This antisense transcript is not made from the maternal chromosome.) Topotecan worked on the paternal chromosome, dampening antisense transcription there.
Inherited neurological disabilities have been extremely difficult to treat. In Angelman’s syndrome, the brain architecture seems normal at birth, so it is possible that the restoration of normal gene expression could correct some of the pathologies. Topotecan is approved for use in people with cancer, and it has been shown to be well tolerated in children. Hopefully, it could be therapeutically valuable for those with Angelman’s syndrome; it has definitely been valuable in showing how a dormant but functional gene can be reactivated.

'Bionic' boy Robbie looks forward to his best ever Christmas after op relieves painful brain condition

Robbie ovenstone and sisterChloe

'Bionic' boy Robbie is looking forward to Christmas with sister Chloe
A BRAVE “bionic boy” is looking forward to the best Christmas of his young life.
Robbie Ovenstone, six, suffers from a painful brain condition which causes muscle spasms and means he spends most of his time in a wheelchair.
But after surgeons planted electrodes in his brain, he is able for the first time to join in many of the festive activities other children his age take for granted.
His dad Dougie, from Kirkcaldy, said: “Robbie is now opening up his own Advent calendar, which he wasn’t able to do before without help.”
And he’s looking forward to playing with the toys he’ll get at Christmas like any other child.
Robbie suffers from child onset dystonia, which muddles electronic signals from the brain, causing his arm and leg muscles to twist.
He needs help with tasks such as feeding and dressing – but now his life is being gradually transformed thanks to the pioneering surgery he underwent at King’s College Hospital in London.
The six-hour operation involved implanting two electrodes into his brain. They are connected by wires leading from his skull to a battery, which needs to be recharged for 15 minutes each day.
Dougie , 46, and his wife, Jane, 37, are delighted with their son’s “miraculous” recovery.
The former telecoms worker, who is now a full-time carer for Robbie, said: “The day after his operation, he was sitting up in the bed playing games and he can now develop muscles he’s not used for years.”
But he admitted the bionic implant raised eyebrows, saying: “We get some strange looks when we say we’ve got to go and ‘charge’ Robbie.”
Since being “switched on” after his operation, the P2 pupil at St Marie’s Primary in Kirkcaldy is now able to walk on his own around the house and play with his sister Chloe, four, and brother Rhys, 15.
Dougie said: “He is joining in with his brother and sister when they are playing, whereas before he used to watch them.”

No more blind mice? Prosthetic device sends images directly to brain - and could help humans

Blind mice could be a thing of the past thanks to a new prosthetic device that’s been tested on the animals.
A Weill Medical College of Cornell University team has developed a device that takes information from the outside world and decodes it into a pattern that the brain can ‘read’ as an image.
What’s more, they are hoping that it could be used to help blind humans in less than a decade.

Eye eye: Researchers developed a device that helped to restore the vision of mice

Neuroscientist Sheila Nirenberg, the lead researcher, explained at a TEDMED seminar in San Diego recently that the key was converting the data into patterns of electrical activity for the brain to process.
She said: ‘I study how the brain uses patterns of electrical activity to see, to hear, to reach for an object.
I’ve been starting to use what we’ve learned about these patterns of electricity to develop prosthetic devices.’
She explained that if a person has a retinal disease, there’s very little that can be done for them, with drug treatments only effective on a small number of sufferers.
There are prosthetic devices, but they only allow patients to see simple images, mainly just outlines.
Professor Nirenberg describes her device as something ‘that could make a difference’.
She told the audience that the retina contains circuits that process images, but that these circuits can die from disease.
The device she’s pioneered ‘mimics the action of the front end circuitry of the retina’, enabling images to be fired to the brain once more.
So far it’s only been tested on mice, but when asked if it could be adapted for humans in 10 years, she replied: ‘I’m hoping less.’

Early Relationships and Brain Development

The research and knowledge about how early relationships shape brain development has been exploding in recent years. Three new studies caught my attention. The more we know about this area, the more we recognize how important it is to support parents and young children in the early years when the brain is most rapidly developing and so most "plastic," or able to change.

The first study, using neuroimaging techniques, showed that children exposed to severe maternal depression since birth had larger amygdalas at age 10. Much research has shown that postpartum depression can have long term impact on child development. In addition we know that the amygdala plays a critical role in emotional regulation. Trauma researcher Bessel van der Kolk has referred to it as "the smoke alarm of the brain." It makes sense that when mothers, because of their own emotional distress, are not able to be attuned with their babies as the would wish, the centers of the baby's brain responsible for emotional regulation may not develop as well. So the amygdala is, in a sense, unchecked.

The take home message is not that mothers should feel guilty if they are depressed, but that they should get help. I have written in a previous post about the dearth of services for women with PPD and new initiatives to address this problem. I have added my efforts to the cause by starting the Early Childhood Social Emotional Health Program at Newton Wellesley Hospital where mothers struggling with a range of perinatal emotional complications can be seen with their baby.

The second study, is also about the amygdala: Amygdalar Activation and Connectivity in Adolescents With Attention-Deficit/Hyperactivity Disorder. Also using neuroimaging, these researchers showed that the amygdala was overactive in a group of teenagers with the diagnosis of ADHD. I have written previously about ADHD as a problem of regulation of emotion, attention and behavior. The authors of the study link this finding to the difficulties with emotional reactivity seen in teenagers with ADHD. If we combine these findings with the previous study, it seems that treating mother-baby pairs in the setting of postpartum depression might in fact prevent ADHD! Such a study, known as an intervention study, is yet to be done, but certainly it seems to make sense to place our efforts in that direction.

