Lamotrigine off label

"Scientists switch off autism using lamotrigine" ... well, "Lamotrigine normalized not only the network hyperactivity ... but also several behavioural hyperactivity phenotypes observed in mice."

If researchers mutate MYT1L in mice, they show behaviors like those of humans with autism. Maybe the mechanism is the same in humans, though "the genetic heterogeneity of ASD is enormous, and multiple transcriptional regulators have recently been associated with this group of disorders." as the paper says. The paper is about some mechanisms that might play a role and the effects of lamotrigine on them. If this has similar effects on humans, and if there aren't any unhappy side effects (lots of luck there), and if this represents the important part of the autism impact on humans, and if this works for more than one variety of autism, we've got some interesting progress. But not a "switch".

I suppose it is hopelessly naive to expect headline writers to try to get the facts right.

It is not something I'd try to monkey with, even if lamotrigine were readily available.

hyperbaric therapy

I hadn't heard this before. hyperbaric treatment for autism. Seems odd--

One of the well-defined deficits in brain physiology related to ASD is hypoperfusion [15,22] and the consequence of cerebral hypoxia. Based on this physiological deficit, hyperbaric oxygen therapy (HBOT) has the potential to be a beneficial and appropriate treatment to alleviate hypoperfusion [23] and thus improve brain functionality and behavioral outcomes.

After an anecdotal treatment of a girl whose parents claimed improvement ("these aspects were not measured quantitatively and are not presented"), the team picked mice with a genetic defect like that related to autism in humans and

"1-month-old mice for 40 sessions for 2 months, 5 days a week, 1 h a day. A total of 30 mice were divided into 4 groups: ... The HBOT group received 100% oxygen gas in 2 ATA pressure levels, while the placebo group received air (containing 21% oxygen) with 1 ATA pressure levels. ... All mice survived the procedures with no indications of irregular behavior or discomfort."

They see some improvement in their tests for mouse "social and novelty" behavior. I'm a little less sanguine, but it looks like it might be promising. And, of course, there look (to my eye) to be various causes of ASD, so there might not be a single treatment. A larger study is probably in order, and some attempt to see how long effects last.

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UPDATE: Before you try "do it yourself", recall that every treatment has risks.

Touch and autism

Lots of folks on the autism spectrum are uncomfortable with touching (bundling tightly is a different kind of sensation), and a Flemish group had a look at one aspect of touching: namely the difference between what you expect to touch when you grasp someone and what extra sensations you feel. They used hands and touched different fingers. (If I poke something with my index finger, I don't expect sensation on my pinky, and interpret that as whoever-it-is touching back.)

OK, interesting idea. They see a difference in reaction. It's a small study, and I wasn't overwhelmed with the differences, but maybe they're onto a connection there.

Aspergers and emotions

I read the NYT review of Switched On the other day, and didn't quite know what to make of it. John Robison underwent "transcranial magnetic stimulation" to see if that would have any effect on his Aspergers. Apparently it did, and the book is a description.

I'd like to know more, and am on the on-hold list at the library. A few questions come to mind after reading the review.

• What exactly is this supposed to be doing?
• What exactly became of the other patients and why is he different?
• Did his newfound emotions map correctly onto what they were supposed to? He said that most people seemed sad to him now--not sure that's an accurate observation.

Anybody know more?

Variants of autism

Some researchers are using genetic analysis to find out what the different kinds of autism come from. That there are different kinds seems almost obvious if you hang around with a number of them (e.g. the AUsome Social Group, though you could argue that the main effect is from one broken gene and the variations come from other broken genes. (Simplifying a bit) But their work suggests that there are different mutations, each of which can cause symptoms in the autism spectrum.

I hope the work pans out.

Not ready for diagnostic prime time, but interesting.

Is autism diagnosable by fMRI? According to the headline, maybe...but there were 34 (17+17) participants, all adult, all willing to get inside a fMRI machine and be scanned while listening to various words: notably the word "hug".

Whereas the control subjects showed activity in the part of the brain associated with self-representation, the subjects with autism did not. This means that the autistic individuals envisioned the words and actions being told to them (actually they read the words on a screen) without themselves as a participant in defining the scenario, while the control group saw themselves being hugged, complimented, kicked, and insulted when thinking about these concepts.

The article itself is on PLOS.

That there are only 17 neurotypical participants means there is no good estimate for the number of false positives, since autism shows up at the 1% level. And quite a few participants had to be removed from the study:

The data from the 25 excluded participants (12 with autism and 13 controls) had been affected by either excessive (above 3.5 mm) head motion (6 with autism and 3 controls) or lack of attention to the stimulus in a substantial number of trials (6 with autism and 10 controls). Participants in such studies comment that occasionally their mind wanders when processing some items, and we have previously found such inattention to be characterized by an abnormal occipital activation time course.

