Atypical minds and developmental support: we haven't learned much in 15 years

I wrote the first ‘best you can be’ post almost 12 years ago. #1 was 7 then, #2 was 5. E and I already had years of experience with cognitive disabilities, autism spectrum, and atypical minds. We already understood how worthless the classifications we’d studied in medical school were. Autism, ADHD, Asperger’s (defunct now) — very rough labels that are primarily useful for obtaining services and perhaps for initial medication selection.

We thought there would be progress. 

There really hasn’t been much that we’ve seen. We still have most of the original classifications (frozen in DSM V) and I haven’t seen any useful research emerge. We’re going nowhere.

If someone were to drop a few million dollars on me I’d start by defining 5-8 axes of thinking/feeling — measures of things like external-word vs. internal-world orientation, spatial processing, impulsivity, short-term memory, etc. Things that can be tested and measured. 

I’d mine the existing literature for axes to study, but otherwise I’d toss out most of it. Test a few thousand late teens/early adults and plot them on a “spider graph”. Run the analysis to see if there are any useful clusters. If there are useful clusters, then name them. Use that as the basis for future research.

Basically, start over.

One day autism may be treatable

It's good that some researchers are asking these questions ...

 Progress toward treatments for synaptic defects in autism. Nat Med. 2013 Jun;19(6):685-94

Delorme R, Ey E, Toro R, Leboyer M, Gillberg C, Bourgeron T

... There is currently no cure for ASD; however, results from mouse models indicate that some forms of the disorder could be alleviated even at the adult stage. Genes involved in ASD seem to converge on common pathways altering synaptic homeostasis. We propose, given the clinical heterogeneity of ASD, that specific 'synaptic clinical trials' should be designed and launched with the aim of establishing whether phenotype 'reversals' could also occur in humans....

In other words, we seem to be able to make adult "autistic mice" better, so maybe we can make adult humans "better", hopefully with a different outcome than Flowers for Algernon. To put it mildly, this will be a long and tricky road. 

My #1 is 16, so it's not impossible that sometime in his life, depending on his particular neurobiology, there might be a medication that might, among other things, increase his IQ score.

It won't be in the next 20 years though. 

Rebooting pyschiatry: time for a new set of disorders

I can't remember when I first decided that the psychiatric classifications I'd learned in medical school had outlived their usefulness. It was probably a gradual process, but by 2005 I wrote to a colleague "DSM IV was great in its day, but new knowledge is breaking down the simplistic classifications of the 1960s and 1970s. Schizophrenia, autism, etc -- bah, humbug. Those labels are better than nothing, but humans tend to confuse labels with reality …".

A few months later I took my rants public and went on for about 30 posts or so.  Soon I learned I wasn't alone, and by 2010 victory was in sight. I was a solitary crank no more.

After a bit of a hiatus the end came quickly, first with a frontal attack by the director of the National Institutes of Mental Health, then, amazingly, a NYT editorial. I mean, really, an editorial?

It's been one heck of a ride over the past 8 years. This rebellion must have been brewing for much longer in the research community, but I've been following this area pretty closely and it was cool to see it grow from nowhere to become a consensus. (I may be a crank, but I'm not crazy. I know my posts had no effect on this transformation.)

Okay, science has won. So now what ….

*cough*

Well, for now, we keep on using our legacy classifications -- either DSM IV or V, they're equally valid and equally invalid. Terms like "autism" [1], "schizophrenia", "depression",  OCD, ADHD, and "bipolar disorder" will remain guides to initial pharmaceutical therapy. Even more importantly, they will be the basis of reimbursement, regulation, disability support, and legal process for years (decades?) to come.

At the same time researchers will be using new terms to group people who seem to share common biology, including genetic programs and common protein expression. Those groups will cross traditional boundaries like childhood schizophrenia and autism; they will include some atypical minds that may be highly functional or advantageous in certain environments -- but that share traits with persons who live with disability. 

From new classifications will come better prognosis, better guides to treatment, and better outcomes. Our best guide to what lies ahead is to look back to the early 20th century, when people like William Osler and his colleagues rewrote the medical textbooks. In those days terms like "dropsy" were used to describe patients with heart failure, renal failure, lymphatic obstruction and venous valve failure. Four very different biological processes were assigned the same label and similar treatments. Reclassifying those patients was a first step towards scientific medicine.

Psychiatry, powered by the neuroscience renaissance of the past thirty years, is now taking the same journey.

[1] Aspergers', traditionally considered an autism variant, was dropped in the revised classification of disorders called DSM V. I understand the logic, but I actually think Aspergers was a relatively useful label. Ironic that we lost that one first.

Update 5/18/13 - my favorite psychiatrist blogger summed up our past and future worlds in two short posts:

• New Efforts to Overhaul Psychiatric Diagnoses Spurred by DSM Turmoil | Follow Me Here...
• Suicidal behaviour is a disease, psychiatrists argue | Follow Me Here...; An impulse disorder?

Nature November 2011: Special issue on Autism, Mottron's view of the employed autistic and Calgary's Ability Hub

The Nov 2011 issue of Nature (v479, n7371, pp5-144) focuses on "The Autism Engima". It includes 3 reviews/news articles and 1 research article:

• Special issue on neuroscience: The autism enigma - introductory editorial
• The prevalence puzzle: Autism counts - a thorough 'news' review of the prevalence of autism. I came away with the impression that novel environmental changes might account for 0-20% of the increased diagnostic prevalence of autism, but that most of it is better diagnosis and reclassification. Studies of adults suggest that autism was far more common than most imagined -- these children were invisible.
• Scientists and autism: When geeks meet - autistic traits may be advantageous in some careers, but the hypothesis that assortative mating accounts for autism clusters doesn't sound too solid.
• Changing perceptions: The power of autism - this one is a research article, and is behind a closed-science paywall. Science Daily has a summary: Autistic people superior in multiple areas: Scientists must stop emphasizing autistics' shortcomings, expert urges.

I followed up on the Mottron article and came across an excellent National Post article ...

