Assessment Week at School and Cognitive Enhancement in Autism

 In earlier posts I have touched upon the problems of clinical trials in autism:-

·        Highly subjective, or ineffective, rating scales for autistic behaviours

·        Lack of biomarkers, or any other marker, to target a specific sub-types(phenotypes of autism

·        Very small sample sizes and often amateur execution, meaning the results cannot be replicated

I think one of these problems has a ready solution, at least for verbal primary school children with ASD. 

Assessment Week

Last week, Monty aged 10 with ASD, had assessment week at school.  The academic subjects he participates in, are Maths, English and Science.  We have chosen to skip Geography, History and French.  Monty already has another second language.

Following the tests at school, I decided to make a test of my own.  I stopped all of my therapies and waited to see what would happen and if anyone would notice.

The first therapy I had to reintroduce was bumetanide, which in his case makes him far more aware of himself and his surroundings; it makes him more “present”.  The reason for this was, for the first time in years, on day one, he forgot to go to the toilet and peed in his pants.  A coincidence?  I think not.  Also, when I told him that I was going out, instead of the expected “see you later, Dad” I got “see you Monday”.

Then the next day having restarted bumetanide we drive to school.  I hear lots of relevant comments like “There’s a Peugeot lion taxi car”, “The soldier has a gun, that fires bullets”.  The day before there were no comments at all.

But the day at school was not so good; all the stereotypy with his hands and fingers returned, so while the day was not hard for his assistant, she said it was hard for Monty.  He was commenting, like the things he could see through the window of his classroom, but work was not good.  Handwriting degenerated to oversized sloppy writing, that did not follow the lines on the paper. In the afternoon, I reinstated NAC, just in time for the arrival of his assistant who works with him at home, following an ABA-style programme.  During the rest of the afternoon, all stereotypy with his hands and fingers disappeared, just as expected.

Today, I met the school teacher and not only were his grades As and Bs, but he finished his tests much faster than most of the other children.  This is remarkable, because he has never received any real academic grades before; the teachers did not think it fair to give him grades.  I should point out that Monty is at least 2 years older than his classmates; but then he was pretty much entirely non-verbal until he was 4 years old, so he has lost a lot of learning time.

The relevance of all this is that while psychological and behavioral testing is very subjective, basic cognitive testing, as practiced in schools around the world, is very well understood, fair and easy to replicate.

With children who are verbal, can read a bit, write and do some very basic maths, a simple cognitive test, measuring these basic skills, assessing both  accuracy and speed would produce a pretty good surrogate index of cognitive functioning.  You could easily use such an index to measure the effectiveness of a drug in autism.  If large scale trials were done in Special Schools, this could work really well.  One week the class is on the placebo and the next week on the trial drug.  Then you could have trials with several hundred participants.

I think coming up with measurements for things like “social withdrawal”, as is currently done, is far too esoteric.  Let’s go back to the three Rs (reading, writing and arithmetic).

Nootropic drugs

I find it more than a coincidence that several of the autism drugs I am investigating, happen to be classed as nootropic.  Nootropic drugs are cognitive enhancers.

I have demonstrated that as you improve autism, you increase cognitive function; but perhaps as you improve cognitive function, you improve autism.  If this were true, it would open up new avenues for investigation.

There is an underground scene of cognitive enhancers, and if you probe the internet, you will readily find what works and what does not.

On the serious research front, here is a recent paper that is very comprehensive:-

Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting withTargets other than Receptors or Enzymes. Disease-modifying Drugs

 

 

 

Autism, a Dynamic Encephalopathy, Indeed

 

With a title like that, not many people will stumble upon this post with Google.

So, for the hard-core of readers, today I am going to develop an idea of Martha Herbert, the pediatric neuroscientist from Harvard, who writes a lot about autism.

Incidentally, most researchers do not like publicity, and particularly those looking at autism.  Martha, herself makes some side remarks as to why this is; as I suggested in earlier posts it dates back 10+ years to a certain Dr Wakefield.

