Schizophrenia revelations - implications for autism

Following close on the heels of findings that major gene scramblings are common in "normal" brains comes more startling news about brain disorders:

Gene-Hunters Find Hope and Hurdles in Schizophrenia Studies - NYTimes.com

... The variants discovered by the two groups, one led by Dr. Kari Stefansson of Decode Genetics in Iceland and the other by Dr. Pamela Sklar of Massachusetts General Hospital, are rare. They substantially increase the risk of schizophrenia but account for a tiny fraction of the total number of cases.

This finding, coupled with the general lack of success so far in finding common variants for schizophrenia, raises the possibility that the genetic component of the disease is due to a large number of variants, each of which is very rare, rather than to a handful of common variants...

... The new focus on rare mutations suggests that natural selection is highly efficient at removing schizophrenia-causing genes from the population. Despite selection against the disease, according to this new idea, schizophrenia continues to appear because it is driven by a spate of new mutations that occur all the time in the population....

“This may be the case in other brain diseases, too,” Dr. Goldstein said, “because successful cognitive functioning is a highly complex system and there are many independent ways to take it down.”

The search for common variants in schizophrenia, however, has not been very successful so far, though not for want of trying. There have been more than a thousand studies, implicating 3,608 genetic variants.

But when all the data are pooled, only 24 of those variants turn out to be statistically significant, according to an analysis in the current issue of Nature Genetics by a group led by Dr. Lars Bertram of Massachusetts General Hospital...

I read this as consistent with recent literature telling us that the human brain has been undergoing rapid evolution for a few thousand years, perhaps with an unusually accelerated mutation rage and high selection pressures.

Rapidly evolving organs are often fragile things -- like a car slapped together in a rush. Thousands of thousands of things can go wrong. Some are manageable, others produce schizophrenia and perhaps autism.

The bad news is we were hoping gene studies would identify common genetic mechanisms; we could then use these to characterize disease subtypes, better evaluate therapies, and identify new drug targets. Now that door seems to have shut. We have to look further up the bioinformatics chain for common functions that meds could act on, and we may fear that they'll be hard to find.

Autism and ADHD are not so different after all

More evidence that our current categorization of early onset cognitive disorders needs a rewrite.

Evidence for overlapping genetic influences on aut...[J Child Psychol Psychiatry. 2008] - PubMed Result

BACKGROUND: High levels of clinical comorbidity have been reported between autistic spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD). This study takes an individual differences approach to determine the degree of phenotypic and aetiological overlap between autistic traits and ADHD behaviours in the general population.

METHODS: The Twins Early Development Study is a community sample born in England and Wales. Families with twins born in 1994-6 were invited to join; 6,771 families participated in the study when the twins were 8 years old. Parents completed the Childhood Asperger Syndrome Test and the Conners' DSM-IV subscales....

RESULTS: Significant correlations were found between autistic and ADHD traits in the general population (.54 for parent data, .51 for teacher data). In the bivariate models, all genetic correlations were >.50, indicating a moderate degree of overlap in genetic influences on autistic and ADHD traits...

CONCLUSIONS: These results suggest there are some common genetic influences operating across autistic traits and ADHD behaviours throughout normal variation and at the extreme. This is relevant for molecular genetic research, as well as for psychiatrists and psychologists, who may have assumed these two sets of behaviours are independent.

I suspect all clinicians with significant experience with autism are accustomed to children who have features of both ADHD and autism. So no surprises there. Unfortunately, most studies of ADHD or autism focus on "pure" subjects, so they exclude children who have features of both.

That means there's very little research about children with both ADHD and autism spectrum disorder -- we don't know what medications, behavioral or educational interventions are most effective.

These results may justify research on the large number of children and adults who aren't "pure" examples.

Please don't feed the nasty man

Imagine there exists a nasty man of limited insight who's income depends on national attention.

Isn't giving him attention like feeding a bear with a bad tooth? He'll just come back for more.

Lessons from gene deletions affecting learning and autism both

On the one hand, this article annoyed me. It demonstrates the usual confusion between association and causation, and it extrapolates from an exotic genetic disorder to the much larger group of children labeled as "autistic".