Autism’s advantages: Researcher says autistics need opportunities more than treatment | News | National Post

Because autism — characterized by repetitive behaviours, restricted interests and preoccupations and difficulties in basic social and communicative behaviours such as eye contact, intonation and facial expressions — is a lifelong disorder, parents can be caregivers for life. But as the population ages and parents get sick and die, there’s an even greater need to integrate people with autism into society by giving them the skills they need to become independent adults, experts say. Children tend to be the focus, autism organizations admit. Adults are overlooked.

“After 18 years of age they’re not kids anymore and they’re forgotten,” Dr. Mottron said over the phone this week from Lyon, France. “People have a cliché, that if he’s autistic you can do nothing with him. That’s not true. The fact that you have some terrible autistic life is not representative of autism in general.”

In his commentary, Dr. Mottron cites recent data, including an epidemiological study from Korea published this June that found the disorder is three and a half times more prevalent than common statistics suggest. “Among these 3.5%, about two-thirds have no adaptive problem at all,” he said, meaning they function relatively normally in society and should be able to take on a job.

... Ms. Dawson said it’s unfair to categorize someone as low functioning or high functioning. She and Dr. Mottron believe many tests that are used to determine level of functionality are inappropriate. Less commonly used tests such as Raven’s Matrices, which doesn’t require verbal instruction to complete, can actually reveal very high intelligence levels.

“To estimate the true rate, scientists should use only those tests that require no verbal explanation,” Dr. Mottron wrote in his paper. “If we were to measure the intelligence of a person with a hearing impairment, we wouldn’t hesitate to eliminate the components of the test that can’t be explained using sign language; why shouldn’t we do the same for autistics?”

Ms. Dawson said an entire session at this year’s International Meeting for Autism Research in San Diego focused entirely on finding out how to measure the intelligence of non-speaking autistics, who might be considered low-functioning....

... The founder of Specialisterne, a Danish company that has helped more than 170 autistics find work since 2004, said it’s OK to start such a movement with people who would be considered higher functioning.

“If we will be able to run a business on the skills of medium- or low-functioning, I’m not sure,” Thorkil Sonne said from Copenhagen. “But everyone deserves a chance to feel that they can produce something that others appreciate.”

... the Sinneave Family Foundation’s Ability Hub, a 17,000 square foot centre on the University of Calgary campus dedicated to helping people with autism gain life skills and work training...

... The Ability Hub opened in October and is just one of a few new centres devoted to getting autistic adults ready for the real world, said its executive director, Dr. Margaret Clarke, who has spent a career working with people who have autism — the Ability Centre is under construction in Whitby, Ont., and the Pacific Family Autism Centre to be built in Vancouver.

“Around the world we know that average lifetime cost to society to an individual with autism … is $3.4-million per individual. Three-quarters of those costs are incurred in adulthood largely around services to enable and facilitate individual vocations,” Dr. Clarke said, adding that some data suggests every dollar you invest in pre-vocational programming for people gives you a $7 return. “I actually think that number is going to be even better in the area of autism because individuals with autism have a great capability to learn, they’re just often held back by specific skill deficits or not given a chance.”

Information wants to be licensed?

We're always on the lookout for new therapeutic interventions, particularly behavioral interventions for our guys.

Since we're physicians, we're used to finding those interventions in handbooks, manuals and the like. Knowledge that comes with a creation history, but that is public.

Of course even in medicine that's not quite true. I've always been struck by how little ophthalmology, for example, is actually written down. Yes, there are lot of ophthalmology textbooks, but they seem to leave out a lot of the actual practice of eye care. Orthopedics was the same way. General medicine had the best public coverage.

In the 1980s medical-process patents began to appear in clinical practice [1], though, surprisingly, Congress actually moved to limit their impact in 1996. In Nursing care several "instruments" are owned by publishing companies and cannot be used without license.

There are similar issues in science, particularly in genomic research. The "iceman" (Otzi) genome is still a carefully held sequence, worth fame and grants to its owners. Archeologists are infamous for restricting access to ancient documents (ex: Dead Sea Scrolls).

So in the worlds of science, engineering and medicine there's a spectrum of open knowledge.

We're discovering that much of behavioral therapy for autism tends towards the closed end of this spectrum; many programs are patented and unpublished.

I'm unsure how important this is. It may be that patented programs are not only "secret" but also unstudied. Idiosyncratic therapeutic interventions may be harmful or wasteful (in this world, since time is limited, wasteful is harmful). Perhaps we're better off not knowing what's in them.

On the other hand, secret knowledge is yet one more obstacle to information sharing in the cognitive disability community. It's a part of a bigger problem that's getting more of my attention...

[1] Link intentionally made to a NEJM restricted access article.

Intrauterine contributors to autism

A recent twin study (NYT.com) claims that only 40% of what the researchers considered "autism" was clearly genetic. Previous studies estimated a 90% rate. The greater causes was something occurring prior to birth.The researchers further claimed that most (about 58%) of the environmental causes were shared.

These are remarkable claims, and they will require remarkable evidence. I am very skeptical.

If there is a common intrauterine cause of brain injury, however,  we do need to look again at obstetric ultrasound.

See also:

• Be the Best You can Be: Ultrasound, neuronal migration, and autism (8/2006)
• Gordon's Notes: General weirdness on the net: ultrasound, autism and satire (An essay was published in 2006 on ultrasound, school violence, and autism. It was a satire.)
• Gordon's Notes: Ultrasound and the developing brain – lessons from manipulation of mouse neuron (1/2009)

The twilight of "schizophrenia"

Neurologic disorders, alas, are not going away. The concept of "schizophrenia", however, is shuffling off the stage.

Today's obit comes from Kwang-Soo Kim, a stem-cell scientist at McLean Hospital in Belmont, Massachusetts:  "These disorders are not really disorders. There's no such thing as schizophrenia. It's a syndrome. It's a collection of things psychiatrists have grouped together."[1]

Just like autism. Autism is a collection of "things" psychiatrists have grouped together, sustained by law, regulation, tradition -- and the current lack of a better alternative.

