The King Provides Clues to Human Emotion

Last year, while waiting to catch a plane from Washington DC to San Antonio TX, I was joined by a young gentleman, around 24 or 25 years of age and his super-glamorous mom. Initially I was somewhat surprised that they had chosen to sit right next to me, given that the departure area was otherwise empty.

Within seconds he had struck up a conversation, within minutes I was practically his new BFF and before the flight was called he was holding my hand, whispering in my ear and grinning like a teenager.

Before you start thinking “wedding bells” or “cougar time”, what I learned from his mom, was that he had Williams syndrome. What I learned later, after googling the condition, was that people with Williams syndrome have an unusually gregarious personality. They view everyone as their friend, and it’s not unusual for them to rush up to total strangers and strike up conversations as though they are old acquaintances.

Those with the disorder look at the world through a unique lens. Despite their desire to befriend people they have high levels of generalized anxiety poor social judgment, disturbed peer relationships and altered responses to fearful and happy faces.  Their average IQ is 60, they experience severe spatial-visual problems, and suffer from cardiovascular and other health issues. They also have an affinity for music.

This week, I learned that the latter trait is helping scientists shed light on the mystery of emotion and human interaction. Social and emotional responses are so fundamental to human behavior that they are often taken for granted. However, the genetic and neurobiological bases of social behavior are largely unknown, as are the mechanisms for disruptions in social behavior and emotional regulation that appear throughout the lifespan as features of mental illnesses.

In a study led by Julie R. Korenberg, Ph.D., M.D. one of the world’s leading experts in genetics, brain, and behavior of Williams syndrome, people with and without Williams syndrome listened to music while researchers  gauged emotional response by measuring the release of oxytocin and arginine vasopressin – two hormones associated with emotion.

The study, published in PLoS One, signals a paradigm shift both for understanding human emotional and behavioral systems and expediting the treatments of illnesses such as Williams syndrome, post-traumatic stress disorder, anxiety, and possibly even autism.

The study is also the first to reveal new genes that control emotional responses and to show that arginine vasopressin is involved in the response to music.

The trial involved  21 participants – 13 with Williams syndrome and a control group of 8 without the disorder. Before the music was played, participants’ blood was drawn to determine a baseline level for oxytocin. Those with Williams syndrome had three times as much of the hormone as those without the syndrome.

Blood also was drawn at regular intervals while the music played and was analyzed afterward to check for real-time changes.

While other studies have examined how oxytocin affects emotion when artificially introduced into people through nasal sprays, this is the one of the first significant studies to measure naturally occurring changes in oxytocin levels in rapid, real-time as people undergo an emotional response.

Researchers asked the first participant to listen to the 1950’s Elvis Presley classic, “Love Me Tender.” The woman showed no outward response to the song. So, to elicit a greater response from the remaining study participants, the researchers invited them to bring along their favorite music.  Many of them chose heavy metal, but again, there was little outward response to the music.

However, when the blood samples were analyzed, they showed that oxytocin levels, and to a lesser degree arginine vasopressin (AVP), had not only increased but begun to bounce among the William syndrome group. In contrast, both oxytocin and AVP levels remained largely unchanged as those without Williams syndrome listened to music.

Interestingly, the oxytocin level in the woman who’d listened to “Love Me Tender” skyrocketed compared to the levels of participants who listened to different music.

Korenberg believes the blood analyses strongly indicate that oxytocin and AVP are not regulated correctly in people with Williams syndrome, and that the behavioral characteristics unique to people with the condition are related to this problem.

To ensure accuracy of results, study participants were also asked to place their hands in 60° Fahrenheit water to test for negative stress. The same results were produced as when they listened to music. Those with Williams syndrome experienced an increase in oxytocin and AVP, while those without the syndrome did not.

In addition, study participants took three standard social behavior tests that evaluated willingness to approach and speak to strangers, emotional states, and various areas of adaptive and problem behavior. Those test results suggest that increased levels of oxytocin are linked to both increased desire to seek social interaction and decreased ability to process social cues.

The association between abnormal levels of oxytocin and AVP and altered social behaviors found in people with Williams Syndrome points to surprising, entirely unsuspected deleted genes involved in regulation of these hormones and human sociability,” Korenberg said. “It also suggests that the simple characterization of oxytocin as ‘the love hormone’ may be an overreach. The data paint a far more complicated picture.”

