Autism and trauma to the prefrontal ventromedial cortext

Adults with injuries to the ventromedial prefrontal cortex have social cue problems and a utilitarian style of moral decision making.

Dysfunction of the ventromedial prefrontal cortex has also been implicated in some types of autism.

Reversing the cognitive dysfunction of Down's Syndrome

Yesterday I wrote about an experiment that reversed an artificially induced autism-like syndrome in mice and mentioned an old science fiction story - Flowers for Algernon. Today I'm stunned by another, similar, story (emphases mine)

Drug May Counteract Down Syndrome: Scientific American

Researchers may have finally found a drug candidate for reducing the mental retardation caused by Down syndrome, which afflicts more than 350,000 people in the U.S. Researchers gave low doses of a human drug to mice bred to mimic the learning and memory problems in people with Down syndrome. After as little as two weeks, the impaired mice performed as well as normal ones in learning tests, and the improvement lasted for up to two months after treatment ended.

But there is a catch: the drug was taken off the market 25 years ago after being found to cause dangerous seizures in some people. And many compounds that boost learning in mice fail in human trials.

... Researchers tested the drug, pentylenetetrazole (PTZ), as well as two other compounds—picrotoxin and a gingko biloba extract called bilobalide—because they all interfere with tiny ion channels on brain cells (neurons). When activated, the channels, known as GABAA receptors, inhibit the cells, making it harder for them to form new synapses, or connections, with neighboring neurons.

The deficits of Down syndrome may occur because the brain contains too many such inhibitory signals, says Stanford University neurobiologist Craig Garner, whose group performed the experiments. "In order to learn, you have to have a period during which synapses can get stronger or weaker," he says. "This changing is what's not possible when you have too much inhibition."

So Garner, his student Fabian Fernandez, and their colleagues gave their mice either low doses of PTZ mixed with milk, or low-dose injections of picrotoxin or bilobalide, daily for two to four weeks to slightly raise the level of excitation in the brain. Immediately after treatment, the animals' scores on two memory tests—for recognizing objects they had seen before or remembering how they last entered a maze—were on par with normal mice; two months later, they still did much better than they normally would, the researchers report in a paper appearing online February 25 in Nature Neuroscience.

The treatment "is allowing the normal properties of neurons to work," Garner says. "This slowly over time leads to an improved circuit."

Reeves says there may be other ways to treat Down syndrome, but "you can see your way to clinical testing most easily from here," because researchers identified specific chemicals. "It's hugely promising," he says. "Maybe it will have a big effect, but we don't know that." The inhibition model is plausible, but still unproved in people, he notes, and until researchers better understand the mechanisms by which the compounds work, "I'm wary of rushing into the clinic."

Garner says clinical trials of PTZ could begin in the next year or two, and evaluating them might take five to 10 years. He notes that although PTZ is nearly 100 years old and was used to treat psychiatric disorders and later dementia, researchers never concluded it was effective. It also caused seizures (at doses 100-fold higher than those given to the mice), so the FDA revoked its approval in 1982.

In Down syndrome, chromosome 21 is present in three copies instead of two. Similarly, the mice used in the study have a duplicated piece of chromosome 16. As in Down syndrome, these animals have malformed facial bones and problems forming new memories...

This is so stunning we must consider the possibility of fraud, but Nature Neuroscience must have been extra cautious given these results.

I would expect this not to work in humans, or to have very nasty side-effects with longterm use, but the game has most definitely changed.

Are cognitive improvements preceded by behavioral deterioration?

After several weeks of discouraging behavioral deterioration, a child of my acquaintance abruptly demonstrated a new sent of cognitive skills. As of the past few days, he is able to connect "good behavior" with the accelerated return of privileges, to make an internal and prolonged attempt to "behave well", to comprehend the delayed gratification of earning a future allowance [1] incrementally, to grasp the meaning of a "budget" and of "change", and to understand that "change" can be saved for future actions.

This is a staggering amount of new capability that appears to have manifested all at once, though clearly it must have been building for some time. It implies a significant new range of behavioral affordances (levers) that we and he can use.

I find it interesting that these new capabilities were preceded by weeks of discouraging behaviors that felt like a regression. Is this correlation entirely coincidental? In retrospect it seems we've seen this before -- a step forward preceded by a half-step forward.