“A further barrier to considering the body’s impact on the brain was the reaction to the work of Wakefield, who argued not only that there was a link  between  autism  and  vaccines  but  also  that  this  link was mediated through the gastrointestinal system. For the better part of a decade any attempt to discuss gastrointestinal or immune issues with autism was construed as a support of Wakefield’s vaccine hypothesis, and it was difficult to discuss, let alone get funding for, clinical or research observations about these problems.  One way around the essentially taboo character of somatic problems in autism was to treat them as coincidental symptoms. For example, one could  talk about gut problems provided one made  it clear that they did not cause the autism in the brain. Improvement after treatment of gut problems, which is often observed, would then be explained as a consequence of reduction of pain and discomfort, but not of any direct impact on core brain mechanisms generating autistic behaviors.”

Another fearless autism researcher, not shy to voice his opinions by blog and tweet, is Paul Whiteley, in Sunderland.   Paul is very much a believer in the role the gut/diet in autism, he and Paul Shattock are the driving force behind the gluten and casein free diet as a therapy for autism.  Given what Martha writes above, and the association between Shattock and Wakefield, is it surprising that the GCF diet remains on the fringes?  I know some parents who wholly endorse it.

Here is a link to one of Martha’s recent works, for Herbert fans:-

From Static Genetic Brain Defect to Dynamic Gene- Environment- Modulated Pathophysiology

Dynamic Encephalopathy

It was Martha who called autism a dynamic Encephalopathy.  Encephalopathy just means a brain disease.

What she means is that over time autism changes, day to day and year to year.  Just as during fever, autism symptoms may wane, other environmental provocations may cause flare ups.  With age come hormonal changes that will inevitably change the central hormonal homeostasis, I hope for the better, as generally is the case.

Other than being a fancy word, Encephalopathy, is probably a much better word than autism.  There are many types of Encephalopathy and there are multiple causes, it refers to a syndrome of global brain dysfunction; this syndrome can have many different organic and inorganic causes.  As with autism the hallmark of encephalopathy is an altered mental state.

 
Forget Autism think Encephalopathy

If you have not already opened up Wikipedia, I suggest you do.

http://en.wikipedia.org/wiki/Encephalopathy

From my desk research and primary research, I know that one factor behind this encephalophy is chronic inflammation, otherwise known as neuroinflammation.

At this point, we should look at what neuroscience can tell us about neuroinflammation

The Dana Foundation is a private philanthropic organization committed to advancing brain research.  Founded in 1950 and with $230+ million in assets I think they should be a good source.  Here  is an excellent paper, that is written for non-scientists. 

 Consequences of the Inflamed Brain

Among the many interesting insights are these:- 

 “Until recently the CNS and peripheral immune sys­tem were thought to operate independently.”

“However, new research has led to important advances in our understanding of how immune-related events in the periphery can influence CNS processes, thereby altering cognition, mood, and behavior, and these advances are suggesting that inflammation may have important long term implica­tions for the brain.”

 “Inflammation in the body can lead to inflammation in the brain”

“The same cytokines that participate in produc­ing the inflammatory response in the body also initiate the communication process to the CNS. They accumu­late in the bloodstream and thereby travel to the brain”

“They cross into the brain in regions where the barrier is weak, and they bind to receptors on the insides of the cerebral vascular blood vessels, thereby inducing the production of soluble mediators within the epithelial cells that can cross into the brain.”

“In addition, there are neural as well as blood-borne communication routes. For example, there are cytokine receptors on nerves, such as the vagus, that innervate peripheral immune organs, and these nerves communicate to the brain and are activated during infection.”

“During a normal infection, neuroinflammation and the resulting adaptive sickness behaviors persist only for several days. However, if these responses become exaggerated or prolonged, the outcomes may well become estab­lished, leading to cognitive impairment instead of brief memory disruption,”

 “… physiology can become pathology when a set of processes designed to be rela­tively brief becomes prolonged.”

