Fragile X and memory

Pretty far from human application, but noteworthy ...

Fruit Flies, Fragile X and Foolery: Scientific American Podcast:

University of Alberta researcher Francois Bolduc keeps 300,000 fruit flies in a basement laboratory. He discovered that disrupting one gene known as FMR1 in the flies’ brains can wipe out their long-term memory. What’s interesting for us is that damage to that gene in people is associated with learning and memory problems, epilepsy and autism. That constellation of traits is known as fragile X syndrome. Bolduc then worked on curing his forgetful flies—he found a class of drugs that reduces the activity of the FMR1 gene. And the insects were able to regain their memory...

Working memory and COMT inhibitors - the nicotine example

Obviously, I'm not considering smoking as an aide to my son's limited short term memory. It is interesting, however, to note how substances associated with smoking act on the brain ...

FuturePundit: Gene Variant Makes Nicotine Withdrawal Harder

....

Spurred by their previous findings that carriers of the catechol-O-methyltransferase (COMT) val gene variant are more susceptible to smoking relapse, the Penn researchers set out to learn if smokers with this genetic background would be more likely to exhibit altered brain function and cognitive deficits during periods of abstinence from smoking.

...Results showed that smokers with the COMT val/val genotype suffered greater deficits in working memory and brain function when they had refrained from smoking for 14 or more hours, compared to their performance on this task when they had been smoking as usual....

... Inhibitors of this COMT enzyme might work to ease withdrawal from nicotine. Inhibitors of COMT already are known to increase working memory...

One method may be to offer carriers of this gene targeted therapies with drugs like COMT inhibitors, some of which have been shown to increase working memory in healthy volunteers.

The researchers were trying to understand why some people have a much harder time stopping smoking that others. It seems at least some of these persistent smokers experience brain dysfunction when they stop. The article does not tell us whether these people are experiencing a return to baseline cognition or whether they're experiencing a transient impairment. I assume the latter.

Even as smoking has become mercifully unusual in wealthier parts of North America, there's been more interest in the pharmacologic action of chemicals produced by the nicotine plant.

This related ticle on COMT inhibitors and executive function is interesting. Tolcapone is used to treat Parkinson's Disease (emphases mine):

Tolcapone improves cognition and cortical information processing in normal human subjects....

Prefrontal cortical dopamine (DA) regulates various executive cognitive functions, including attention and working memory. Efforts to enhance prefrontal-related cognition, which have focused on catecholaminergic stimulant drugs, have been unsatisfactory. Recently, the demonstration that a functional polymorphism in the catecholamine-O-methyltransferase (COMT) gene impacts prefrontal cognition raises the possibility of a novel pharmacological approach for the treatment of prefrontal lobe executive dysfunction.

To explore in a proof of concept study the effects of tolcapone, a CNS penetrant specific COMT inhibitor, we performed a randomized, double blind, placebo controlled, and crossover design of this drug in normal subjects stratified by COMT (val158met) genotype. COMT enzyme activity was determined in peripheral blood.

Forty-seven normal volunteers with no family history of psychiatric disorders underwent neuropsychological testing and 34 of those subjects underwent physiological measurement of prefrontal information processing assessed by blood oxygen level-dependent functional magnetic resonance imaging (fMRI).

We found significant drug effects on measures of executive function and verbal episodic memory and a significant drug by genotype interaction on the latter, such that individuals with val/val genotypes improved, whereas individuals with met/met genotypes worsened on tolcapone. fMRI revealed a significant tolcapone-induced improvement in the efficiency of information processing in prefrontal cortex during a working memory test. This study demonstrates enhancement of prefrontal cortical function in normal human subjects with a nonstimulant drug having COMT inhibitory activity. Our results are consistent with data from animal studies and from computational models of the effects of selective enhancement of DA signaling in the prefrontal cortex.

Please note that some people got worse on Tolcapone. I think we're a long way (20 years) from a safe medicine that can improve working memory, but this will be an interesting thread to follow.