This suggests a testable hypothesis:

1. Significant cognitive improvements reflect significant changes to the deep structures and networks of the prefrontal cortex.
2. These transformations are akin to redoing the engine and transmission of a running vehicle, or rewiring the circuits of a flying 747, or replacing the software of a running server module by module. In each of these cases we would expect system performance to deteriorate, even to "crash" periodically.
3. We would then expect, in humans, that major changes to critical cortical systems would be associated with substantial behavior and cognitive disruptions.

This could be tested by longitudinal measurement of cognitive performance and behavior in a cohort of children, looking for correlation between behavior disruption and subsequent cognitive improvement.

In the meantime, the hypothesis is useful for getting parents, family and teachers through those nasty and discouraging bad patches. Consider them as "growing pains of the mind".

[1] The current allowance scheme, which has been substantially more successful than expected, works like this:

• allowance is displayed in a visible jar in the kitchen. Any removal of items from the jar causes a reset to the starter level.
  
• 50 cents at the start of a cycle
  
• 5 - 10 cent payments for various positive actions (we don't pay for the absence of negative actions, that has never worked in any form) such as getting dressed on awakening, unloading the dishwasher, feeding the dog, staying in bed until 6:30am, paying a game for 10 minutes with a sibling, etc.
• allowance claimed after 7am Saturday.
• all of the siblings get the same amount of money as the child who earns the allowance.

The last of these is the inspired step -- providing an incentive for sibling collaboration and fostering favor/reward sibling transactions. We may migrate to separate transactions and varying share levels as things evolve.

Reversing a severe brain disorder in adult mice

Mice with an artificially disabled gene (MECP2) developed a severe autism-like disorder. After the mice became adults researchers reactivated the gene. The disorder largely resolved...

Progress Is Reported on a Type of Autism - New York Times

Researchers have found that Rett syndrome, a severe form of autism, may not be so entirely beyond repair as supposed. In mice that carry the same genetic defect as human patients and have similar symptoms, the disease can be substantially reversed, even in adult mice, by correcting the errant gene.

.... Rett syndrome strikes mostly girls, who around the age of 3 start to lose their speech and movement faculties. It is one of the spectrum of autistic disorders, but unlike most of the others it is caused by mutations in a single gene. [jf: in the last few days there's a suggestion that other forms of autism maybe associated with up to 6 single gene defects.]

The gene, known as MECP2, was identified in 1990 by Adrian Bird, a molecular biologist now at Edinburgh University. In 1999, Ruthie Amir and Huda Zoghbi at the Baylor College of Medicine discovered that mutated forms of this gene are the cause of Rett syndrome.

Dr. Bird, as part of his continuing study of what the gene does, engineered a strain of mice whose MECP2 genes had been inactivated with the insertion of an extra block of DNA. When the mice were several weeks old, they started to develop the symptoms of Rett syndrome, including the loss of movement control seen in human patients.

Dr. Bird and his colleague Jacky Guy had engineered a second gene into the mice, one with the ability to snip out the interfering block of DNA in MECP2. The second gene could be activated at will by dosing the mice with the drug tamoxifen. When the stricken mice were fed tamoxifen, even at quite advanced ages, they lost the symptoms of Rett syndrome, Dr. Bird and his colleagues reported last week in the journal Science.

A similar finding was published this month in The Proceedings of the National Academy of Sciences by Dr. Rudolph Jaenisch and colleagues at the Whitehead Institute, though in this study the mice’s recovery was not as complete.

Dr. Bird believes that the mice’s symptoms are reversible because the MECP2 gene is not involved in any of the steps that lead neurons to grow and make the right connections among themselves. The gene comes into play only afterward, in maintaining the genetic decisions the developing neurons have made. Among the most important of these are steps to permanently switch off many genes that the neurons will no longer need. Each of the various symptoms of Rett syndrome presumably arises because a specific gene that should have been shut down is left on, causing havoc.

The MECP2 gene plays a central role in this silencing process. Its job is to recognize chemical tags called methyl groups that get added to DNA at what are called CpG sites, and to recruit proteins that silence or switch off the genes at these regions. “What MECP2 does is to go where the methyl groups tell it to go,” Dr. Bird said. “So when you put it back, normal service is resumed.”

Dr. Bird believes that this is the first time a neurological disease has been corrected by restoring a missing component of cells, and that researchers should now reconsider the view that little can be done to repair the brain after birth. “Our result shows it’s not too late,” he said, “so there’s no excuse for not going hell-for-leather to find some sort of therapy.”