“However, peripheral inflammation is highly complex and involves many immune cells and their products. Existing anti-inflammatory drugs often target only one of these. For example, non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, inhibit only a hor­mone, prostaglandins, leaving other actors in inflam­mation (cytokines, chemokines, etc.) untouched.”

“A second way that central neuroinflammation could be prolonged is less obvious. The CNS may come to over-respond to the same signal from the peripheral immune system. As noted above, microglia and the cytokines they produce when activated are at the core of the neuroinflammatory response that pro­duces sickness behaviors. If microglia were to become “sensitized,” which means they respond in exagger­ated or prolonged fashion, then sickness behaviors would become intensified and prolonged—pathology instead of physiology.”

“Most encouragingly, studies in numerous animal models show that the development and expression of chronic pain can be blocked with drugs that inhibit either microglial activation within the spinal cord, or the inflammatory cytokines that microglia produce.”

“In addition, microglia also can become sensi­tized without a prolonged peripheral inflammation. For example, aging appears to sensitize microglia so that microglia, particularly in the hippocampus, respond in exaggerated fashion to input. Thus, neuroinflammation produced by surgery, peripheral infection, and the like, is greatly exaggerated in aged subjects. Correspond­ingly, aging also augments the chances of depressive behaviors, cognitive impairments, and pain produced by peripheral inflammatory events. Encouragingly, however, some human studies show that inhibition of microglia and cytokines in the brain blunts such patho­logical outcomes.”

“Blockade of inflammation in the periphery and microglial activation/cytokine action in the CNS, may well become important therapies for a range of disorders not often thought of as mediated by these factors.”

Conclusion

There is nothing new to me in the Dana paper; this in itself is rather a shock.  If you have followed my blog from the start, you should also not be surprised; but I have never seen quite so much scientific good sense written in just four pages.  It tells me a lot and reassures me that I am on the right track with my cytokine blocking therapies, mast cell stabilization and somewhat far fetched, vagus nerve stimmulation ideas.

There are other science-based "inflammation control" therapies and I will be writing about them later.

P.S.  Why no Dean’s List for Martha?

Regular readers of my blog may have noticed that a small number of the several hundred researchers, whose papers are discussed here, are given a pat on the back and moved to the Dean’s List.  Why not Martha?

There is a good reason.  For many years Martha keeps going on about the “Fever Effect” in autism.  This is the strange phenomenon where autistic behaviours abate during fever, i.e. sickness associated with high temperature.  I myself witness this every time Monty, aged 10 with ASD, has a high temperature.  I think that conclusively solving this, might indeed tell us something profound about this wide phenotype of autism.

I think with the resources of Harvard, she should be able to figure this out.  Her TRANSCEND Program gives her a pool of research subjects.

Peter has just one mouse model of autism and, at the age of 10, he is getting a big to be called a mouse.

So Martha, put aside the MRIs and the calcium channelopathies, if you figure it out before me, you get on the Dean’s List.

If I can prove the underlying reason, I will put myself on the Dean’s List.

 

A Hypothesis: Vitamin D, Calcium, Milk, and the Autism Epidemic

by Seth Bittker

My name is Seth Bittker, and I am the father of a boy with ASD.  My son’s development was slow up until about 2 1/2 years of age.  Around this time, his milk consumption increased, and it began crowding out other sources of sustenance.  Within a few months he regressed, and we received an autism diagnosis soon after this.  Stopping his milk consumption was the first step in helping him get better.

Like some other parents of those with ASD children, I noticed that his behavior varies significantly with what he eats.  When he consumes large amounts of calcium fortified foods or beverages, his behavior gets worse: he becomes more autistic in a behavioral sense.  Since milk has a lot of calcium, and calcium fortified foods do as well, it seemed like there might be some connection to calcium and his symptoms.  Later based on a doctor’s recommendation we gave him supplemental vitamin D.  We did not notice much initially, but a few weeks later he developed hives, and he regressed.  Since supplementation with vitamin D increases absorption of calcium, it appeared that the bad reaction to calcium and vitamin D might be connected.  Based on these experiences and others, I eventually inferred that we should keep him on a relatively low-calcium diet and avoid vitamin D supplementation or fortification (milk as well as many other foods in the US are fortified with vitamin D).