However, the results of the study offer great hope. By regulating levels of oxytocin and vasopressin it should be possible to relieve suffering and improve the lives of those with Williams syndrome.

In the meantime, this study certainly brings new meaning to the phrase “mood music.”

Of Mice and Men…and Mental Health

One in five Americans suffers a major depressive episode in their lifetime. Twenty-eight per cent will develop an anxiety disorder, such as post-traumatic stress, phobias, obsessions, or compulsions. Another 15% will fall prey to alcoholism or drug addiction. If you gather 100 people from any square mile on earth, odds are that one will have autism or schizophrenia.

Just about everything we know about drug treatments for psychiatric disorders we learned from mice.  Just how the mouse became our avatar is part tradition and part biological accident. In the past, rats were traditionally used to test experimental drugs. Rats are small enough to be affordable but big enough to make their brains easy to dissect. And they are smarter than mice. You can swiftly teach a rat to solve a maze, for instance, and then test whether your new drug has a side effect of making rats forgetful.

However, rats missed the knockout revolution of the late 1980s. Knockout technology allows researchers to silence, or knock out, individual genes.

With mice, researchers can insert altered DNA in a mouse stem cell, insert the cell in a newly fertilized egg, and insert the egg in a surrogate mother. That egg might develop as a normal mouse or a knockout. The offspring born with knocked-out genes are mated for a few generations to create a pure strain. Once the geneticists perfected these procedures, mice almost instantly assumed the lead role in modeling human mental malfunctions.

These days, you won’t find more mentally ill mice per square mile anywhere than in Bar Harbor, Maine. Mice with anxiety, depression, autism, learning disabilities, anorexia or schizophrenia – they all congregate here. Name an affliction of the human mind, and you can probably find its avatar on this sprucy, secluded island built for America’s richest and most powerful families — including the Rockefellers, the Fords, the Vanderbilts, the Carnegies, the Astors and the Morgans.

The imbalanced mice are kept under the strictest security, in locked wards at the Jackson Laboratory, a nonprofit biomedical facility internationally renowned for its specially bred deranged rodents.

There are no visiting hours, because strangers fluster the mice and might carry in contagious diseases. The animals are attended only by highly qualified caregivers.

But, accurately reproducing a human mental illness in the tiny brain of a mouse is still hugely challenging. The basic structure of a mouse brain is mostly analogous to a human brain.  They have a hippocampus, we have a hippocampus; they have a prefrontal cortex, we have a prefrontal cortex, albeit one that is much larger. We even share about 99% of their genes. But no one would mistake you for a mouse. The mouse is a nocturnal animal with poor eyesight, adapted to fear predators that strike from above. Mice are fundamentally alarmed by light, open spaces, and sudden movements. It is no surprise then, that they manifest depression and anxiety differently than humans do, if they manifest such ailments at all.

You cannot mimic an entire human psyche in a mouse or a rat,” says 
Jacqueline Crawley, a behavioral neuroscientist at the National Institutes of Health (NIH) “Mice aren’t a one-to-one correspondence to humans. But they are better than zero.”

Disorders like depression and schizophrenia are each linked to hundreds of genes. No one gene is likely to make much difference. But genes are only one part of the story. Other clues to human mental health can be found in the neural circuits of mouse brains. By tracing the wiring that connects one brain region to the next, researchers hope to develop more precisely targeted medications.

Many vintage psychiatric drugs, such as Valium, Ritalin, and antipsychotics, were stumbled upon rather than tailor-made to solve a problem. As a result, they are too broad.  They affect more than one type of receptor, on more than one kind of nerve cell, in more than one part of the brain. Many patients decide the cure is not worth the many side effects.

Mice may be the best models we have of psychiatric disorders, but best does not mean great, or even decent. Gerald Dawson, founder and chief scientific officer of P1Vital, a pharmaceutical consulting firm in the United Kingdom, had his heart broken by the mouse mismatch. In the late 1990s, Dawson set out to eliminate the drowsiness from anxiety drugs.The class of drugs he wanted 
to modify, benzodiazepines such as Valium, Xanax, Ativan, and Klonopin, target the GABAa system.