The reconsideration could extend to other neurological diseases in which the neurons appear to be intact. “Given that features of Rett can be reversed in a mouse model,” Dr. Zoghbi said, “one would predict that postnatal disorders like autism and schizophrenia might be reversible.

It's hard not to think of Flowers for Algernon reading this. However, I believe most forms of "schizophrenia" and "autism", both of which are probably collections of nameless diverse disorders do show some structural changes on brain imaging, so it is unlikely they could be fully reversed. We should note that two experiments are described, and in the second the mice did not fully recover. Also mice are far better at healing themselves than humans are. Lastly, and most importantly, this only worked because the gene knockout was designed to be readily reversible. Gene therapy in adult humans has been a miserable failure.

And, of course, the hero of Flowers for Algernon had only a short lived response to treatment.

Even so, it is a stunning result. I imagine that funding agencies and researchers are frantically rewriting grants and guidelines. Now that we know this is conceivable, we will be looking for medications that may alter the expression of defective genes, such as medications used to treat sickle cell anemia.

I suspect any possible therapeutic measures for humans that would do something like this are 20-30 years away. Even so, that is well within the lifespan of today's autistic children.

Neurexin: one of 6 autism genes?

The Autism Genome project has released one gene candidate involved in "autism" on chromosome 2, they suspect they'll find at least five more including one on chromosome 11.

Scientific American: Largest Ever Autism Study Identifies Two Genetic Culprits

The largest genome scan ever conducted to get to the bottom of autism has pinpointed two locations in the human genetic makeup that may trigger the mysterious mental condition. The Autism Genome Project, a collaboration of 120 scientists representing 19 countries and 50 institutions, compared the genomes of 1,168 families with at least two autism sufferers in them to try to track down the regions. The consortium reports its findings in this week's issue of Nature Genetics.

... In the two-fold analysis, the researchers implicated the gene neurexin 1, located on chromosome 2, as well as a swath of sequence on chromosome 11.

Neurexin 1 is part of a three-member family of genes coding for proteins involved in communication between neurons. It is associated with glutamate, the neurotransmitter known to elevate neuronal activity and play a role in early wiring the brain. Glutamate g has been implicated in other syndromes involving mental retardation of which autism is often a symptom, such as Fragile X and tuberous sclerosis. Neurexin 1 is specifically believed to be involved in building glutamate synapses, the links through which glutamate neurons send and receive electrical signals.

... "As for the chromosome 11 location, we think there is another susceptibility gene there and we are actively pursuing it. We are in the neighborhood and have a plan to find it." The section of chromosome 11 identified in the study has been linked to proteins that ferry glutamate across synapses.

... Among the variations found in the Autism Genome Project subjects was the deletion of the neurexin gene. Much of the autism research community believes there may be roughly six major genes involved in autism, and maybe 30 others that may confer some risk. A combination of mutations in any of these genes could contribute to the likelihood of being born with autism.

As we identify the genes we'll be able to divide autism into subtypes based on gene mutations and combinations of mutations and adaptations. That will help with developing prognostic measures and subtype specific medications and interventions. We'll be able to detect at risk persons earlier, and see if there are interventions that will mitigate disability. One day, perhaps, we may even be able to identify medications and therapies that might facilitate healing of the injured brain -- though that is likely at least 10 years away.

I would not be surprised to learn that there are adaptive advantages to some of these mutations in some persons ...

Update 2/20/07: Thinking it over, it's probably worth pointing out that the major implications of identifying these genes will be eugenic. A significant portion of people carrying the autism-associated variants may opt for sperm egg/selection, selective abortion, etc. I wonder if Isaac Newton would have been born under these circumstances ...

Cognition, autism and schizophrenia

More evidence that genes that underlie some cognitive and behavioral disorders may also have adaptive advantages:

Gordon's Notes: More evidence of hacked wetware: the DARPP-32 gene and schizophrenia

...The sooner we understand how buggy all our minds are, the sooner we'll learn wisdom, tolerance, and forgiveness...

There must be people with near perfect minds, but most of us make do with something a few grades below prime. As we come to understand that, we'll become more sympathetic and supportive of those who struggle with profound disabilities.

Autism and the brain: PSTS and the altruism zone

Functional brain imaging continues to deliver some startling claims.

