Posts tagged neuroscience

Researchers at the Stanford University School of Medicine have identified mutations in several new genes that might be associated with the development of spontaneously occurring cases of the neurodegenerative disease known as amyotrophic lateral sclerosis, or ALS. Also known as Lou Gehrig’s disease, the progressive, fatal condition, in which the motor neurons that control movement and breathing gradually cease to function, has no cure.

Although researchers know of some mutations associated with inherited forms of ALS, the majority of patients have no family history of the disease, and there are few clues as to its cause. The Stanford researchers compared the DNA sequences of 47 patients who have the spontaneous form of the disease, known as sporadic ALS, with those of their unaffected parents. The goal was to identify new mutations that were present in the patient but not in either parent that may have contributed to disease development.

Several suspects are mutations in genes that encode chromatin regulators — cellular proteins that govern how DNA is packed into the nucleus of a cell and how it is accessed when genes are expressed. Protein members of one these chromatin-regulatory complexes have recently been shown to play roles in normal development and some forms of cancer.

"The more we know about the genetic causes of the disorder, the greater insight we will have as to possible therapeutic targets," said Aaron Gitler, PhD, associate professor of genetics. "Until now, researchers have primarily relied upon large families with many cases of inherited ALS and attempted to pinpoint genetic regions that seem to occur only in patients. But more than 90 percent of ALS cases are sporadic, and many of the genes involved in these cases are unknown."

Gitler is the senior author of the study, published online May 26 in Nature Neuroscience. Postdoctoral scholar Alessandra Chesi, PhD, is the lead author. Gitler and Chesi collaborated with members of the laboratory of Gerald Crabtree, MD, professor of developmental biology and of pathology. Crabtree, a Howard Hughes Medical Institute investigator, is also a co-author of the study.

Chesi and Gitler combined deductive reasoning with recent advances in sequencing technology to conduct the work, which relied on the availability of genetic samples from not only ALS patients, but also the patients’ unaffected parents. Such trios can be difficult to obtain for diseases like sporadic ALS that strike well into adulthood when a patient’s parents may no longer be alive. Gitler and Chesi collaborated with researchers from Emory University and Johns Hopkins University to collect these samples.

The researchers compared the sequences of a portion of the genome called the exome, which directly contributes to the amino acid sequences of all the proteins in a cell. (Many genes contain intervening, non-protein-coding regions of DNA called introns that are removed prior to protein production.) Mutations found only in the patient’s exome, but not in that of his or her parents’, were viewed as potential disease-associated candidates - particularly if they affected the composition or structure of the resulting protein made from that gene.

Focusing on just the exome, which is about 1 percent of the total amount of DNA in each human cell, vastly reduced the total amount of DNA that needed to be sequenced and allowed the researchers to achieve relatively high coverage (or repeated sequencing to ensure accuracy) of each sample.

"We wanted to find novel changes in the patients," Chesi said. "These represent a class of mutations called de novo mutations that likely occurred during the production of the parents’ reproductive cells." As a result, these mutations would be carried in all the cells of patients, but not in their parents or siblings.

Using the exome sequencing technique, the researchers identified 25 de novo mutations in the ALS patients. Of these, five are known to be in genes involved in the regulation of the tightly packed form of DNA called chromatin — a proportion that is much higher than would have been expected by chance, according to Chesi.

Furthermore, one of the five chromatin regulatory proteins, SS18L1, is a member of a neuron-specific complex called nBAF, which has long been studied in Crabtree’s laboratory. This complex is strongly expressed in the brain and spinal cord, and affects the ability of the neurons to form branching structures called dendrites that are essential to nerve signaling.

"We found that, in one sporadic ALS case, the last nine amino acids of this protein are missing," Gitler said. "I knew that Gerald Crabtree’s lab had been investigating SS18L1, so I asked him about it. In fact, they had already identified these amino acids as being very important to the function of the protein."

When the researchers expressed the mutant SS18L1 in motor neurons isolated from mouse embryos, they found the neurons were unable to extend and grow new dendrites as robustly as normal neurons in response to stimuli. They also showed that SS18L1 appears to physically interact with another protein known to be involved in cases of familial, or inherited, ALS.