As with most neurotransmitters, the GABAa system is so evolutionarily ancient that it has diversified to serve many purposes. Hence, the brain has six different GABAa receptor types, presumably to perform six different jobs. Dawson had a suspicion that the sleepiness side effect originated from just one of those six receptors. If he could determine which one, corporate chemists could design a molecule that would avoid activating it. He began to make mice.

One by one, he manipulated the receptor genes, breeding a new line of mice each time. With each new strain, he would administer a tiny dose of Valium. If the animals grew drowsy, he knew he had not yet knocked out the right receptor. Knocking out receptor 1 made little difference. Receptor 3 proved too hard to knock out. Receptor 5 seemed to account for the amnesia that people (and mice) experience when they take anxiety drugs. Targeting receptor 2, Dawson identified a chemical that reduced a mouse’s startle response—a measure of anxiety—without impairing its ability to balance. Success!

Or, so he thought. “When these compounds went into humans, they turned out to be just as sedating as the original drugs.”

Dawson blames the mice. “There’s not enough predictability in animal research.”

But, for all Dawson’s frustration with mice, the rodents did yield a couple of interesting drug leads.

That receptor 5 implicated in the amnesia side effect?  An experimental chemical that blocked its action created temporary geniuses: Mice on it were whizzes in the Morris water maze. A drug company is testing the compound to treat people with Down syndrome. And in the process of trying to eliminate drowsiness, Dawson and his team homed in on one of the chemical switches that cause mammals to go to sleep. Ambien locks onto that switch associated with receptor 1.

So, despite the problems, mice remain the undisputed top animal for research on mental health therapies.

Which just goes to show that mice, like us, have minds of their own.

Finding the Perfect Genes?

Despite a plethora of the “Men Are From Mars…” type of self-help books, many people still think that the differences between men and women are unfathomable. Others think of the differences in terms of broad stereotypes, i.e. women are more nurturing and men are more aggressive.

So it was with great interest that we read some new research that could drastically alter the way we think about what drives us to be who we are.  It turns out that male or female behaviors are regulated by very specific genes that can be turned on and off at will.

The research, which was conducted by scientists at the University of California, San Francisco, aimed to locate those genes that are influenced by the sex hormones- testosterone and estrogen– and that dictate male and female behaviors.

The research team, led by Dr. Nirao Shah, managed to locate 16 genes that were expressed differently in male and female mice and showed that the different expressions were regulated by the sex hormones. They found that they could isolate parts of classic male and female behaviors and pinpoint them as being governed by their own particular genes. They also noticed that each gene regulates a few components of a behavior without affecting other aspects of male and female behavior.

In other words, by flipping the switch, they could turn off a mouse’s sex drive, willingness to spend time with their young, and even their desire to pick fights while leaving every other behavioral element unaffected.

Imagine how crazy it would be if we could do that in humans.

Don’t like that your boyfriend gets into fights or that your girlfriend has “yet another headache?”  Simple…just flip the switch!

Fortunately, there are more serious applications of this research. Understanding the genes that drive male and female behavior could, for example, guide researchers to locate which genes are involved in diseases such as autism, which affects four times as many males as it does females.

As good as all that sounds, there is something a bit unnerving about contemplating your genes as a collection of switches that govern your behaviors. On some level it would be a dream to be able to turn behaviors off and on at will. While it would revolutionize the way we interact, it could also change our conception of what makes us who we are. Fortunately, manipulating them is a complicated process. So it looks like we’ll have to wait a while before we start popping pills to fine tune ourselves.

That’s a relief, because for most of us, managing the hormones we already have is a big enough job!

Daily Asthma Treatment No Different from Intermittent Treatment in Toddlers

As most parents of toddlers with asthma know, a daily dose of an inhaled steroid is usually prescribed to keep the frequent bouts of wheezing at bay. But, the results of a recent study published in The New England Journal of Medicine could likely change all that.

A group of pediatric asthma researchers nationwide, found that daily inhaled steroid treatment was no better at preventing wheezing episodes than treating the child with higher doses of the drug at the first signs of a respiratory tract infection.

They also found that daily treatment was comparable to use of the inhaled steroid intermittently at decreasing the severity of respiratory-tract illnesses, reducing the number of episode-free days or school absences, lowering the need for a “rescue” inhaler for acute asthma symptoms, improving quality of life or reducing visits to urgent care or the emergency room.