The reasoning errors, incidentally are not the journalist's. They come from the researchers. Researchers are as prone to this fallacy as anyone else.

On the other hand, it has some interesting hints. So I'll delete the worst parts, and focus on the interesting hints.

Autism Genes That Control Early Learning: Scientific American

A new genetic analysis of large, inbred Middle Eastern families... pinpointed six new genes that may contribute to autism ....

They report in Science that all of the linked genes are involved in forming new and stronger connections, called synapses, between nerve cells in the brain, which is the biological basis of learning and memory formation...

The researchers studied 88 families in which one or more children had been diagnosed with autism, and the parents of each autistic child were cousins. Marrying second and third—and even first cousins—is not uncommon in the Middle East...s

The team found a total of six mutations affecting genes that had previously not been linked to autism. The mutations came in the form of deletions, where part or all of both copies of the genes were missing in a child with the disorder. All of the genes are known to be involved in parts of the same process: creating and strengthening synapses...

...Walsh says the team believes these deletions—which in most cases found here only remove some, but not all, of the DNA that makes up a gene—may mean that the genes can regain some of their normal function. In fact, some of these genes may just be switched off. "This presents the possibility that in some kids we could get the gene going again without necessarily having to put it back in the brain," he says...

...Walsh notes that many children diagnosed with autism tend to show vast improvement when they are placed in environments that allow them to practice learning repetitively. He says that these activities essentially train the neurons to make up for their lost function.

From a science perspective it's another advance in studying neurodiversity, and it fits in the context that large numbers of "normal" people have significant neuro gene deletions.

From a parent's perspective, I was struck by the idea that these neurons can form connections, but they take a lot of persistence to form. In particular, highly repetive learning.

It's hard to do that kind of teaching in a conventional classroom. It bores most students and teachers to tears. This fits with our experience in trying to teach reading however ...

Guanfacine for ADHD in children with autism -- and a recent literature report

Guanfacine in Children with Autism and/or Intellec...[J Dev Behav Pediatr. 2008] is basically reassuring. Guanfacine substantially improves ADHD behaviors in children with autism and similar cognitive disorders. It doesn't have other behavior score benefits. Side-effects were as expected.

I have a standing PubMed search on Guanfacine because it's a long used medication that was recently found to be an "alpha 2A adrenoceptor". That's making it the subject of extensive research, such as:

• changes in neuronal connectivity
• extended release works well in children and adolescents
• strengthening working memory networks (?)
• better prefrontal cortical regulation of behavior in aging animals (?)
  

Guanfacine (Tenex) is not FDA approved for use in ADHD, but the recent crop of articles expect approval shortly. It has been widely used for several years. Our son has taken it for about 2 years.

The challenge is that this medication will be taken for a very long time by very large numbers of children, often in combination with Ritalin. There are sure to be surprises, both good and bad. We don't know it nearly as well as we do Ritalin.

Games for focal abilities: Set and visual perception

Last week I wrote about focal abilities in the context of cognitive disability, and implications for employment in a distributed world. I was partly inspired by a friend who knew of an autistic child who was very good at the card game "Set":

Be the Best You can Be: Employment for special needs persons – hints from the classification of galaxies

...These [larger] disabilities are often offset by domains of relative, and even, absolute, strength, such as rapid pattern recognition in the card game “Set”, or rapid discrimination of large amounts of visual data. Tasks similar to the Galaxy Zoo classification, but with payment attached, might become an option – in time...

Since Child A has almost savant abilities to locate family members in a crowd, Andrew suggested I try him with "Set" -- a "game of visual perception".

The directions seem complex at first. Players choose groups of 3 cards from a larger set of 12 in which each of four attributes (color, shape, shading, number) are either identical or unique. I wasn't sure my son would get the game.

He saw me practicing as I thought about how to teach this, walked over, and started stamping out sets.

I guess he's played this before.

I'm not sure he's brilliant at Set, but for now he's much better than I am. Unsurprisingly, given his ADHD, he doesn't have much patience for the rules. He prefers to lay out all the cards, and pick out sets without keeping score.

It's great to have a game he can excel at, even though we'll need to be flexible with the rules.