Although the results are intriguing, the researchers caution that more work is necessary to conclusively prove whether and how mutations in SS18L1 contribute to sporadic cases of ALS. But now they have an idea of where to look in other patients, without requiring the existence of patient and parent trios. They are planning to sequence SS18L1 and other candidates in an additional few thousand sporadic ALS cases.

"This is the first systematic analysis of ALS triads for the presence of de novo mutations," Chesi said. "Now we have a list of candidate genes we can pursue. We haven’t proven that these mutations cause ALS, but we’ve shown, at least in the context of SS18L1, that the mutation carried by some patients is damaging to the protein and affects the ability of mouse motor neurons to form dendrites."

(Source: med.stanford.edu)

The adult brain is far more malleable that we thought, and so learning can be child’s play if you know how.

Some 36-year-olds choose to collect vintage wine, vinyl records or sports memorabilia. For Richard Simcott, it is languages. His itch to learn has led him to study more than 30 foreign tongues – and he’s not ready to give up.

During our conversation in a London restaurant, he reels off sentences in Spanish, Turkish and Icelandic as easily as I can name the pizza and pasta on our menu. He has learned Dutch on the streets of Rotterdam, Czech in Prague and Polish during a house share with some architects. At home, he talks to his wife in fluent Macedonian.

What’s remarkable about Simcott isn’t just the number and diversity of languages he has mastered. It’s his age. Long before grey hairs appear and waistlines expand, the mind’s cogs are meant to seize up, making it difficult to pick up any new skill, be it a language, the flute, or archery. Even if Simcott had primed his mind for new languages while at school, he should have faced a steep decline in his abilities as the years went by – yet he still devours unfamiliar grammars and strange vocabularies to a high level. “My linguistic landscape is always changing,” he says. “If you’re school-aged, or middle-aged – I don’t think there’s a big difference.”

A decade ago, few neuroscientists would have agreed that adults can rival the learning talents of children. But we needn’t be so defeatist. The mature brain, it turns out, is more supple than anyone thought. “The idea that there’s a critical period for learning in childhood is overrated,” says Gary Marcus, a psychologist at New York University. What’s more, we now understand the best techniques to accelerate knowledge and skill acquisition in adults, so can perhaps unveil a few tricks of the trade of super-learners like Simcott. Whatever you want to learn, it’s never too late to charge those grey cells.

The idea that the mind fossilises as it ages is culturally entrenched. The phrase “an old dog will learn no tricks" is recorded in an 18th century book of proverbs and is probably hundreds of years older.

When researchers finally began to investigate the adult brain’s malleability in the 1960s, their results appeared to agree with the saying. Most insights came indirectly from studies of perception, which suggested that an individual’s visual abilities were capped at a young age. For example, restricting young animals’ vision for a few weeks after birth means they will never manage to see normally. The same is true for people born with cataracts or a lazy eye – repair too late, and the brain fails to use the eye properly for life. “For a very long time, it seemed that those constraints were set in stone after that critical period,” says Daphne Bavelier at the University of Rochester, New York.

These are extreme circumstances, of course, but the evidence suggested that the same neural fossilisation would stifle other kinds of learning. Many of the studies looked at language development – particularly in families of immigrants. While the children picked up new tongues with ease, their parents were still stuttering broken sentences. But if there is a critical period for foreign language learning, everyone should be affected equally; Simcott’s ability to master a host of languages should be as impossible as a dog playing the piano.

Bearing this in mind, Ellen Bialystok at York University in Toronto, Canada, recently turned to the US census records, which detailed the linguistic skills of more than 2 million Hispanic and Chinese immigrants. A “critical period” for learning a second language in infancy should have created a sharp difference between those who had moved country in early childhood and those who were uprooted in adolescence. In reality? “There was absolutely no discontinuity,” Bialystok says. Instead, she saw a very gradual decline with age among immigrants – which could reflect differences in environment as much as the adults’ rusty brain circuits. “People talk more slowly and clearly to children in short, simple sentences,” she says. “And the child’s entire social and educational network is organised around that language.”

Yet while Bialystok’s study suggested that adult brains are more pliable than had once been imagined, there was still the suspicion that children might have the edge in certain skills. Adult learners sometimes find it harder to learn to sing in tune, hit a home run or mimic an accent convincingly. At first glance, the problem might seem to lie in adults’ perception and motor skills. Learning involving these abilities differs from the acquisition of factual knowledge, because it needs us to rewire the eyes, ears and muscles.