I also concluded that my son was different from most others affected with autism as some have suggested that vitamin D deficiency is involved in inducing autism,[1] and he evidently did not have a deficiency based on the vitamin D trial even though vitamin D levels in his blood were relatively low.

But is he really different than others with autism?  If one examines the evidence from a number of genetic syndromes that are comorbid with autism, in many cases the cause is over-active calcium channels (effectively too much intra-cellular calcium).[2]  You can see this by looking at syndromes such as Timothy syndrome, Williams syndrome, and Sotos syndrome, which have high comorbidity with autism and seem to be caused by too much intra-cellular calcium.  In Williams syndrome the connection is through a gene which upregulates vitamin D.[3]  In some of these syndromes is it well known that supplementation with calcium and vitamin D are contraindicated.[4]

In addition there are certain biochemical markers that are typical in autism, and my son seems to have this same biochemical gestalt.  For example two types of immune system cells released by the thymus are called “Th1” cells and “Th2” cells, and Th2 cell levels relative to Th1 cells are much higher in the blood of those with autism than in controls.[5]  As Th2 is associated with extra-cellular immunity, this suggests that those with autism will be prone to allergies,[6] which fits with anecdotal observation.  In addition with autism we see elevated markers for oxidative stress and endothelial damage.[7]  Also those with autism typically have functional deficiencies of magnesium[8] and potassium.  By functional we mean the levels may not be low in the blood relative to controls, but there is a biochemical need for greater consumption.  To see the latter you can give somebody with autism a small dose of supplemental potassium, and the result is generally a reduction in autistic symptoms.  For more on this, see Peter’s work: http://epiphanyasd.blogspot.com/2013/08/potassium-may-play-important-role-in.html.

It turns out that vitamin D skews the immune system to produce elevated levels of Th2 cells.[9]  One can infer that it also produces functional deficiencies of potassium and magnesium as these minerals offset the effect of calcium on calcium channels and vitamin D increases the absorption of calcium.  In addition in high doses vitamin D causes oxidative stress and endothelial damage as we see in autism.[10]

Oral supplementation with vitamin D can cause other consequences as well.  Supplementation with significant doses of vitamin D early in life, results in more cases of allergies, asthma, and dermatitis later.[11]  Asthma, allergies, and dermatitis all feature high levels of Th2 cells like autism.[12]  Is it too much of a stretch to suggest that supplementation with vitamin D early in life, might result in more cases of autism later as well?

On looking at the data we can see that my son as well as most other babies in much of the civilized world received, and in many cases continue to receive, large oral doses of vitamin D starting from birth.  As a baby we gave him vitamin D drops, and he also occasionally received some formula.  Starting at one year of age he consumed increasing amounts of milk (fortified with vitamin D in many countries) as well as children’s multivitamins, which also contained vitamin D.   Here is a graph showing vitamin D content of various beverages:

 

We are giving babies today much more oral vitamin D than they would consume from human milk alone and also much more than they would have consumed in past decades through formula and food sources when vitamin D fortification was more restrained.  In fact based on nutrition data and caloric intake, a baby just out of the womb consuming Similac baby formula today will receive approximately 855 IU per day of vitamin D.[13]  I am 190 pounds.  If we assume that dose should be proportional to weight, which is a good baseline assumption for most vitamins, I should consume 16,245 IU per day of vitamin D.  This is a huge dose, and based on past experience I know it would have a devastating effect on my health.  Why should it not be the same for some subset of babies?