Employment for special needs persons – hints from the classification of galaxies

The  Galaxy Zoo uses humans as “computers”. We’re very good at grouping things by resemblance, so hobbyists are used to group images of galaxies into “types”

... With your help, we've been able to collect millions of classifications, with which to do science faster than we ever thought possible...

…If you're already familiar with basic Galaxy Zoo analysis, click here to read the instructions and click here to take part. Galaxy Zoo 2 will go live in the near future featuring a much more detailed classification system, while further off we plan GalaxyZoo 3 with lots of exciting new data...

One amateur astronomer made an important original discovery.

Some persons on the autism spectrum with a personal interest in astronomy might be interested in the Galaxy Zoo today, but from a special needs perspective I’m mostly interested in where things might go in the future.

There will likely be tasks that humans do much better than computers for at least a few years. A few decades, I hope.

Some of these tasks will be open to people with focal cognitive disability. These disabilities are often offset by domains of relative, and even, absolute, strength, such as rapid pattern recognition in the card game “Set”, or rapid discrimination of large amounts of visual data. Tasks similar to the Galaxy Zoo classification, but with payment attached, might become an option – in time.

Incidentally, the first “computers” were humans. Even into WW II men and women did computational tasks by hand and were known as “computers”. (Engineers, of course, used slide rules until the late 1970s, but they weren’t called “computers”.) So this is a “back to the future” story.

See also:

• Outsourcing your crowd sourcing
• Distributed transcription using Amazon’s Amazing Turk

Does Ritalin specifically target the prefrontal cortex?

I've long been impressed by the unexpected safety of Ritalin (methylphenidate). It's rare for a medication to both alter brain function and have low toxicity, yet many years of use have given us little bad news.

Now FP reports on a study that suggests why Ritalin is both safe and effective for ADHD. It might not the drug we thought it was ...

FuturePundit: Research On Ritalin Mechanism Of Action

... In a paper publishing online this week in Biological Psychiatry, University of Wisconsin-Madison psychology researchers David Devilbiss and Craig Berridge report that Ritalin fine-tunes the functioning of neurons in the prefrontal cortex (PFC) - a brain region involved in attention, decision-making and impulse control - while having few effects outside it.

... Mounting behavioral and neurochemical evidence suggests that clinically relevant doses of Ritalin primarily target the PFC, without affecting brain centers linked to over-arousal and addiction. In other words, Ritalin at low doses doesn't appear to act like a stimulant at all.

Ritalin at lower doses appears to cause the prefrontal cortex (PFC) to be more sensitive to signals coming in from the hippocampus.

When they listened to individual PFC neurons, the scientists found that while cognition-enhancing doses of Ritalin had little effect on spontaneous activity, the neurons' sensitivity to signals coming from the hippocampus increased dramatically. Under higher, stimulatory doses, on the other hand, PFC neurons stopped responding to incoming information. "This suggests that the therapeutic effects of Ritalin likely stem from this fine-tuning of PFC sensitivity," says Berridge. "You're improving the ability of these neurons to respond to behaviorally relevant signals, and that translates into better cognition, attention and working memory." Higher doses associated with drug abuse and cognitive impairment, in contrast, impair functioning of the PFC...

I wonder if this will change thoughts about optimal dosing of Ritalin. I would very much like to see animal models studied to look for tolerance of Ritalin's alleged PFC effects.

When ADHD is an adaptive advantage ...

First, the news article (excerpt from FuturePundit: Hyperactivity Gene Helps Nomadic Tribesmen?). Then the anecdote ...

.... Kenyan nomads do better with an ADHD gene whereas those who have converted to settled living do worse with this same version of the DRD4 gene.

A propensity for attention deficit hyperactivity disorder (ADHD) might be beneficial to a group of Kenyan nomads, according to new research published in the open access journal BMC Evolutionary Biology. Scientists have shown that an ADHD-associated version of the gene DRD4 is associated with better health in nomadic tribesmen, and yet may cause malnourishment in their settled cousins....

... A study led by Dan Eisenberg, an anthropology graduate student from Northwestern University in the US, analyzed the correlates of body mass index (BMI) and height with two genetic polymorphisms in dopamine receptor genes, in particular the 48 base pair (bp) repeat polymorphism in the dopamine receptor D4 (DRD4) gene.