It’s something that Marcus can identify with. At the age of 38, he devoted himself to learning the guitar, an experience he detailed in his book Guitar Zero. “My family’s initial response was laughter – but they soon saw I was making progress,” he says. Still, during his research, he attended a musical summer camp for 8 to 15-year-olds. He says he was quicker to catch on to the structure of songs, but his younger bandmates had better coordination and sense of pitch.

Yet the available evidence hints that children may not always be inherently better at such tasks. One study by Yang Zhang at the University of Minnesota in Minneapolis that focused on the acquisition of foreign accents in adults suggests we may simply be suffering from poor tuition. When the researchers gave them recordings that mimicked the exaggerated baby talk of cooing mothers, the adult learners progressed rapidly.

Nor do adults necessarily fumble over the intricate movements that are crucial for music or sport. When volunteers visiting Virginia Penhune's lab at Concordia University in Montreal, Canada, learned to press keys in a certain sequence, at certain times – essentially a boiled-down version of keyboard practice – the adults tended to outshine the younger volunteers.

During a more challenging test of hand-eye coordination, nearly 1000 volunteers of all age groups learned to juggle over a series of six training sessions. As you might expect, the senior citizens aged 60 to 80 began with some hesitation, but they soon caught up with the 30-year-olds and by the end of the trials all the adults were juggling more confidently than the 5 to 10-year-olds.

Old dogs, then, are much more adaptable than folklore would have it – and if we do have deficits, they aren’t insurmountable. The reason that children appear to be better learners may have more to do with their environment, and factors such as physical fitness (see “Faster body, faster mind”).

Indeed, many researchers believe that an adult’s lifestyle may be the biggest obstacle. “A child’s sole occupation is learning to speak and move around,” says Ed Cooke, a cognitive scientist who has won many memory contests. “If an adult had that kind of time to spend on attentive learning, I’d be very disappointed if they didn’t do a good job.”

A glut of free time and a carefree existence are out of reach for most of us, but there are other behaviours that boost children’s learning, and these habits can be easily integrated into even an adult’s schedule. For example, children are continually quizzed on what they know – and for good reason: countless studies have shown that testing doubles long-term recall, outperforming all other memory tactics. Yet most adults attempting to learn new skills will rely more on self-testing which, let’s be honest, happens less often.

That’s why Cooke developed a website, called Memrise, which helps take some of the pain out of testing and, crucially, can integrate learning into the adult day. It is designed to track your learning curve with cunningly timed tests that force you to retrieve the information just as you are about to forget it.

"Memrise engages your brain to the greatest possible extent," says Cooke, who has himself used the site to learn thousands of words of foreign vocabulary. Users can create their own courses – the topics range from art to zoology – and importantly, it is easy to load the site in the few spare minutes of your lunch break or while you are waiting for a train. Cooke also plans to launch a smartphone app.

What about tasks that involve perceptual learning or motor skills – like battling against a lifetime of tone deafness, or perfecting that golf swing? Here too, there are guiding principles that can help you rediscover the seemingly effortless learning of youth.

Adults can hamper progress with their own perfectionism: whereas children throw themselves into tasks, adults often agonise over the mechanics of the movements, trying to conceptualise exactly what is required. This could be one of our biggest downfalls. “Adults think so much more about what they are doing,” says Gabriele Wulf at the University of Nevada, Las Vegas. “Children just copy what they see.”

Wulf’s work over the past decade shows that you should focus on the outcome of your actions rather than the intricacies of the movements. She applies this finding in her own life: as a keen golfer, she has found it is better to think about the swing of the club, for instance, rather than the position of her hands. “I’m always trying to find where best to focus my attention,” she says. Similarly, if you are learning to sing, then you should concentrate on the tone of the voice, rather than on the larynx or the placement of the tongue. Study after study shows that simply shifting your mindset in this way accelerates your learning– perhaps by encouraging the subconscious, automatic movements that mark proficiency.

Misplaced conscientiousness may also lead adults to rely on overly rigid practice regimes that stifle long-term learning. The adult talent for perseverance, it seems, is not always a virtue. Left to their own devices, most people segment their sessions into separate blocks – when learning basketball, for instance, they may work on each shot in turn, perhaps because they feel a desire to master it. The approach may bring rapid improvements at first, but a host of studies have found that the refined technique is soon forgotten.