[1] Schizophrenia 'in a Dish': Scientific American 4/13/2011

See also:

• Victory: The war against 20th century psychiatric diagnoses is all but won

Victory: The war against 20th century psychiatric diagnoses is all but won

I started rabble rousing about the fallacies of psychiatric classifications (diagnoses, nosologies) about eight years ago. Five years ago I went public, since that time I've labeled 29 posts as "diagnostic definition" related [1] including my most recent rant...

... We're due for another DSM edition, but I doubt that will be any better.

The good news is that in the last 8 years it's become clear to every researcher that all of the common neurospychiatric conditions, from "ADHD" to "ODD" to "Autism" to "Aspergers" to "Bipolar disorder" to "Schizophrenia" are very rough categorizations of thousands of different "phenotypes" (where a phenotype is the end-result of the interaction between genes and environment) that are themselves dynamic over the lifetime of the brain. (Even after adolescence, we see major changes in schizophrenic symptoms between 20 and 50.

Over the last 3 years we've seen that many different combinations of diverse gene variants, combinations, "malfunctions" and prenatal genetic express modification can produce superficially similar clinical presentations that we squeeze into the garbage bins of "mental retardation", schizophrenia, and "autism spectrum disorder". Most surprisingly, many brains with extraordinary genetic disorders appear normal.

This classification problem isn't simply an annoyance for researchers and industrial ontologists. It has important legal, educational, financial and, yes, clinical implications. The legal, educational and financial implications are large but outside the scope of this post. Suffice to say there is a reason that the diagnosis of "autism" has exploded while the diagnosis of "mental retardation/DCD" has shrunk (clinically speaking both diagnoses are about equally useless)...

I think I can stop now. When Scientific American starts to talk about the problems with our current classifications of mind and brain disorders the war is over (emphases mine) ...

Slipping the 'Cognitive Straitjacket' of Psychiatric Diagnosis

...  In a recent article in the American Journal of Psychiatry, a Swedish team of researchers led by Paul Lichtenstein studied 7,982 twin pairs. They found a heritability of 80% for autism spectrum disorders, but also found substantial sharing of genetic risk factors among autism, attention deficit hyperactivity disorder, developmental coordination disorder, tic disorders, and learning disorders.

In another recent article in the American Journal of Psychiatry, Marina Bornovalova and her University of Minnesota colleagues studied 1,069 pairs of 11-year-old twins and their biological parents. They found that parent-child resemblance was accounted for by shared genetic risk factors: in parents, they gave rise to conduct disorder, adult antisocial behavior, alcohol dependence, and drug dependence; in the 11-year-olds these shared factors were manifest as attention deficit hyperactivity disorder, conduct disorder, and oppositional-defiant disorder. (Strikingly, attention deficit disorder co-occurs in both the autism spectrum cluster and disruptive disorder cluster.)

... , DSM disorders do not breed true. What is transmitted across generations is not discrete DSM categories but, perhaps, complex patterns of risk that may manifest as one or more DSM disorders within a related cluster. Second, instead of long-term stability, symptom patterns often change over the life course, producing not only multiple co-occurring diagnoses but also different diagnoses at different times of life.

Please read the above excerpt. I tear up looking at it.

This is progress! This is what Osler did for medicine in around 1900 when he tore down the outworn and deceptive strictures of 19th century medicine. He had to throw out the old ideas to move medicine forward. At long, long, last psychiatry, and neurology, are ready to be refactored.

The battle may rage for years, but the war is done. It's just mopping up now.

Now we can move forward.

[1] Greene's Explosive Child, by the way, led the way in 2005 by setting aside non-useful ICD-9 and DSM classifications in favor of a label that tied symptoms to effective management.

Brain scans for autism diagnosis - a lesson in press interpretation

There will probably be some discussion about a diagnostic test for autism that sounds very accurate ...

[citation needed] - trouble with biomarkers and press releases

... The latest issue of the Journal of Neuroscience contains an interesting article by Ecker et al in which the authors attempted to classify people with autism spectrum disorder (ASD) and health controls based on their brain anatomy, and report achieving “a sensitivity and specificity of up to 90% and 80%, respectively...

It's being marketed as a screening test for autism.

Not.

In a technical but very well written post Tal Yarkoni adds to a takedown by Carl Henegan writing for the Guardian (he's Director of the Center for Evidence Based Medicine at Oxford). Briefly, it's interesting science, but the spin is a load of hooey.

Yarkoni and Henegan walk through the basic statistics of pre-test and post-test probability. I say "basic" because the math is high school, but there's nothing simple about the underlying concepts. Most physicians learn them for an epi exam, and forget them within a week. The true summary of the research is "The method relies on structural (MRI) brain scans and has an accuracy rate approaching that of conventional clinical diagnosis."

So, no, it won't be useful for screening any time soon. On the other hand, it might be a big help in understanding many brain disorders, and even in redefining the classification of developmental disorders of the brain.

The end of autism

No, the problems of suboptimal neurodevelopment are not going away. The concept of "autism" has lasted longer than I'd expected, but the assault continues ...

Syndromic autism: causes and pathogenetic pathways. [World J Pediatr. 2009] - PubMed result

... Genetic syndromes, defined mutations, and metabolic diseases account for less than 20% of autistic patients. Alterations of the neocortical excitatory/inhibitory balance and perturbations of interneurons' development represent the most probable pathogenetic mechanisms underlying the autistic phenotype in fragile X syndrome and tuberous sclerosis complex. Chromosomal abnormalities and potential candidate genes are strongly implicated in the disruption of neural connections, brain growth and synaptic/dendritic morphology. Metabolic and mitochondrial defects may have toxic effects on the brain cells, causing neuronal loss and altered modulation of neurotransmission systems...

Of course even if we abandon use of the term "autism" in quality clinical care and research it will remain tightly bound to service delivery. It will take decades to remove the concept from legal, reimbursement, educational and policy frameworks - and the slow, ponderous, archaic evolution of the DSM "classification" will keep it in psychiatry texts.

Autism will be preceded, I hope, with the end of "Asperger's" - at least in scientific writing. "Asperger's" will join "the planet Pluto" in the netherworld of meaningless terms. Within 10 years "autism" should also be replaced with a classification of neurodevelopmental disorders (the neuroconnectopathies?)