When and where vitamin D consumption by the young is high, is where autism rates are high.  For example, in the United States autism rates are high relative to much of the rest of the world and they rose gradually starting around 1980 as much of the population transitioned to lower fat milks, which increased consumption of vitamin D.[14]  Later rates rose again in the early 1990s as the amount of vitamin D in milk was increased significantly with no change in the label.[15]  Rates continued rising with the popularization of the Sippy Cup starting in the 1995.[16]  They rose further during the 2000s as the Institute of Medicine increased the supplementation recommendations for babies in 2003 and again in 2008.[17]

When looking internationally, the evidence also points to a role for oral consumption of vitamin D in inducing autism.  Cuba for example has extraordinarily low rates of autism.[18]  The Cuban Health Service does not supply vitamin D drops to babies.  Nor do they fortify milk or other foods with vitamin D in Cuba.[19]  The Amish also have very low rates of autism as well.  They do not provide vitamin D drops to babies, and the milk they consume comes straight from cows: no vitamin D is added.[20]  In the United Kingdom rates of autism are lower than in the United States.[21]  Fortification and supplementation are common in the United Kingdom, but at somewhat lower levels than in the United States.[22]

Vitamin D is also used as a rodenticide, and experiments in rats show that it is more deadly to male rats than female rats.[23]  Is it any coincidence that autism strikes many more males than females?  Babies who get most of their sustenance from formula also receive more vitamin D than those who receive vitamin D from human milk.  Not surprisingly autism rates are higher among those who are formula fed.[24]

Vitamin D’s involvement also explains why some with autism benefit from a “casein” free diet as such diets avoid milk, which has high calcium content and is fortified with vitamin D in many countries.  It also explains why low-oxalate diets are beneficial as well as ketogenic diets.  Oxalates cause excess calcium salts to precipitate in the body and ketones effectively remove excess calcium due to acidity.[25]  Both lower the calcium load.  Oral supplementation with vitamin D also explains why some with autism have a favorable reaction to chelation.  Chelation agents remove excess calcium at the same time as they remove other metals.[26]  So they also lower the calcium load.

So the evidence suggests that over-consumption of vitamin D by babies and toddlers may induce autism in a genetically susceptible subset of the population.  This explains the biochemistry of autism as well as the nature of the autism epidemic.  There are a number of other data points that fit with this hypothesis.  If you are interested in this topic, here is an ebook with a lot more detail: http://www.amazon.com/dp/B00GVB46ES.

I want to thank Peter for allowing me to be a guest blogger here, and I also want to thank you for reading this. How do you view this hypothesis?  Do you have observations that are relevant to it?  Are you aware of existing data that would help confirm it or refute it?

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[1] http://www.medical-hypotheses.com/article/S0306-9877(07)00537-3/abstract

[2] For more on calcium channels and autism, please see http://www.autismcalciumchannelopathy.com/Genetic_Factors.html.

[3] http://www.ncbi.nlm.nih.gov/pubmed/6977721

[4]  http://www.fpnotebook.com/pharm/Vitamins/VtmnD.htm

 

[5] http://www.ncbi.nlm.nih.gov/pubmed/9627004

[6] http://www.sciencedirect.com/science/article/pii/S1380293397100057

[7] http://www.ncbi.nlm.nih.gov/pubmed/21651783 and http://www.ncbi.nlm.nih.gov/pubmed/16908745.

[8] http://mdheal.org/magnesiu1.htm

[9] http://www.jneuroinflammation.com/content/8/1/56

[10] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3052582/ and Gross, David Ross, Animal Models in Cardiovascular Research, p. 316.

[11] http://www.direct-ms.org/sites/default/files/Hypponen%20Vit%20D%20allergy%2006.pdf

[12]http://www.nature.com/jid/journal/v133/n10/full/jid2013148a.html and http://www.ncbi.nlm.nih.gov/pubmed/10919498.

[13] http://nutritiondata.self.com/facts and www.nal.usda.gov/fnic/DRI/DRI_Energy/energy_full_report.pdf.

[14] http://future.aae.wisc.edu/

[15] FDA, M-I-92-13.