The last study comes out of the Minnesota Longitudinal Study of Risk and Adaptation, which has followed a group of children from birth into adulthood. They showed a link between secure early attachment relationships and satisfying romantic relationships in young adults. The results were affected by quality of social skills in preschool and having a best friend in adolescence. The authors conclude that early relationships are very important, but other relationships along the way to adulthood can influence the effects.

While this study is not about neuroimaging, if we think about how being in a successful romantic relationship as an adult requires a good degree of emotional regulation, we can make a connection. Secure early attachment relationships are characterized by attunement between mother and infant. When something is amiss, as in the case of postpartum depression, these relationships may develop a quality of insecurity. This may show itself in the brain as an overactive amygdala, perhaps with relative underdevelopment of the centers of the brain responsible for regulating the amygdala. These studies together offer insight into how brain development may affect later adult relationships.

These studies span the developmental spectrum, from childhood to adolesence and on to adulthood. With such far reaching implications, it certainly makes sense to put our efforts into helping these young brains to grow in a healthy way from the start.

'Baby brain' syndrome IS real... and it makes you a better mother

• Pregnant women DO suffer short-term memory loss, new research claims...
• ... but that's so your brain can focus on the needs of your baby

Truth in the rumour? New research claims that pregnant women do forget, but it's because the brain is focusing on more important needs

Pregnant women have long complained that their condition makes them forgetful.
Now a researcher has claimed there may be scientific truth in this ‘baby brain’ syndrome – and that there is a very good reason why expectant mothers develop short-term memory loss.
The suggestion is that women’s brains change during pregnancy so that they will be better able to concentrate on their newborn’s needs after the birth, with the result that they become less focused on other things, such as where the car keys might be.
Laura Glynn, a psychologist at Chapman University, California, claims that these changes may be brought about by massive fluctuations in women’s hormones as well as tiny movements by the foetus.
Dr Glynn has carried out extensive research on already published studies that look at how women’s brains and emotions change during pregnancy.
She said that there ‘may be some cost’ of these changes – such as absent-mindedness – ‘but the benefit is a more sensitive,  effective mother’.
Dr Glynn also says that just the slightest movement of the foetus in the womb can affect a woman’s brain and make her become more sensitive.
She claims that even though the woman may not be aware of these movements they will raise her  heart rate.
‘Pregnancy is a critical period for central nervous system development in mothers,  yet we know virtually nothing about it,’  said Dr Glynn, whose research is published in the journal Current Directions In Psychological Science. 

Exciting: The latest findings suggest even the slightest movement by the foetus can change a woman's brain as can its cells when they pass into her bloodstream

   
She also says that cells from the foetus will pass into the mother’s bloodstream which will also affect the way her brain works.
‘It’s exciting to think about whether those cells are attracted to certain regions in the brain,’ she added.
There has been considerable debate in recent years among academics as to whether ‘baby brain’ really exists.
Last year, Australian scientists who had studied  1,200 women claimed there was no evidence to suggest that they had become any  more forgetful.
The researchers made women sit memory tests before, during and after pregnancy  and found there was very little difference in the scores.
In fact the study claimed that women ‘tricked themselves’ into thinking they were becoming more absent-minded simply because they had been told this was a likely symptom of pregnancy.
But Dr Glynn insists that we do not know enough about what really happens because there has so far there has been very little research into what occurs to women’s brains during pregnancy.

Size of Brain Regions Tied to Early Alzheimer’s

Size may matter in predicting the chance for Alzheimer’s disease as new research suggests an association between the size of various brain regions and the risk for very early Alzheimer’s disease.
The study suggests people with smaller regions of the brain’s cortex may be at risk.
Researchers have published their findings in the online issue of Neurology, the medical journal of the American Academy of Neurology.
“The ability to identify people who are not showing memory problems and other symptoms but may be at a higher risk for cognitive decline is a very important step toward developing new ways for doctors to detect Alzheimer’s disease,” said Susan Resnick, Ph.D.
For the study, researchers used brain scans to measure the thickness of regions of the brain’s cortex in 159 people free of dementia with an average age of 76.
The brain regions were chosen based on prior studies showing that they shrink in patients with Alzheimer’s dementia.
Of the 159 people, 19 were classified as at high risk for having early Alzheimer’s disease due to smaller size of particular regions known to be vulnerable to Alzheimer’s in the brain’s cortex, 116 were classified as average risk and 24 as low risk.
Investigators tested subjects at the beginning of the study and over the next three years. Researchers administered tests that measured memory, problem solving and ability to plan and pay attention.
The study found that 21 percent of those at high risk experienced cognitive decline during three years of follow-up after the MRI scan, compared to seven percent of those at average risk and none of those at low risk.
“Further research is needed on how using MRI scans to measure the size of different brain regions in combination with other tests may help identify people at the greatest risk of developing early Alzheimer’s as early as possible,” said study author Bradford Dickerson, MD.
Researchers also discovered that 60 percent of the group considered most at risk for early Alzheimer’s disease had abnormal levels of proteins associated with the disease in cerebrospinal fluid — which is another marker for the disease — compared to 36 percent of those at average risk and 19 percent of those at low risk.