It's not mere pedantics. Names are powerful. Names determine how we interpret research results, how we predict outcomes, and, above all, how we decide which therapies to try first, and how we assign services and support. More precise names for the the complex mix of neurologic injury and repair we currently call "autism" will mean less time wasted on ineffective treatments, quicker use of what works, better targeted research, and more creative thinking.

See also:

• Be the Best You can Be: diagnostic definition
• Be the Best You can Be: Controlling nerve cell connectivity - more developments
• Autism turns into Asperger's - how did that happen?
• Be the Best You can Be: Autism: the label given to a wide and diverse variety of neurodevelopmental disorders (May 2007)
• Be the Best You can Be: Autism no more -- the end of a diagnosis (Dec 2006)
• Be the Best You can Be: Psychiatric diagnoses: 200 years behind
• Be the Best You can Be: Very annoying: the diagnostic criteria for Asperger's are not all that useful (2005)
• Be the Best You can Be: A breakthrough in understanding the genetics of schizophrenia -- and perhaps of autism too

Brain changes related to intense remedial reading programs

Remedial reading programs are common - but I don't think there as intensive as this paper published in Neuron ...

White Matter and Reading in Children - Health Blog - WSJ

... Researchers found that kids who were weak readers fared poorly on a common measure of white matter in a key region of the brain. But after 100 hours of intensive reading instruction, the kids showed significant improvement in white matter (and in reading). Similar children who didn’t get the intensive instruction didn’t show improvement. The study included 47 weak readers and 25 strong readers, and the kids were between ages 8 and 12...

The abstract doesn't tell us much about the reading program, and the full text article is not freely available at this time. I'd love to know what program they used.

Scientific American goes nuclear on Ritalin

Edmund Higgins, a clinical associate professor [1], has written a blistering attack on Ritalin, and gotten it published in Scientific American – a magazine that’s presumably sharing the industry’s revenue problems.

Dr. Higgins compares Ritalin (methylphenidate) to methamphetamine. This is the rhetorical equivalent of comparing a human to Hitler; it’s chemically correct but it’s the mark of a crank. It’s a Godwin’s Law violation.

On the other hand, as someone who’s child has been on Ritalin and other ADHD meds for years, I’ve long had the same sort of concerns. Ritalin has an astounding safety record, but we’re messing with the neurochemistry of a rapidly evolving brain over a period of years and decades. I personally wouldn’t use this, or any other, long-term psychiatric medication medication in my child unless all other options had been exhausted and the disability and risks of non-treatment were severe. I’ve previously made the comparison to treating cancer. Nobody should expose a child to life threatening chemicals with severe long term effects– unless the alternative is worse.

Another point in Higgins favor is his interest in animal models. Given the immense difficulty of studying psychiatric medications in children, animal models are pretty much all we’ve got. So let’s see what he says about the animal models, stripping out some inflammatory rhetoric and considering only studies of meds used to treat ADHD. Note that much of this research is more recent that a 2006 review of mine that was pretty reassuring, but that means it won’t have been validated by other researchers …

Do ADHD Drugs Take a Toll on the Brain?: Scientific American

Edmund S. Higgins is clinical associate professor of family medicine and psychiatry at the Medical University of South Carolina and co-author, with Mark S. George, of The Neuroscience of Clinical Psychiatry (Lippincott Williams & Wilkins, 2007) and Brain Stimulation Therapies for Clinicians (American Psychiatric Publishing, 2009).

… In an experiment published in 2003 psychiatrist Eric Nestler of the University of Texas Southwestern Medical Center and his colleagues injected juvenile rats twice a day with a low dose of methylphenidate similar to that prescribed for children with ADHD. When the rats became adults, the scientists observed the rodents’ responses to various emotional stimuli. The rodents that had received methylphenidate were significantly less responsive to natural rewards such as sugar, sex, and fun, novel environments than were untreated rats, suggesting that the drug-exposed animals find such stimuli less pleasurable. In addition, the stimulants apparently made the rats more sensitive to stressful situations such as being forced to swim inside a large tube. Similarly, in the same year psychiatrist William Carlezon of Harvard Medical School and his colleagues reported that methylphenidate-treated preadolescent rats displayed a muted response to a cocaine reward as adults as well as unusual apathy in a forced-swim test, a sign of depression.

In 2008 psychopharmacologist Leandro F. Vendruscolo and his co-workers at Federal University of Santa Catarina in Brazil echoed these results using spontaneously hypertensive rats, which—like children with ADHD—sometimes show attention deficits, hyperactivity and motor impulsiveness. The researchers injected these young rats with methylphenidate for 16 days at doses approximating those used to treat ADHD in young people. Four weeks later, when the rats were young adults, those that had been exposed to methylphenidate were unusually anxious: they avoided traversing the central area of an open, novel space more so than did rats not exposed to methylphenidate. Adverse effects of this stimulant, the authors speculate, could contribute to the high rates of anxiety disorders among ADHD patients…

… In February 2009 neuroscientists Yong Kim and Paul Greengard … injected … mice with either methylphenidate or cocaine daily for two weeks. Both treatments increased the density of tiny extensions called spines at the ends of neurons bearing dopamine receptors in the rodent nucleus accumbens. Compared with cocaine, methylphenidate had a somewhat more localized influence; it also had more power over longer spines and less effect on shorter ones…

Furthermore, the scientists found that methylphenidate boosted the amount of a protein called ΔFosB, which turns genes on and off, even more than cocaine did…

So when I strip out everything else, the bulk of Higgins’ article is coming from 3 animal studies in 2003, 2008, and 2009. All of the studies involved injecting methylphenidate, which is not how it’s used in humans. Injecting Ritalin is a mark of abuse with pretty different pharmacology from oral use.

The most interesting of these articles is Nestler et al in 2003 [2], an article with a rather strange title (emphases mine – incidentally, Nesler is the last listed author, so why did Higgins credit the study to him?) …

Methylphenidate treatment during pre- and periadolescence alters behavioral responses to emotional stimuli at adulthood.

Bolaños CA, Barrot M, Berton O, Wallace-Black D, Nestler EJ.
Department of Psychiatry and Center for Basic Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, USA.
Biol Psychiatry. 2003 Dec 15;54(12):1317-29.

