Sunday, December 28, 2008

Guanfacine (Tenex) for ADHD - more good news

These results are gratifying, but not surprising ...
Guanfacine Extended Release in Children and Adoles...[J Am Acad Child Adolesc Psychiatry. 2008] - PubMed Result

.... Guanfacine extended-release was effective in reducing symptoms of ADHD. Adverse events were mild to moderate, did not interfere with improvements in attention, and rarely led to discontinuation....
Guanfacine is a curious and perhaps powerful drug, so we need to treat it with cautious appreciation. The value comes because it's complementary to methylphenidate (Ritalin); it works by different mechanisms and the two seem to mesh well. Although Ritalin is exceedingly safe, it has some street value and can be problematic with adolescents. Ritalin can also exacerbate OCD symptoms and tics; Guanfacine doesn't seem to.

Even more interestingly, many believe Guanfacine can reduce "explosive" type behaviors.

Overall, good news.

Saturday, December 27, 2008

Provigil and ADHD

This is old news (2006) but recent enthusiasm for using Provigil (modafinil) as a productivity enhancement for scientists brought it to mind:
Use of Drug to Treat ADHD in Children Opposed -

... A Food and Drug Administration advisory committee voted 12 to 1 against recommending modafinil as safe for children with ADHD. Earlier, the psychopharmacologic drugs panel unanimously agreed that modafinil works as a treatment for ADHD...

... The committee recommended that Cephalon Inc. undertake a 3,000-patient trial to determine the risk modafinil may pose for Stevens-Johnson syndrome...

... one out of 900 children involved in earlier studies of the drug developed the disease. He and Cephalon spokeswoman Jenifer Antonacci said the agency and the company will discuss the committee's recommendation ...

Please note that the enthusiasm for Provigil use by healthy people is occurring at the same time as a series of studies showing accelerated aging associated with lack of sleep.

A new drug for ADHD would be interesting, but it's hard to beat the incredible safety record of Ritalin. Provigil would have to have some really unique or complementary effect to be worth serious consideration.

Wednesday, December 17, 2008

Software for disabled persons

Hmm. I wonder if they'd consider doing an iPhone version of the Jaeggi working memory trainer ...

Entrepreneurial Edge - Software That Opens Worlds to the Disabled -

ONE computer program would allow vision-impaired shoppers to point their cellphones at supermarket shelves and hear descriptions of products and prices. Another would allow a physically disabled person to guide a computer mouse using brain waves and eye movements.

The two programs were among those created by eight groups of volunteers at a two-day software-writing competition this fall. The goal of the competition, sponsored by a nonprofit corporation, is to encourage new computer programs that help disabled people expand their capabilities.

The corporation, set up by computer science students and graduates at the University of Southern California, is named Project:Possibility. It grew out of an idea two years ago by Christopher Leung, then a master’s degree candidate in computer science and engineering at the university, who was working on a project at NASA’s Jet Propulsion Laboratory in Pasadena....

I don't know what will come of this effort, but it's encouraging that many people are thinking (again) of how software can help people "be the best they can be".

Tuesday, December 16, 2008

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.

Saturday, December 13, 2008

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.