Improving working memory in low IQ children

Working memory, sometimes called short-term memory, is currently thought to be closely related to IQ test results (for example) and perhaps to the cognitive performance that IQ tests try to measure.

It's also generally assumed that IQ cannot be improved, that individual capacity is determined almost entirely by genetics, intrauterine life, and perhaps the first few months of postnatal life. [1]. On the other hand, there's some evidence that working memory can be improved by training, though we don't know if the training effects persist.

That's roughly where the published science seems to be, but we're always free to draw some speculative (ok, breathtaking) inferences.

Wild speculation number one is that for most professionals under 50 it's not worth investing a lot of effort into training or improving working memory. My hypothesis is that in healthy brains things are pretty much aligned and that there aren't huge differences in subsystem performance. In other words, there aren't big performance bottlenecks. Improving working memory by, say, 10%, might only boost cognitive performance by 1%. Physical exercise is likely a far better investment than short-term memory practice. (I'm amazed by how important physical exercise seems to be to memory preservation, I never expected that.)

Once you get past 50 or so the rules change. I think the majority of us have some subsystem failure by then, so gains might be larger. I won't explore this one, however, as my major interest now is younger persons.

Consider the child, or young adult, with mental retardation (old term), cognitive disability (newer term), pervasive developmental delay (somewhat meaningless term), autism-spectrum disorders, severe ADHD and the like [2]. They often have patchy cognitive function. Some subsystems might work pretty well, while others, like working memory, might be pretty much shot.

This brings us to wild speculation #2. Imagine that IQ was the measured result of interactions between working memory, processing speed and, "rhubarb". (For this discussion "rhubarb" doesn't matter.) If "rhubarb" was working at 80% efficiency, and working memory at 10%, then working memory would be a performance bottleneck.

In this case a 10% improvement in working memory might become a 7-8% improvement in overall cognitive performance. That's a pretty significant improvement for someone who's on the borderline of social or quasi-independent function.

Now, that's an awful lot of speculation, but it's not hard to imagine how to test the hypotheses. We'd identify a set of children with low IQs, and work on short-term memory training...

Oh. Wait. It's been done. It worked. There are similar articles, including a review of the topic published in the PNAS that pointed out this is only the start of a long research agenda.

In the meantime, what about those low IQ children we know of today?

Well, when I wrote about this topic a few months ago Martin Walker of MindEvolve mentioned he's developed a software program to apply Jaeggi et al's techniques at home [5]. I've also previously written about games for improving focal cognitive weaknesses, and there's a real cottage industry of brain training exercises, including for working memory [3]. On my iPhone there are games like "Garf" [3] and "Matches".

I'm going to think about this a bit more. There might be a way to work this into our regular homework times for one child in particular ...

[1] In the interests of simplicity I'll assume IQ tests are a good approximation to IQ. It also obvious that IQ can be lowered by poor nutrition, head injuries, infection, seizures, trauma and so on.
[2] One of my pet peeves is the futility of classifying cognitive disorders given our limited knowledge of the underlying pathophysiology. Don't get me started on "reactive attachment disorder".
[3] As I wrote above though, I suspect those will have limited effects on the average "balanced" brain.
[4] My wife is very good at this. I am astoundingly bad at it. Hmmm.
[5] Windows only, $50, no trial version. The price is reasonable, but we don't have much Windows left in our home, and it's hard to spend the money without testing it first.

Why I will be flexible even if I am old

We all become less flexible as we age.

I will be more flexible than most.

How can I boast that?

It is a small benefit of parenting some very inflexible children. In middle-age my wife and I have been given a graduate level extended boot camp style program in enhanced flexibility.

Our natural bounds have been shattered.

Assuming a normal decay curve from our artificially elevated heights, we may expect a twenty year flexibility bonus.

It's good to have something to offset the accelerated aging associated with parenting special needs children.

Warner on Risperdal use in children

The NYT's Judith Warner meant well with a recent blog post about Risperdal use in children with "bipolar disorder" but she was ill-served by the research psychiatrists she interviewed.