BACKGROUND: Methylphenidate (MPH) is a psychomotor stimulant medication widely used for the treatment of attention-deficit/hyperactivity disorder (ADHD). Given the extent of prescribed use of MPH, and because MPH interacts with the same brain pathways activated by drugs of abuse, most research has focused on assessing MPH's potential to alter an individual's risk for adult drug addiction. Data examining other potential long-term behavioral consequences of early MPH administration are lacking, however. METHODS: We investigated the long-term behavioral consequences of chronic administration of MPH (2.0 mg/kg) during pre- and periadolescent development in adult rats by assessing their behavioral reactivity to a variety of emotional stimuli.
RESULTS: The MPH-treated animals were significantly less responsive to natural rewards such as sucrose, novelty-induced activity, and sex compared with vehicle-treated control animals. In contrast, MPH-treated animals were significantly more sensitive to stressful situations, showed increased anxiety-like behaviors, and had enhanced plasma levels of corticosterone.
CONCLUSIONS: Chronic exposure to MPH during development leads to decreased sensitivity to rewarding stimuli and results in enhanced responsivity to aversive situations. These results highlight the need for further research to improve understanding of the effects of stimulants on the developing nervous system and the potential enduring effects resulting from early-life drug exposure.

Why did I say that was a “strange title”? Because an article on rats in a journal called Biol Pyschiatry would normally contain the word rats in the title.

If we simply scaled the dose to humans, but the way, this would be 80 mg (twice daily?!) by injection – which would be a whopping abuse dose in humans. The article has gotten very little attention in the past six years, being cited only four times of which two appear to be reviews.

A related articles query produced a very large number of similar rat studies, including one that, surprisingly, found no effects (surprisingly, because these look like “fishing expedition” studies, when you include publication bias they almost always show some effect.) These are boom times for rat studies of methylphenidate, probably reflecting new NIH funding.

On review I’m left with several only mildly related conclusions …

1. I’m happy the animal studies are being done. I’d like to see fewer fishing expeditions, and more replication of results. For example, repeat the Bolanos study with a larger group, maybe a different clonal line, and see if the same results appear. These need to be registered studies, so we don’t get messed up by publication bias (which is a huge problem in the low cost animal studies domain). I would really like to see more studies of tolerance effects in rats.
2. Higgins may turn out to be correct (lots of people are suspicious that stimulants can be used so long, including me) but I think he’s got a crank agenda. His article is more inflammatory than the evidence supports. A more sober article would have been welcome.
3. You shouldn’t put children on psychoactive medications without a very good reason. Of course that was always true.
4. Don’t assume any other medications are in any way safer – Ritalin has been studied far more than, say, Stratera.
5. Scientific American is running out of money. We’ll know they’ve hit rock bottom when they do an article on the scientific evidence for Creationism. They should have known better than to publish this article in its current form.

[1] I have a similar sort of title today, and have had similar roles in the past. In the hierarchy of academia, this title carries less glory than research assistant.

[2] Parenthetically, why does PubMed make it so very hard to find the link to a citation? It’s like they’re trying to hide things.

Autism and savant syndrome

Shortly after reading of an obsessive audiophile savant (definitely spectrum) I came across an Economist article exploring an old theme -- exceptional abilities in atypical minds...

The link between autism and extraordinary ability | Genius locus | The Economist

... A link between artistic genius on the one hand and schizophrenia and manic-depression on the other, is widely debated. However another link, between savant syndrome and autism, is well established...

A study published this week by Patricia Howlin of King’s College, London, reinforces this point. It suggests that as many as 30% of autistic people have some sort of savant-like capability in areas such as calculation or music. Moreover, it is widely acknowledged that some of the symptoms associated with autism, including poor communication skills and an obsession with detail, are also exhibited by many creative types, particularly in the fields of science, engineering, music, drawing and painting. Indeed, there is now a cottage industry in re-interpreting the lives of geniuses in the context of suggestions that they might belong, or have belonged, on the “autistic spectrum”, as the range of syndromes that include autistic symptoms is now dubbed...

... A standard diagnosis of autism requires three things to be present in an individual. Two of these three, impairments in social interaction and in communication with other people ... The third criterion, however, is that a person has what are known as restrictive and repetitive behaviours and interests, or RRBI, in the jargon.

Until recently, the feeling among many researchers was that the first two features were crucial to someone becoming a savant. The idea was that mental resources which would have been used for interaction and communication could be redeployed to develop expertise in some arbitrary task. Now, though, that consensus is shifting. Several of the volume’s authors argue that it is the third feature, RRBI, that permits people to become savants.

Francesca Happé of King’s College, London, is one of them. As she observes, obsessional interests and repetitive behaviours would allow someone to practice, albeit inadvertently, whichever skill they were obsessed by. Malcolm Gladwell, in a book called “Outliers” which collated research done on outstanding people, suggested that anyone could become an expert in anything by practising for 10,000 hours. It would not be hard for an autistic individual to clock up that level of practice for the sort of skills, such as mathematical puzzles, that many neurotypicals would rapidly give up on.

... Dr Happé has drawn on a study of almost 13,000 individual twins to show that childhood talent in fields such as music and art is often associated with RRBIs, even in those who are not diagnosed as classically autistic. She speculates that the abilities of savants in areas that neurotypicals tend to find pointless or boring may result from an ability to see differences where a neurotypical would see only similarities...

Simon Baron-Cohen, a doyen of the field who works at Cambridge University, draws similar conclusions. He suggests the secret of becoming a savant is “hyper-systematising and hyper-attention to detail”. But he adds sensory hypersensitivity to the list. His team have shown one example of this using what is known as the Freiburg visual acuity and contrast test, which asks people to identify the gap in a letter “c” presented in four different orientations. Those on the autistic spectrum do significantly better at this than do neurotypicals...

... The question of how the autistic brain differs physically from that of neurotypicals was addressed by Manuel Casanova of the University of Louisville, in Kentucky. Dr Casanova has spent many years dissecting both. His conclusion is that the main difference is in the structure of the small columns of nerve cells that are packed together to form the cerebral cortex. The cortical columns of those on the autistic spectrum are narrower than those of neurotypicals, and their cells are organised differently.