Follow Me Here...: 01/21/2007 - 01/27/2007

… Researchers at Duke University have shown with functional MRI that the degree of activation of the posterior superior temporal sulcus [PSTS], a brain region activated when people observe others' actions but not perform them themselves, correlated with personality ratings of subjects' degree of altruism…

The capacity to have an interior experience upon watching someone else's behavior similar to the experience of performing that behavior yourself may be a basis of the sense of inherent congruence between others' feelings and thoughts and our own, the ability to have a so-called 'theory of mind', which is an important developmental achievement for humans. As suggested in the article, this body of work may help explicate the neural basis for certain conditions, in which I am interested in my work as a clinical psychiatrist, in which the capacity for empathy or mutuality break down, such as antisocial personality disorder or autistic spectrum disorders.

… Two good starting point reviews of the nascent field of social cognitive neuroscience, which is built on these and similar observations and speculations, are these papers by Rebecca Saxe of MIT (Current Opinion in Neurobiology) and the Friths of London (Science). And, while I was browsing related materials, I came upon this paper by Chatterjee (Journal of Medical Ethics), which you might find intriguing if you are interested in this area at all. ...

FMH has some good links to explore. It’s worth remembering that sweeping claims in the neurosciences have a history of being wrong.

Friendship circle: a volunteer faith-based program of outreach to special needs families

I received a press release today on the “Friendship Circle” a rapidly expanding faith-based (Chabad-Lubavitch) outreach and support program for autistic persons and their families. I can’t vouch for the program, but I’m ok with passing on the press release and and a note from their web page. I’ve not heard of anything like the “Weinberg Life Village” — it certainly sounds impressive! (emphases mine)

Children challenged by Autism, other disabilities share laughter,  love and life lessons with Teen volunteers

West Bloomfield, MI:  The Friendship Circle now embraces over 4000 members internationally and includes a 22,000 square foot facility built by love, and it all grew from the simplest of questions, first posed in 1994.  "Who in the world is most in need of a friend?"

The first voice that came from the community was a mere whisper, but was finally clear. It came from a child.  A child challenged and isolated by unusual physical, mental, or emotional needs is missing a most important ingredient in the recipe for happiness, a friend to call their own.

It was not to be the only answer. As the Friendship Circle sought teen volunteers to develop as special friends of the little ones, it became clear that the gift of friendship enriched both parties. Teens grew and bloomed from the simple acceptance and unconditional love they experienced from their younger friends. As one teen volunteer phrases it, "When I am with these children I feel calm and soothed. I know there are no judgments being passed. I know they don't care what I look like...together we live in the moment, enjoying each second of each other's company". Or as another teen puts it, "I have learned that one hour a week is enough to change a life forever".  Teen volunteers have gone on to establish new Friendship Circle chapters near their colleges just to continue to enjoy the special bond they share with their young friends.

There was yet another answer to that original question. Parents of the special needs children were given the gift of a few hours each week when they knew their children were safe and being entertained by a friend. That precious time might be spent in activities as mundane as paying bills or having an uninterrupted telephone conversation, but are a gift by any measure. "We love our daughter unconditionally, and to know that others love her as well, even with all her behavioral difficulties, brings such a sense of peace to us", writes one mother.

Just twelve years later, a tiny 3 non-profit program that began with just eight volunteers in the Detroit area has grown to include more than 50 chapters across the U.S., Canada and Australia. It has also built, through private contributions, the 22,000 square foot Meer Family Friendship Center in West Bloomfield, Michigan. It was developed by consulting with a group of parents of children with special needs, therapists, educators and professionals from around the world.  The heart of the Friendship Center is the Weinberg Life Village, which gives the children and their friends the opportunity to practice activities such as banking, scheduling and keeping appointments with the salon, dentist or doctor, navigating traffic signals and buying tickets for the 22 seat movie theater. All this is in preparation for their eventual integration into society. Unlike the real world, there is no hurry, and skills can be practiced again and again. Best of all, they have a great time..

"Our mission for 2007 is to expand our circle of friends", states Executive Director Rabbi Levi Shemtov, "There is so many more programs that we can start and more families and volunteers that we can embrace if we would have more charitable funding. We feel confident that the organization has reached a place where it is ready to grow on many levels."