Here are some excerpts of her writing, with the less sensible parts removed ...

Tough Choices for Tough Children - Judith Warner Blog - NYTimes.com

It was disturbing to read in The Times this week that the “atypical” antipsychotic Risperdal, a tranquilizing whopper of a drug with serious, sometimes deadly side effects, is now being widely prescribed to children with attention deficit hyperactivity disorder.

.. why, according to new Food and Drug Administration data on doctors’ prescribing practices, were 16 percent of the pediatric users of Risperdal over the past three years children with A.D.H.D.?

... The biggest controversy in the controversial field of psychiatry these days ... is the issue of pediatric bipolar disorder... a group of children who are really difficult: chronically irritable, extremely aggressive, prone to explosive outbursts and out-of-control rages.

Many doctors, influenced by the work of Dr. Joseph Biederman at Harvard Medical School (whose ties to industry were detailed in The Times in June), say these symptoms are signs of mania, and call these children bipolar. Others label them with “extreme A.D.H.D.” or Oppositional Defiant Disorder or “severe mood dysregulation,” ...

... This will not satisfy the critics of today’s biological psychiatry for whom no drug use is good drug use, nor the critics of today’s culture of parenting who are sure that all the aggression, irritability and out-of-control behavior that psychiatrists call mental illness is actually nothing more than a state of “toddlerhood in perpetuity” caused by ineffective parenting practices, as the conservative family psychologist and writer John Rosemond and his coauthor have asserted in his new book, “The Diseasing of America’s Children.”

And here's what I wrote as a comment (edited) ...

It was a noble effort, but I think you were led astray by your psychiatrist colleagues.

The best writing, by far, on the problem of the "explosive child" is by Ross Greene. For a discussion of Greene, Kazdin and the NYT's own Amy Sutherland see my blog posting.[1]

Greene's book is still in print, still sells well at Amazon, and has a 4.5 star rating.[2]. that's incredible for a book that's aimed at parents with children chronically on the edge of disaster.

You know Greene's book is for real, because not all his case study children do well. Some do horribly. That makes him believable. People who need Greene already know that not all endings are happy.

I'm an expert. Honest. An MD, MS, years of experience, and a child straight out of Greene. He's on two meds and I can easily see how he might have ended up on Risperdal, but, thus far, he's holding. We owe a lot to Greene and Kazdin and our helpers.

I'm also, interestingly, a world-class expert in nosologies and classifications (yeah, it's true).

So I can tell you that every classification we can invent for these children is merely a convenience. We don't know enough about the brain and this class of brain disorders to classify them the way we do heart failure or renal failure. Pediatric brain failure isn't well suited to classification.

One of Greenes many strengths is that he realizes this, and is humble about how much the diagnostic categories like 'childhood bipolar' or ODD or ADHD or PDD or autism really mean. They're better than nothing, but not enormously better. New classifications, in the absence of new science, won't change practice.

There's a vast amount we can do to bring basic behavioral messages (extinction, reinforcement) and teachings like Greenes to psychiatrists (who know very little about this domain). We'll still need to put a significant number of these children on drugs like Risperdal though. These are children facing terrible outcomes, and if the drugs are shown to help the terrible risks are worth bearing.

I didn't bother saying anything about oxygen-sucking dolts like Rosemond. People like him are a canker sore on the parents of troubled children [1]. Enough said.

Update 11/26/08: [1] On reflection, I have an idea where Rosemond and the like get their ideas. One of our children gets more "timeouts" (really calm-down intervals generally lasting under 30 seconds, but we call them "timeouts") on a sub-average day than another child has had in her entire life -- and will probably ever have. That's not an order of magnitude difference, it's a 2-3 order of magnitude difference. A 100 to 1000 times increase in parenting challenges.

Now, both these children are abnormal -- they're just abnormal at different ends of a broad scale. If all we knew was the easier child, we might also have astoundingly stupid ideas about parenting.