The upshot of these differences is that the columns in an autistic brain seem to be more connected than normal with their close neighbours, and less connected with their distant ones...

... Dr Snyder argues that savant skills are latent in everyone, but that access to them is inhibited in non-savants by other neurological processes. He is able to remove this inhibition using a technique called repetitive transcranial magnetic stimulation.

Applying a magnetic field to part of the brain disrupts the electrical activity of the nerve cells for a few seconds. Applying such a field repeatedly can have effects that last for an hour or so. The technique has been approved for the treatment of depression, and is being tested against several other conditions, including Parkinson’s disease and migraines. Dr Snyder, however, has found that stimulating an area called the left anterior temporal lobe improves people’s ability to draw things like animals and faces from memory. It helps them, too, with other tasks savants do famously well—proofreading, for example, and estimating the number of objects in a large group, such as a pile of match sticks. It also reduces “false” memories (savants tend to remember things literally, rather than constructing a mnemonic narrative and remembering that)...

... Savant syndrome, then, is a case where the politically correct euphemism “differently abled” has real meaning. The conclusion that should be drawn, perhaps, is not that neurotypicals should attempt to ape savants, but that savants—even those who are not geniuses—should be welcomed for what they are, and found a more honoured place in society.

The original article is "young and smart" smarmy, but I've excerpted the worst of the tangents. What's left is a compilation of interesting anecdotes.

I don't believe that 30% of autistic persons have "savant abilities". I suspect the journalist just got this wrong, perhaps the study group was made up of high IQ autistic adults. In that group I can imagine the 30% figure is real.

On the other hand I know a boy with a low IQ who has savant-like abilities to identify persons of interest in very large crowds. I keep trying to come up with a business use of his odd talent, but it sure comes in handy finding his prone-to-wander sibling.

In the end there aren't a lot of practical tips from the article, but it reminds us of the extraordinary diversity of mind concealed by our similar bodies. We're still far from understanding all the variations that shade between disability and selective ability, and how these minds develop from childhood through adulthood.

Schizophrenia and autism: the connectopathies?

For the past few years we've been thinking about developmental disorders of cognition, such as "schizophrenia" and "autism", as being fundamentally wiring disorders.

So very different conditions, but both arising from disordered development of neuronal connectivity.

It's not exactly a new idea. I recall the insult "wired wrong" from 40 years ago. It may turn out to be quite wrong, and it's unlikely to have clinical implications for years, but it's still worth tracking (emphases mine) ...

Finding out how the brain is wired | Wired | The Economist

.... Dr Lichtman’s work is the most famous example of the emerging science of connectomics. But it is not the only one. For, just as every organism has a genome (the complete set of its genes, as encoded in its DNA), every organism with a nervous system has a connectome (the complete set of its nerve cells and the connections between them). In practice, of course, a connectome will change over the course of time as new connections form and old ones die. But that does not stop people like Dr Lichtman dreaming of a Human Connectome Project inspired by the success of the Human Genome Project....

...The cerebral cortex—the part of a mammal’s brain that thinks—is composed of 2mm-long units called cortical columns. Winfried Denk of the Max Planck Institute for Medical Research in Heidelberg, Germany, estimates that it would take a graduate student (the workhorse of all academic laboratories) about 130,000 years to reconstruct the circuitry of such a column. But efforts to automate the process are gaining ground.

... The result of all this effort, it is hoped, will be precise circuit-diagrams of brains. The first brains to be mapped will probably have belonged to mice. Besides being cheap and disposable, a mouse brain weighs half a gram and packs a mere 16m neurons. Human brains (1.4kg and 100 billion neurons) will come later, when all the wrinkles have been ironed out in rodents, and proper methods devised to analyse the results. But come they will. And when they do, the most complicated object in the known universe will begin to give up the secrets of how it really works.

Violence and the natural history of Autism - so what do we know?

Ann Bauer has written four stories about her son Andrew

• July 2005: He's been doing well from age 12 to 17.
• May 2007: Andrew is 19. She tells us that he was misdiagnosed with schizophrenia, and that antipsychotic medications made him violent
• Mar 2008: She’s struggling, and still feels that the antipsychotic medications are responsible for Andrew’s worsening condition.
• Mar 2009: Andrew is dangerously violent, and his mother can’t get help in an emergency.

From Mar of 2009 (emphases mine) …

Ann Bauer on autism, violence | Salon Life

... Andrew started life as a mostly typical child. But at 3 and a half he become remote and perseverative, sitting in a corner and staring at his own splayed hand. Eventually he was diagnosed with high-functioning autism, a label that seemed to explain everything from his calendar memory and social isolation to his normal IQ.

We got him into a good program and there was a brief, halcyon phase of near normalcy … from ages 12 to 17… I occasionally even referred to him as "cured."

But in the months before turning 18, Andrew grew depressed and bitter. Huge and hairy -- a young man who grows a beard by twilight -- he suddenly became as withdrawn as he'd been at 4. Many of his old symptoms returned: the rocking and "stimming" (e.g., blinking rapidly at lights), the compulsion to empty bottles of liquid soap. Sometimes he would freeze, like a statue. Classic catatonia, the experts told us...

… When Andrew finally landed at the county hospital, after 10 hours in the circling ambulance and another three in the E.R., I was still looking for a different answer. This wasn't autism. Surely he had a brain tumor, a seizure disorder, or a delusional condition such as schizophrenia. Maybe, on one of his crime sprees, he'd gotten ahold of some PCP.

But the psychiatrist assigned to my son said no. The MRI was clean; the EEG normal. The doctor's specialty happened to be schizophrenia, and he saw none of the signs. Street drugs would have left Andrew's body by now. This was isolation, frustration, hormonal surges, poor impulse control and hopelessness. It was adult autism, the psychiatrist told me: one awful direction it can take…

So what's going on here? What does this mean for parents of children who carry the label “autism”?

Not to much by itself. Andrew’s tragedy is one of hundreds of thousands of stories. It defines boundaries, but how typical is this path?