 For more on the Friendship Circle, please visit www.friendshipcircle.org, local chapter links can be found at www.friendshipcircle.com.

There’s more about the organization on their web site. They have expanded a bit beyond special needs …

The Friendship Circle - About Us, http://www.friendshipcircle.org/page.aspx?pid=47

The Friendship Circle provides assistance and support to the families of children with special needs as well as to individuals and families struggling with addiction, isolation, and other crises.

In addition to helping those in need, the Friendship Circle empowers and enriches its network of volunteers, the majority of whom are teenagers, by enabling them to reap the vast rewards of giving of themselves.

The Friendship Circle was founded in 1994 by Lubavitch Foundation of Michigan, a branch of Chabad-Lubavitch. Since then, the Friendship Circle has been providing assistance and support to the families of children with special needs as well as to individuals and families struggling with addiction, isolation, and other crises through our Daniel B. Sobel Friendship House.

The Friendship Circle is committed to serving all members of the community regardless of religious affiliation.

In addition to helping those in need, the Friendship Circle empowers and enriches its network of volunteers, the majority of whom are teenagers, by enabling them to reap the vast rewards of giving of themselves.

The Friendship Circle consists of five parts - volunteers, children, parents, staff, and supporters. The true beauty of the Circle is how all of the elements link together to form a seamless community of friendship.

Just as a circle has neither end nor beginning, our community offers promise, hope and love that have no bounds. Who can say who benefits the most from the Friendship Circle programs - the child with special needs who learns how to ride a bicycle, or her parents who get a much needed break, or the volunteer whose spirit soars to new heights?

Through a wide range of services, projects and facilities, including the Morrie and Sybil Fenkell Volunteer Club and the Friendship Circle Fellowship Program, the Friendship Circle is able to touch the lives of thousands of people each year. The success of the Friendship Circle has inspired similar programs throughout the United States and Canada. By offering guidance and instruction to these organizations, the Friendship Circle is able to welcome many more families and volunteers into its midst.

The Meer Family Friendship Center was opened in 2005 – home of the Ferber Kaufman LifeTown building (opened in April) and the Daniel B. Sobel Friendship House (opened in September.)

The majority of the Friendship Circle’s innovative work with children with special needs takes place at the Ferber Kaufman LifeTown building, a 20,000 square-foot state-of-the-art facility, which serves as a therapy and activity center, social meeting place, and hub for our network of volunteers, professional staff, and supporters. The most striking feature of LifeTown is the Weinberg Life Village, a unique, interactive world where children with special needs, our Special Friends, can have fun while they practice important life skills through role play.

At LifeTown, children with special needs and their parents and siblings find a place that has been specifically designed to meet their needs. LifeTown is more than a community center or a therapeutic facility—it is a house of friendship.

The Chabad-Lubavitch are a branch of Hasidic Judaism with a strong emphasis on emotional connection, community interaction, and the integration of good acts with spiritual observance. Jewish clients might anticipate a certain amount of quiet (or not so quiet) proselytizing, but Christians and atheists would probably be left alone. I don’t know how they’d do with Islamic clients.

Scientific American on the "pillow angel"

The News Editor for Scientific American comments on recent media excitement about the care of a severely disabled child: Pillow Angel Parents Deserve Credit, Not Blame: BLOG: SciAm Observations. I agree.

Lesson: No black keyboards for the visually impaired

I learned a lesson, that I passed on via an Amazon review:

Amazon.com: Microsoft Digital Media Pro Keyboard: Electronics

I bought this keyboard under unusual time constraints for my mother's Mac Mini. Yes, Microsoft does supply a quite good driver driver for OS X that enables all the features.

As an OS X keyboard it's not bad if one remembers to turn on F-Lock (OS X makes good use of function keys but XP does not, which is ironic if one knows the history of the function key). There's no 'eject' button but it's easy to remap the 'Messenger' key to be an eject button. It has a sleep and logout button that are very handy; note that the the modern Mac keyboard lacks both of these.

The main problem for an elderly or visually impaired person, however, is that the black keyboard with white lettering just doesn't work. It's also very complex and daunting with lots of special functions of dubious utility, and some of the most useful buttons (sleep, log out) are tiny. The numbered favorites occupies a lot of wasted space and are pretty worthless for most of us.

Not a bad keyboard, though a bit whizzy and silly, for most OS X and XP users. It's not a good choice for the elderly or visually impaired however.