Altering brain chemistry through dietary means: implications from Alzheimer’s research

A BBC Science article on the animal Alzheimer studies caught my attention because of the reference to altering brain function through dietary changes. Emphases mine …

BBC NEWS | Health | Fatty acids clue to Alzheimer's

Controlling the level of a fatty acid in the brain could help treat Alzheimer's disease, an American study has suggested.

Tests on mice showed that reducing excess levels of the acid lessened animals' memory problems and behavioural changes.

Writing in Nature Neuroscience, the team said fatty acid levels could be controlled through diet or drugs…

… Scientists from Gladstone Institute of Neurological Disease and the University of California looked at fatty acids in the brains of normal mice and compared them with those in mice genetically engineered to have an Alzheimer's-like condition.

They identified raised levels of a fatty acid called arachidonic acid in the brains of the Alzheimer's mice …

… Its release is controlled by the PLA2 enzyme.

The scientists again used genetic engineering to lower PLA2 levels in the animals, and found that even a partial reduction halted memory deterioration and other impairments.

Dr Rene Sanchez-Mejia, who worked on the study, said: "The most striking change we discovered in the Alzheimer's mice was an increase in arachidonic acid and related metabolites [products] in the hippocampus, a memory centre that is affected early and severely by Alzheimer's disease."

He suggested too much arachidonic acid might over-stimulate brain cells, and that lowering levels allowed them to function normally…

I doubt this will end up being all that important for Alzheimer’s prevention, but it’s interesting as another hint that we might be able to alter behavior in children and adults with cognitive and behavior disorders through dietary interventions.

I tried looking for more discussions on this general topic, but I found very little. Seems far fetched for now, but I’ll keep an eye open.

Diary of a Special Ed Teacher

Just found this one through a NYT essay "Miss Dennis" wrote - Your Mama's Mad Tedious: Diary of a Special Ed Teacher. I'll be reading the back posts and subscribing to the feed.

I hope to do a post on her NYT article, she does repeat the article in her blog.

OpenOffice for OS X: touts accessibility

I'm impressed that their accessibility support is a touted feature: www: OpenOffice.org 3.0 New Features: "OpenOffice.org integrates well with the Mac OS X accessibility APIs, and thus offers better accessibility support than many other Mac OS X applications."

Accessibility solutions for OS X

Apple has long been a distant 2nd when it comes to accessibility solutions. Microsoft has put more effort into a reasonable foundation, and 3rd party vendors have built on top of Microsoft's base.

Recently, though, Apple has tried a bit harder. Legal threats from several states and fears of being shut out of the education market may have provided valuable motivation. (See: section 508.)

For example, OS X 10.5 has an improved screen reader, though Apple still has a long way to go. On the other hand persons with joint and motor disorders want robust voice commands and speech-to-text recognition -- but OS X provides only the feeble and under-developed "Speech Commands" tool.

In addition to the improved OS X accessibility page (still heavy on the marketing) Apple now has a 3rd party OS X accessibility page. Unfortunately, some of the solutions are only mildly related to accessibility and a few are basically web services that work on any reasonably browser.

There's a general accessibility page for all Apple products with some links I'll explore, such as the lioncourt blog.

At the moment I'm focusing on things I can do with for my mother, but the combination of poor vision, bad joint disease and limited sensation puts things beyond what Apple can do. Now if she had a way to say "open mail" and "read messages" and then listen to the messages ...

Harcourt family learning series - useful

We've been using the Harcourt Family Learning Complete Curriculum books with our kids, including one child who's disabilities make reading and math pretty darned hard.

I'm happy with them. Amazon.com has a pretty good list of the books. The books were published by "Spark Publishing" (Flash Kids), but their web site is gone. I suspect they're no more. I can't find any evidence anyone else is publishing these.

The reading and math exercises are interesting enough and quite polished. The Grade 3 level readings are reasonably interesting to our 11 yo boy; it's tough to find that kind of age interesting/readable combination anywhere else.

Recommended if you can find 'em! We have the "complete curriculum" for grades 1, 3 and 4.