Well, for that we’d like to have some medical research. Like being the operative word …

Let’s start with the phrase “adult autism”, the term Andrew’s psychiatrist is said to have used. There are thousands of medical articles on DNA findings in autism, but only 7 hits on “adult autism” of which only a Japanese study is mildly interesting.

Okay, so what about a search on “natural history”, the medical term for studies of the progression of a disorder?

Those results are little better. With a few minutes of work I found seven articles over about 40 years in Japan, the US, Sweden, and Turkey. That’s not the same as "seven research studies'”, this set includes at least four reviews! …

• Freeman et al, 1991 – 62 patients studied over 12 years. The abstract isn’t very useful.
• Shirataki et al, 1984 – “… poor outcomes might be due to the particular situation in Japan throughout this study period…”
• Kobayashi et al, 1992. Sort of a f/u to Shirataki, also Japanese. “Although 31.5% had shown marked deterioration during adolescence, 43.2% had shown marked improvement during that period. Possible factors contributing to these results are discussed.”
• Rutter 1970 – Infancy to Adulthood. No abstract, this is too long ago to have one.
• DeMyer et al 1973 – Another one too far back to have an abstract.
• Nordin et al, 1998 – See below
• Korkmaz 2000 – See below

Two of the reviews sounded like they might be worth digging into …

Korkmaz 2000 (Turkey, review) … a gradual overall symptomatic improvement including an increase in adaptive skills is observed in most cases with age. Follow-up studies show that the diagnostic features, the differential diagnosis, and clinical problems of adult autistics differ substantially from that of autistic children… Depression, epilepsy, and behavioral problems such as aggression and agitation may be major clinical problems during adolescence…

Nordin et al, 1998 (Sweden, review) … The majority of children with autism show deviance and socially or psychiatrically handicapping conditions throughout life. Only a small proportion of those with classical childhood autism lead independent adult lives. Others, particularly those with 'high-functioning' autism and so-called Asperger syndrome will improve enough to live an independent adult life. The level of mental retardation and other comorbid conditions (such as medical syndromes and other neuropsychiatric disorders, including epilepsy) is important in predicting outcome…There is a continued need for prospective, longitudinal studies of children with autism spectrum disorders, particularly in Asperger syndrome. The role of interventions of various kinds needs to be addressed in such studies.

So over 40 years of “research” on autism, and millions of dollars in NIH money, we have a handful of studies of small numbers of people and a few review articles.

This is pathetic, especially when we think of all the money we’ve wasted on vaccine distractions. In a just world the last five directors of the National Institutes of Mental Health would be grilled by a rabid Congressional subcommittee. What the heck have they been spending their money on?

To underscore just how bad the research record is, the lay literature is competitive. Send in the Idiots traces five people’s story from childhood to adulthood; in this context it qualifies as qualitative research.

So what can we say from Andrew’s story, other than that there’s a hell of a lot of suffering in this world?

Not much. In 2009 we know about as much about developmental brain disorders as 19th century physicians knew about fluid balance. In those days doctors couldn’t meaningfully distinguish right sided heart failure from renal failure from venous insufficiency from lymphedema. We didn’t make much progress until new instruments (the stethoscope for one) and new thinkers (William Osler) tore up the old classifications and started over with careful observation.

Today, 100 years after Osler, we seem to have forgotten how to observe the natural history of disorders we don’t understand.

With autism and other disorders of brain development, we need to start over with new diagnostic definitions, new qualitative research, and new retrospective and prospective studies of the course of the disorder. We’ve screwed around long enough.

Oh, and fire the Director of the NIMH ok?

Update 3/27/09: After sleeping on this, and thinking how incredibly hard it is to do natural history studies on this particular topic, I decided to give the current and former NIMH directors a break. So maybe time outs rather than termination. Our knowledge is so incredibly limited, however, that it would be well worthwhile to qualitatively profile four or five hundred adults with a history of childhood autism or Asperger's. Forget representative selection, just find whoever we can get and do the interviews. That's a study we could do and fund this year, and I'm confident it would tell us a lot. It would also make it impossible to ingore the depth of our ignorance.

I have two additional comments on the specific story of Andrew. One is that, if he can be restrained from harming himself or others, the future need not be hopeless. We all know of schizophrenics who, with medication and time, improved considerably.

Secondly, if the description we've been given is reasonably accurate, I believe a thoughtful psychiatrist would delcline to place Andrew in any pre-established diagnostic category -- neither schizophrenia nor autism nor anything else. So there is no ability to predict outcomes, and all treatment will be empirical.

Vaccines and autism - a fraud from day one?

My distress at the Autism Society of America's vaccine obsession doesn't mean that it was necessarily always a bad idea to look for a link between immunization and autism. A legitimate study showing a correlation would deserve investigation, and when the correlation was disproved it would then be appropriate to move on (years ago, in this case).

Happens all the time. That's science.

But what if there never was a correlation to begin with? That would be one of the most harmful cases of scientific fraud in the past fifty years (emphases mine) ...

Aetiology: Vaccines and autism--can we stick a fork in it now, please?

Last fall, I wrote about a new research paper which tried to replicate some of Andrew Wakefield's original results, which not only claimed a correlation between MMR vaccination and autism, but also the presence of measles virus in intestinal tissue. Wakefield had suggested that an inappropriate response to the presence of measles virus in this tissue may trigger conditions such as bowel disease and autism. The more recent study was unable to replicate any of Wakefield's findings--not surprising, since so many papers in the last decade have found no connection between vaccination and autism.

There are plenty of reasons why the study may not have been replicated. The design of the new study was a bit different from Wakefield's (case-control versus a case series); it had larger numbers; investigators were blinded to the status of the patients and so less likely to bring in bias. However, a recent investigation by the Sunday Times (London) has another reason why the results of the two papers differ: Wakefield made up his data. More after the jump...

From the Times Online:

Confidential medical documents and interviews with witnesses have established that Andrew Wakefield manipulated patients' data, which triggered fears that the MMR triple vaccine to protect against measles, mumps and rubella was linked to the condition.