Instead, you do better to take a carousel approach, quickly rotating through the different skills to be practised without lingering too long on each one. Although the reason is still unclear, it seems that jumping between skills makes your mind work a little harder when applying what you’ve learned, helping you to retain the knowledge in the long term – a finding that has helped people improve in activities ranging from tennis and kayaking to pistol shooting.

Such an approach might not be to everyone’s taste – with intricate skills, it might feel like you are making no progress. But even if you do revert to stints of lengthy practice, you can still reap some of the same benefits by occasionally trying out your skills in an unfamiliar situation. In tennis, you might move to a different part of the court for a couple of serves before returning to the regular position; while playing scales on a musical instrument, you might switch hands temporarily. According to work by Arnaud Boutin at the Leibniz Research Centre for Working Environment and Human Factors in Dortmund, Germany, venturing out of your comfort zone in this way helps to ensure that you improve your overall performance rather than confining your progress to the single task at hand. “Otherwise, the longer you practise, the harder it becomes to transfer the skills that you’ve learned to new situations,” says Boutin.

If none of that helps you learn like a child, simply adopting the arrogance of youth may do no harm. “As we get older, we lose our confidence, and I’m convinced that has a big impact on performance,” says Wulf. To test the assumption, she recently trained a small group of people to pitch a ball. While half were given no encouragement, she offered the others a sham test, rigged to demonstrate that their abilities were above average. They learned to pitch on target with much greater accuracy than those who didn’t get an ego boost.

Whether your itch to learn will ever match Simcott’s appetite for foreign languages is another matter. “What I do – it’s like an extreme sport. There’s no need to learn that many languages,” he says. He has recently turned to Chinese, and has no plans to stop after that. “I’m like a linguistic butterfly. There’s always another, really far away, that suddenly feels appealing.”

Still, embrace the idea that your mind is as capable as Simcott’s, and the lure of extreme learning might take hold of you too.

-by David Robson, New Scientist

Women at a particular stage in their monthly menstrual cycle may be more vulnerable to some of the psychological side-effects associated with stressful experiences, according to a study from UCL.

The results suggest a monthly window of opportunity that could potentially be targeted in efforts to prevent common mental health problems developing in women. The research is the first to show a potential link between psychological vulnerability and the timing of a biological cycle, in this case ovulation.

A common symptom of mood and anxiety problems is the tendency to experience repetitive and unwanted thoughts. These ‘intrusive thoughts’ often occur in the days and weeks after a stressful experience.

In this study, the researchers examined whether the effects of a stressful event are linked to different stages of the menstrual cycle. The participants were 41 women aged between 18 and 35 who had regular menstrual cycles and were not using the pill as a form of contraception. Each woman watched a 14-minute stressful film containing death or injury and provided a saliva sample so that hormone levels could be assessed. They were then asked to record instances of unwanted thoughts about the video over the following days.

“We found that women in the ‘early luteal’ phase, which falls roughly 16 to 20 days after the start of their period, had more than three times as many intrusive thoughts as those who watched the video in other phases of their menstrual cycle,” explains author Dr Sunjeev Kamboj, Lecturer in UCL’s Department of Clinical, Educational and Health Psychology.

“This indicates that there is actually a fairly narrow window within the menstrual cycle when women may be particularly vulnerable to experiencing distressing symptoms after a stressful event.”

The findings could have important implications for mental health problems and their treatment in women who have suffered trauma.

“Asking women who have experienced a traumatic event about the time since their last period might help identify those at greatest risk of developing recurring symptoms similar to those seen in psychological disorders such as depression and post-traumatic stress disorder (PTSD),” said Dr Kamboj.

“This work might have identified a useful line of enquiry for doctors, helping them to identify potentially vulnerable women who could be offered preventative therapies,” continued Dr Kamboj.

“However, this is only a first step. Although we found large effects in healthy women after they experienced a relatively mild stressful event, we now need to see if the same pattern is found in women who have experienced a real traumatic event. We also need further research to investigate how using the contraceptive pill affects this whole process.”

(Source: ucl.ac.uk)