The effect is certainly dramatic, and it may be real, but this needs a lot more study before we can talk about "diagnosis", especially diagnosis of children young enough that intervention might help. Can you imagine a 2-year old inside a noisy machine lying quietly and listening to Mommy say "hug!"?

The data they are dealing with is somewhat fuzzy, so they use what we call a "neural net" to try to analyze the results. It works something like this: for a given event (a particular patient i, for example), you have several different measurements on channels A, B, C: values A_i, B_i, C_i. If you know in advance that the first 10 events are from bald Martians and the rest are from hairy Venusians, and if you "notice" that in the first 10 cases A_i=B_i but in the rest of them A_i=-B_i, you can generate a "bald Martian" formula (A_i+B_i). When this is 0 you probably have a hairy Venusian, otherwise you have a bald Martian.

The "noticing" is the secret to making the process work. You can use algorithms to combine the data with weights based on the a priori known type of the event, and after a few iterations get a formula (generally linear in the variables) that gives you a kind of probability that a event is one type or the other. There's typically a spectrum, but everybody hopes there will be a nice sharp peak at 1 or 0.

With enough variables you can easily "over train", and the usual procedure is to train on either simulations (risky) or part of the dataset, and then apply the formula to the rest of the data. The experimenters here did something like the latter. If I read the article correctly, they did 34 different neural net training exercises, each time omitting one event and then trying out the resulting formula on the omitted event. They got accurate predictions 33 times out of 34--which is quite good.

"Intense world"

The idea that some autistic behavior is due to hypersensitivity is a little older than the story suggests. Youngest Daughter had "Auditory Training", which seemed to help for a while, but then after a couple of weeks there was no further improvement. (The music in the headphones had random glitches, with the intention of desensitizing the hearer to noise.)

I've met more people on the autism spectrum than average, and am comfortable with the notion that there are many causes--there are certainly many presentations. The causes might hit the same general machinery, though.

If the thesis above is correct, and autistic children have sensory overload with consequent fear and defensive behaviors, then it might, as they also suggest, be possible to reduce its severity with very early intervention. Except that another study suggests that it is hard to distinguish it before about 3 months.

A couple of things don't seem to quite fit their model, though. One is the deficit in "cognitive empathy" (not "affective"--autistic children do like people):

In a now famous experiment, children watched two puppets, “Sally” and “Anne.” Sally has a marble, which she places in a basket and then leaves. While she’s gone, Anne moves Sally’s marble into a box. By age four or five, normal children can predict that Sally will look for the marble in the basket first because she doesn’t know that Anne moved it. But until they are much older, most autistic children say that Sally will look in the box because they know it’s there. While typical children automatically adopt Sally’s point of view and know she was out of the room when Anne hid the marble, autistic children have much more difficulty thinking this way.

The other is: if life is so overwhelming, how can they maintain focus so well? I suppose if it is life or death to learn to focus, you do.

Ancient autism

To a recent post AVI commented that autism didn't seem adaptive, and might be a recent development. I googled around, and in among the fever swamps of the vaccine-autism crowd are some suggestions: This paper suggests (cannot prove, of course) that folktales about changelings might refer to parents dealing with autistic children.

The new child—the changeling—is characterised by unresponsiveness, resistance to physical affection, obstreperousness, inability to express emotion, and unexplained crying and physical changes such as rigidity and deformity. Some are unable to speak.

Sometimes the fairies fancy mortals, and carry them away into their own country, leaving instead some sickly fairy child, or a log of wood so bewitched that it seems to be a mortal pining away, and dying, and being buried. Most commonly they steal children.

The parallels between changeling tales and autism, have been briefly noted by writers on the history of the disorder. Some of the features of these stories, including the initial health and beauty of the human child, the change after some period of “normalcy”, and the specific behaviours of the changeling (listed above) are well matched to symptoms in some presentations of autism.

This site also speculates:

Autism can be equated with the 'blessed Fools’ of old Russia, “who were revered for their unworldiness. The apparent insensitivity to pain, bizarre behaviour, innocence, and lack of social awareness that these “Blessed Fools” showed, suggest that they may have had autism. ” (Happe). Similarly in almost all cultures one can find anecdotes and folktales about foolish boys (note that it is a boy and not a girl as autism has always been more prevalent in boys) who take what their mother said too literally- word for word , rather than figuratively and metaphorically or idiomatically.

And quite a few people noted that in a small rule and role-bound village, Aspergers isn't a great handicap. Maybe things might get awkward at fairs, but most of the time you know your job and you just do it.