The research was published in February 1998 in an article in The Lancet medical journal. It claimed that the families of eight out of 12 children attending a routine clinic at the hospital had blamed MMR for their autism, and said that problems came on within days of the jab. The team also claimed to have discovered a new inflammatory bowel disease underlying the children's conditions.

However, our investigation, confirmed by evidence presented to the General Medical Council (GMC), reveals that: In most of the 12 cases, the children's ailments as described in The Lancet were different from their hospital and GP records. Although the research paper claimed that problems came on within days of the jab, in only one case did medical records suggest this was true, and in many of the cases medical concerns had been raised before the children were vaccinated. Hospital pathologists, looking for inflammatory bowel disease, reported in the majority of cases that the gut was normal. This was then reviewed and the Lancet paper showed them as abnormal.

This is truly incredible. Even being familiar with Wakefield's statements over the past decade about his research, and his complete denial about studies that have contradicted his own findings, it's still pretty shocking that he completely made up data, and then pushed it for ten years as children around the world became ill and even died in light of his research. It's even more disgusting in light of the fact that I doubt this new information will change many minds when it comes to vaccination--the meme has already spread too far to let a little thing like atrocious scientific misconduct rein it in now.

Wakefield's original Lancet coauthors retracted their interpretation of the data in 2004. The wikipedia article on Wakefield (reads like it's in an edit war) says his research misconduct trial was to commence a year ago, but it seems like this Feb release from the Times of London is the most definitive response thus far.

If the charges are corect, then was Wakefield delusional himself, or is he a sociopath? I'm hoping the former, it's not all that rare in science, but given his subsequent career I fear the latter.

Update 2/9/09: Excellent summary of reactions to the Times article. I scanned some of the skeptics responses, and this is also a list of interesting blogs to consider reading.

Autism Society of America has lost our donations – anti-Vaccine madness

The ASA has turned from the best available science. There are no roads on the trackless wasteland they’re traveling now (emphases mine) …

Autism Society of America: research_envirohealth_vaccines

Individuals living with autism need help today. There is a clear and present need for the government, scientific, medical and autism communities to probe further into all possible environmental causes of autism spectrum disorders (ASD) in a fair, unbiased and thorough way, particularly because findings may help us approach treatment and prevention more effectively. Research needs include, but are not limited to, research into the causal or contributory relationship to autism that may be attributed to thimerosal containing vaccines (TCV’s), the measles-mumps-rubella (MMR) inoculation and/or a combination of the two. The interaction of these vaccines with other potentially contributory environmental factors and vulnerabilities also needs serious investigation.

ASA strongly believes that:

1. Vaccines administered to children, teens and adults must be safe;
2. More unbiased and credible research needs to be done to:
   1. ensure and optimize safety,
   2. identify those who are at higher risk of injury and develop and implement appropriate accommodations for them,
   3. avoid injury altogether, and
   4. prevent unnecessary overexposure;
3. All those who are vaccine injured need to be justly compensated;
4. Development and availability of treatment for injuries from environmental factors, including but not limited to vaccines, needs to be prioritized.

Madness.

This is worse than a distraction from understanding the causes, prevention, treatment and management of the range of cognitive disorders we currently label as “autism”, it is going to cause harm to children and families by reducing immunization levels.

Science is never perfect, but it has a vastly better track record than the alternative. It’s an imperfect guide, but it’s the best guide we have. The science is as clear as it gets on thimerosal and MMR vaccination – they don’t make significant contributions to autism. We need to look elsewhere to understand the genetic and environmental interactions that alter brain development.

The ASA has done good things, but we can’t send them financial donations knowing that they going to use our contributions to, unwittingly, cause great harm.

This is a shame.

Update: The Executive Director of Autism Speaks has resigned over their anti-vaccination obsession.

Update 10/16/09: See also Jim Carrey - enemy of the enlightenment

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.

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.

Controlling nerve cell connectivity - more developments

A day or two ago my post on Fragile X and autism research included a discussion of a general theme in current autism research ...

... Bear and other scientists have also identified several drugs that seem to correct the problem. The drugs don't replace the missing brakes in the brain. Instead, they limit acceleration by reducing the activity of a group of receptors on brain cells known as mGluR5 receptors.

The drugs have reversed most of the effects of Fragile X in mice. They are now being tried in humans. And at least one small study found that a single dose of a drug had an effect....

The idea is that neuronal connectivity is a delicate, dynamic, balance. Too much connectivity, or too little, can both prevent cognition from working correctly.

So now there's research on modulating neuronal interconnectivity. If they worked safely these drugs would inevitably be used on "normal" brains, probably illegally, but they could be of enormous benefit to persons with impaired cognition.

Note in this review the implication that autism and schizophrenia may be, in a simplistic sense, two sides of one coin.

A Switch to Turn Off Autism?: Scientific American

Scientists say they have pinpointed a gene in the brain that can calm nerve cells that become too jumpy, potentially paving the way for new therapies to treat autism and other neurological disorders...

... The brain is continually trying to strike a balance between too much and too little nerve cell activity. Neurologists believe that when the balance tips, disorders such as autism and schizophrenia may occur. They are not sure why neurons (nerve cells) go berserk. But Greenberg says he and his colleagues located a gene in mice and rats that helps keep neural activity in check—and may one day be manipulated to prevent or reverse neurological problems.

Researchers report in Nature that they discovered a gene called Npas4 churns out a protein that keeps neurons from becoming overexcited when they fire (communicate with one another through connections known as synapses). When scientists blocked the protein, the nerve cells fired or sent out more signals than normal; when they beefed up production, the neurons quieted down...

As scientists learn more about how brain cells stay balanced, Greenberg says they will be able to identify people who are genetically at risk for neurological disorders and develop new drugs to prevent and treat them. He notes that some of the other genes that Npas4 affects also have been linked to autism...

Drugs to treat these disorders are years away from common use -- if ever. In the near term understanding the protein products of these genes may help us better classify and organize brain disorders, though we can also expect that prenatal testing will lead to more abortions.

These developments may also increase the value of doing genetic testing on persons with cognitive disorders, so that if appropriate trials are available one might, very carefully, consider enrolling.