The researchers, from the National Institutes of Health (NIH)-funded Childhood Asthma Research and Education (CARE) Network, studied nearly 300 preschool-age children with frequent wheezing in a trial called MIST (Maintenance and Intermittent Inhaled Corticosteroids in Wheezing Toddlers).

We wanted to understand how to best treat young children who have repeated episodes of wheezing, most of whom appear symptomatic just when they have colds,” says Leonard B. Bacharier, MD, a Washington University pediatric asthma and allergy specialist at St. Louis Children’s Hospital. “Our goal was to start therapy at the first signs of a viral respiratory tract infection or cold to interrupt or slow the progression of symptoms. This trial was aimed to try to prevent wheezing severe enough that requires oral steroids and really gets in the way of children’s lives.”

Children in the yearlong MIST trial were between 12 and 53 months old, had recurrent wheezing and were at high risk for a worsening of asthma-like symptoms that could require treatment with oral steroids and/or a visit to urgent care or emergency room. During the trial, the children received either a dose of budesonide once a day through a nebulizer or a placebo.

At the first signs of a respiratory tract illness, those children who received the inactive placebo received a higher dose of budesonide twice a day, while those who received daily budesonide received a placebo twice daily and kept taking their regular budesonide. Neither the patients nor the physicians knew who received the active drug until the trial was over.

During the study, parents were asked to keep a daily diary of symptoms, such as coughing, wheezing, difficulty breathing or other symptoms that interfered with normal activities, as well as a list of medications, visits to a health-care provider or absences from daycare or school.

Because previous studies had shown that daily inhaled corticosteroid therapy was more effective than placebo, the researchers expected to see the same in the MIST trial. But that’s not what they found.

The two groups were comparable in terms of episodes requiring oral steroids, symptom days, albuterol use and the time before oral steroids were needed,” Bacharier says. “All of the relevant indicators of disease activity were comparable.”

These results indicate that there are a variety of treatments physicians can consider for children with frequent wheezing, who are not compliant with daily therapy.

Clinical Research under scrutiny?

If you watched the news at all over the past week you probably saw CNN‘s Sanjay Gupta‘s confrontation with disgraced doctor Andrew Wakefield.  He, as you may recall was the author of the 1998 study that linked autism to some childhood vaccines and set off a worldwide scare for parents.

In the intervening years there have been countless lawsuits against vaccine manufacturers and millions of children who, perhaps needlessly, have gone unvaccinated.  Recently,  an investigative report published in the British Medical Journal called the original study an elaborate fraud.

So, is Dr Wakefield alone in manipulating clinical trial data?  Can we rely on other clinical studies to provide us with the truth?

No, not according to researchers at Johns Hopkins.  In a report published January 4th in the Annals of Internal Medicine the authors concluded that the vast majority of published clinical trials of a given drug, device or procedure are routinely ignored by scientists conducting new research on the same topic.

Trials being done may not be justified, because researchers are not looking at or at least not reporting what is already known.  In some cases, patients who volunteer for clinical trials may be getting a placebo for a medication that a previous researcher has already determined works or may be getting a treatment that another researcher has shown is of no value. In rare instances, patients have suffered severe side effects and even died in studies because researchers were not aware of previous studies documenting a treatment’s dangers.

Not surprising then that they go on to say, “the failure to consider existing evidence is both unscientific and unethical.”

The report argues that these omissions potentially skew scientific results, waste taxpayer money on redundant studies and involve patients in unnecessary research.

Conducting an analysis of published studies, the Johns Hopkins team concludes that researchers, on average, cited less than 21% of previously published, relevant studies in their papers. For papers with at least five prior publications available for citation, one-quarter cited only one previous trial, while another quarter cited no other previous trials on the topic. Those statistics stayed roughly the same even as the number of papers available for citation increased. Larger studies were no more likely to be cited than smaller ones.

The extent of the discrepancy between the existing evidence and what was cited is pretty large and pretty striking,” said Karen Robinson, Ph.D., co-director of the Evidence Based Practice Center (EPIC) at the Johns Hopkins University School of Medicine and co-author of the research.  “It’s like listening to one witness as opposed to the other 12 witnesses in a criminal trial and making a decision without all the evidence. Clinical trials should not be started — and cannot be interpreted — without a full accounting of the existing evidence.”

The Hopkins researchers could not say why prior trials failed to be cited, but Robinson says one reason for the omissions could be the self-interest of researchers trying to get ahead.

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