[16] http://www.nytimes.com/2013/08/11/magazine/

[17] http://www.ncbi.nlm.nih.gov/pubmed/12671133 and http://pediatrics.aappublications.org/content/122/5/1142.

[18] http://healthimpactnews.com/2013/study-evidence-that-acetaminophen-especially-in-conjunction-with-vaccines-is-a-major-cause-of-autism-and-asthma/

[19] http://www.ncbi.nlm.nih.gov/pubmed/12947458

[20] http://www.ncbi.nlm.nih.gov/pubmed/22513133

[21] http://www.bmjopen.bmj.com/content/3/10/e003219.full

[22] http://mpkb.org/home/food/vitamind/vitamin_d_supplementation_policy

[23] http://www.toxicologyinternational.com/article.asp?issn=0971-6580;year=2008;volume=15;issue=2;spage=143;epage=144;aulast=Kaur

[24] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1578554/

[25] http://www.news-medical.net/health/Ketogenic-Diet-Side-Effects.aspx

[26] http://link.springer.com/article/10.1385/BTER:83:3:207#

 


 

Future Science - Accurate Diagnosis of Autism Phenotype using Brain Biopsies grown from Skin Cells

 

This is a post for the scientists among you, that like to separate science from pseudoscience.

You may not be aware that in recent years some revolutionary science has been developed allowing you to create a brain biopsy from a sample of skin.  I was rather taken aback when I first read about it, but it is true.  Researchers are now creating their own artificial biopsies, on which to experiment.

I first read about this in work being done at Stanford, looking at Timothy Syndrome.  I did not really focus on the importance of what they had done.  Without physical samples, it almost impossible to develop medical therapies and you cannot take brain biopsies from living people.  Rats and other lab animals are never going to be an adequate substitute.   

Here is a link to Johns Hopkins, where there used the same technology to make a brain sample with Huntington’s disease.

Turning Skin Cells Into Brain Cells

The true potential of this technology is amazing.  Today, it is being used to create samples, with which researchers can carry out experiments.  In future, it could be used as a diagnostic tool, just like when somebody goes to the gastroenterologist and has an endoscopy.  The doctor takes a sample from your intestines and sends it to the lab for analysis; hopefully a few days later you get a call saying the sample had no cancerous biomarkers, or other nasties.

In the case of autism, the skin sample would be turned into stem cells and then neurons from specific parts of the brain could be made.  These samples would then be tested to reveal specific dysfunctions.  This is exactly what was done at Stanford to make samples of Timothy Syndrome, a rare condition nearly always comorbid with autism.

Stanford Research

“We developed a way of taking skin cells from humans with Timothy syndrome and converting them into stem cells, then converting those stem cells into neurons,” says Ricardo Dolmetsch.

He then identified an experimental drug that could reverse the effects.  This phenotype can be reversed by treatment with roscovitine, a cyclin-dependent kinase inhibitor and atypical L-type-channel blocker.

Roscovitine, also known as Seliciclib or CYC202, is an experimental cancer drug produced by a Scottish/American company called Cyclacel. Don’t expect it to be a cheap drug; Goldman Sachs is one of the main shareholders.

Ricardo is from Cali in Colombia and so I had better shift him to my Dean’s List post-haste.

Conclusion

At some, not so distant point in time, people with a lot of money will be able to identify the precise phenotype of their child’s ASD and then they will know exactly what the optimal treatment is.

Once this technology becomes established, maybe in 50 years, I think Psychiatrists will become an endangered species.  We will need a lot of neurologists and for many people with mental health problems, there will at last be the chance of a very precise diagnosis and a matching drug therapy, created and tested on “human” brain samples made from stem cells.

Hopefully by then, the American Psychiatric Association’s DSM nonsense will be relegated to the trash can (or dustbin, for British readers).  Patients with brain disorders will be diagnosed and treated by neurologists and supported by psychotherapists, psychologists, behavioural analysts and other professionals.