I can't see my way to the "autism advantage", but something like Aspergers might be advantageous in the right environment--some modern children with a bent for programming have proved to be quite focused and efficient programmers.

Antibodies and autism

The report studied the possibility that there might be maternal antibodies to brain proteins in the developing baby. (Followed from SciTechDaily) I'm not familiar enough with the methods to decide if their approach is solid, but they do find indications that mothers with certain antibodies mostly have an autistic child. At this point there's not enough known to decide if the antibody reaction causes problems or merely indicates them, nor is this a source of all kinds of autism, but it looks like another part of the puzzle.

Trying to focus on a constellation

Naviaux et al have a paper out on "Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC) Mouse Model", so naturally I was interested. One of the key points is in the introduction, which I reproduce below.

The majority of children with ASD develop disease as the result of interactions between large sets of genes and environmental factors. Common comorbidities in non-single-gene forms of ASD provide important clues to shared mechanisms of disease. Comorbidities include epilepsy [2], GI abnormalities [3], sleep disturbances [2], abnormalities in tryptophan metabolism and platelet hyperserotonemia [4], altered intracellular calcium and mitochondrial dynamics [5], hypoimmunoglobulinemia [6], hyperuricosuria [7], methylation disturbances [8], disturbances in sulfur [9] and glutathione metabolism [10], neuroinflammation [11], cerebellar vermis hypoplasia [12], and Purkinje cell loss [13]. We hypothesized that all of these clinical comorbidities can result from a single, evolutionarily conserved, metabolic state associated with a cellular danger response (CDR). Since mitochondria are located at the hub of the wheel of metabolism and play a central role in non-infectious cellular stress [14], innate immunity [15], inflammasome activation [16], and the stereotyped antiviral response [17], we searched for a signaling system that was both traceable to mitochondria and critical for innate immunity. Purinergic signaling via extracellular nucleotides like ATP and ADP satisfied these requirements. In the following study we tested the role of purinergic signaling in the maternal immune activation mouse model of ASD and show that antipurinergic therapy reverses the abnormalities found in this model.

I left the footnote references in as an aid to counting. That’s quite a constellation of problems, and it would be fascinating, and quite a coup for the authors, if they revolved around a common mechanism.

Their results seemed to show some improvement, but a larger study would be more convincing. One the brighter side, the intervention was at 6 weeks, which is roughly (4-8 weeks) when mice become sexually mature, which suggests that even fairly late intervention might be fruitful. If it all works, of course. We won’t know if this has any bearing on humans for a long time, nor whether this sort of thing addresses the whole constellation.

Still, something to keep an eye on.

Autism "spectrum"

I saw this story "revealing" a link between gut bacteria and autism, and so of course I looked it up. I'd heard the anecdotes about "My son was fine until he got that horrible stomach bug and was never the same afterwards."

Naturally, the real report doesn't "reveal" any such link; though it strongly suggests one: propionic acid (PPA).

Executive Summary: autistic children have mitochondrial disease or some biomarkers compatible with it at a rate higher than the general population. Something like autism can be induced in rats infused with PPA. Surveys of autistic and neurotypical youngsters showed fatty acid concentrations that were abnormal, somewhat (not entirely!--their figure 1 has a logarithmic concentration scale and symmetric error bars? and isn't easy to compare) like that in the rats.

Autistic youth typically seem to have a different mix of gut flora than normal, more of which produce PPA, some of which will presumably go into the bloodstream and help disrupt mitochondrial activity. (BTW, antibiotics change the gut flora mix, apparently increasing the proportion of PPA-makers.)

So, since O(17%) of children with ASD apparently had abnormal mitochondrial fatty-acid metabolism (like those rats with pseudo-autism), and some of them showed no genetic abnormalities to account for it, some subset of autism is possibly due to (internal) environmental disruption of mitochondrial activity.

End Executive Summary.

It isn't clear that this is fixable after the fact, though it would be wonderful if it were (assuming this is actually the issue).

But notice the number 17%. We use the term "autism spectrum" but apparently there are quite a few different genes involved: 15 according to the notes in this paper.

That second paper is worth a look too. The authors looked at copper and zinc levels (copper levels are high in autism spectrum children relative to neurotypical children, zinc levels low in autism and PDD (but not Aspergers). They applied a B6 and zinc supplement therapy, and found changes to more normal levels in autistic and PDD children, and apparent improvement in behavior--but not in Aspergers children. (I didn't see where there was any medium-term follow-through to see if there really was improvement.)

I call this sort of thing evidence that the phrase "autism spectrum" is a misnomer. "Autism constellation" would be a better term, since it looks as though there are multiple causes with similar effects.

Which is kind of discouraging when you want to know "What should I do for my kid?"