The DRD4 gene codes for a receptor for dopamine, one of the chemical messengers used in the brain. According to Eisenberg "this gene is likely to be involved in impulsivity, reward anticipation and addiction". One version of the DRD4 gene, the '7R allele', is believed to be associated with food craving as well as ADHD. By studying adult men of the Ariaal of Kenya, some of whom still live as nomads while others have recently settled, the research team investigated whether this association would have the same implications in different environments. 

While those with the DRD4/7R allele were better nourished in the nomadic population, they were less well-nourished in the settled population...  

...It is possible that in the nomadic setting, a boy with this allele might be able to more effectively defend livestock against raiders or locate food and water sources, but that the same tendencies might not be as beneficial in settled pursuits such as focusing in school, farming or selling goods...

There's a personal connection. 

Today we couldn't find child B at the pool. Since he has the classic Aspie tendency to wander, we became a bit anxious. 

We recruited child A, who, among other traits, has pretty severe ADHD. He also has a weird visual talent. He can pick things or people he's interested in out of a very large amount of visual input -- almost instantaneously. 

I told him we needed his "laser eyes" to find his brother, and I walked behind him. Zip. In 1-3 seconds he says "B is not in the big pool". He walks to where I can barely make out people in the diving pool. Zip. "B is by the climbing wall." A few minutes later I was able to spot Child B where Child A said he was.

In our society Child A is disabled. In a hunter gatherer society, at a slightly older age, he'd walk to high ground, spot game across the veldt, then head home to await delivery of the finest cuts of meat and play with his many children. I, in the same society, would be long dead. 

Adaptation is local.


Update: See also an earlier post on the same theme.

Update 7/5/08: The Economist has a more detailed review.

Road vacations: better options than you might think

Vacations with special needs children can be less than restful.

We have gone with long van-bound hotel-staying road trips for years. The first years, when the children were young and our techniques were less advanced, were like hang gliding around a tornado.

We did complex real-time calculations around video length, gasoline levels, food levels, drug levels, bladder volume, local geography, local facility expectations, weather and much more.

Now it's more like base jumping -- risky, but fairly predictable.

Here's a quick (very quick) post on advantages and recommendations for our family. The reality varies from trip-to-trip as we all age and change.

On the last trip we took our dog. That odyssey also involved a very politically challenging 50th anniversary parent celebration and several different family reunions at multiple sites. It spanned two nations, maybe 2,000 miles or so. My back blew out and I needed an ambulance ride to an ED about 60% through, then spent 3 days flat on the floor of the van until I invented a rig that allowed me to sit and drive.

And yet, and yet ... the children thought the trip went well.

Which is to say that if the vacation can work for the children under these circumstances, then the arrangement is more robust than even we expected.

Vacation for us? That was a funny one. Actually, if not for my back, I'd have had fun. I think my wife actually had a good time, and even I will remember the trip fondly after a few more weeks of forgetfulness.

Advantages and advice follow. I'll ask my wife to review and expand so this may develop further.

Advantages

1. In a moving van, no-one can hear your child scream.
2. Variety (external)
3. Consistency and predictability (internal)
4. They'll never see you again
5. You can stop the van, you can't stop the plane.
6. Flexibility

Tips

1. Small town parks, usually by schools.
2. Picnic, not restaurant
3. McDonald's drive through. (Same everywhere)
4. Avoid the big interstate (rest areas on I 90)
5. Avoid poor/destitute/hyper-urban areas (need breaks, need space)
6. Audio CDs ("books on tape") - superb. Little House in the Big Woods, Hank the Cow Dog
7. Activity bags: small toys, coloring books"Yu-Gi-Oh" cards and "duel disks".
8. iPod Playlists.
9. Movie in pm
10. Rituals: breakfast in room.
11. Gas station BID: bathroom, snacks
12. Swim in AM and PM
13. Ideally stay with one or two hotel chains (Baymont, AmericInn, Residence Inn)
14. Try to maintain your usual behavioral management regiment (ours fell apart on our last trip, no doubt)