Lessons from the Autistic Mouse

 

One surprising observation from reading the research on autism is how many times I have come across scientists making a mouse autistic and then showing how this can be reversed.

The important point is that the things the scientists did to the mouse (or its mother) are generally totally unrelated.  The only thing in common is the resulting mouse has “autistic behaviour”.

We can conclude that “autism” can be caused by entirely different events/disorders;  just like a head ache can be.

It would be correct to think of autism as a symptom, not a disease.

Perhaps, put a little clearer:-

• Autism is just a symptom of an underlying neurological disorder.  There are numerous such disorders, each with their own underlying pathology; some of these pathologies may overlap.  Treating the underlying pathology will moderate the symptoms of autism.

• Do not treat autism.  Treat the underlying pathology.

• A treatment that works in one person, with the symptoms of autism, may be completely ineffective in another.

• All treatments that are genuinely effective, in even the smallest group of children, should be carefully documented and shared publicly. Steps should be taken to look for biomarkers associated with each group.   

So, it is fundamental to think of autism as a symptom rather than a disease.

If researchers think of autism as a disease, it will likely remain incurable.  Granted, there is much more talk about autisms, sub-types and phenotypes, but this all goes out the window, so to speak, when it comes to doing clinical trials.

I am reading about a series of autism trials by Forest Laboratories of the US, using an old drug called Memantine.    I was shocked to see that they are trialing this drug in 118 locations around the world, on 906 children

An Open-Label Safety Study of Memantine in Pediatric Patients with Autism, Asperger's Disorder, or Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) 

Autism trials are usually tiny.  Conducting a trial on nearly a thousand kids is very expensive.  You would not undertake this kind of expense, unless you had a pretty good reason to think the drug was effective.

This trial is actually a safety study, in parallel there are a whole series of other studies.

Unfortunately, by trialing the drug on almost any kid, with any kind of autistic feature (Autism, Asperger’s, PDD-NOS), the important lesson from the mice has been completely lost.

While I really wish Forest Laboratories success, I suspect their trial will show that while Memantine is safe, it is not effective.

Over the years, there have been many anecdotal reports of the effectiveness of Memantine in some cases of autism.  Memantine is a drug that acts on the glutamatergic system by blocking NMDA receptors.  This will be explained in some detail in the next post “Ketamine, Memantine, D-Cycloserine and even Magnesium as Glutamatergic Modulators in Autism”.

Conclusion

You might think that much of the above should be common sense; sadly it is not.

PolyPill for Autism - Current Version

The objective was to identify the most effective drugs to treat Classic early-onset autism, having biomarkers of elevated serotonin, cholesterol, thyroid FT3/4 and growth factor IGF-1.  Except for the TRH drug, these drugs are all generic and very cheap.  The total cost per day is about EUR 1 ($1.4).

The dosage is based on a 10 year old child weighing 33kg / 73lbs

The TRH and Clonazepam doses are tiny.

According to the European Medicines Agency (EMA), most countries have an arrangement whereby patients can apply for access to drugs for off-label use, usually based on experimental evidence or clinical trials.  If you use these drugs, it would be helpful to collect data on the effect, so that it can later be used by the EMA to evaluate the Autism Polypill.  You can send me the data or case reports.

Since most doctors continue to regard autism as untreatable, you will have to be proactive, if you want a drug to treat your child. 

True Self

I could have given this post and the above graphic a fancy name like "Psycho-neurobiological model of autism", but True Self seems more appropriate.

If you have ever read a book on autism by a psychologist, it is worlds away from the books by the scientific boffins.  In reality, the psychologists have a simpler job, since they do not have to prove their theories with biological data.

One interesting observation from psychology is the concept that the human body has two parallel control mechanisms, the nervous system and the hormone system.  The nervous system mediates immediate changes, while the hormonal system sets the background changes.

When it comes to fear and stress, there are measurable hormonal changes.  Using willpower or even singing, you can make your self feel better and make a measurable change in the hormone levels.  We saw this earlier with the example of singing lowering the stress hormone cortisol, as measured in saliva.

This NIKE (Just do it!) effect means that you can directly influence your own hormones.  By inference, if you have a hormone imbalance, as seems to be the case on some types of autism, you have some powers to modulate it yourself.  You could think of it as willpower, or mind over matter. 

I suggest that even instincts may fall into this category.  Just as soldiers are taught to react instinctively, without pausing for thought, it should be possible to teach young children to develop their instincts.  The apparent lack of gross motor skills in kids with ASD can often be overcome with practice and repetition (the foundations of ABA);  in effect you are teaching the child what is instinctive in other kids.  If you through a ball at a younger kid with autism, he does not react and will let it hit him.  He does not know what to do and he lacks the instinct to either get out of the way, or to catch it.

As part of a good ABA programme a lot of time is spent practicing both gross motor skills (ball play, jumping, dancing etc) and fine motor skills.  Then you have these skills, without the need to consciously think about them.

People do ask why ABA seems to work so well for some children, is it the child? is it the therapist? it is just the sheer amount of it that matters?  They tend not to wonder what the ABA is actually doing inside the child's head.

It is relevant to this blog, which is all about the biology of the brain.  We have a pretty good idea of some of things that are dysfunctional in autism and how some emerging drug interventions work.  But at the same time, there is this behavioral intervention that seems able to overcome some of these biological deficits.

The NIKE effect (Just do it) and the AVIS effect (We try harder) are extremely potent.  In reality, they are very much part of the body's nervous control system.  In some cases this training is so powerful that instead of being derailed by interference from ion channels and oxidative stress, all that matters is completing the task.

Some typical people's headaches are also caused by ion channel dysfunction; when it happens they might call in sick.  Another type of person is more driven, the fact they have some other obligations is more important than their headache, so they just press on.



The Faucet/Tap/Valve

A conventional faucet/tap might look like this old one on the left.

A so-called "in line valve" has a pipe on both ends and as you turn it, you gradually reduce the flow to zero

If you make a technical drawing involving a valve, there are various special symbols, but they generally look like this.  Sometimes if the valve is closed it would be solid black.






Why does drug intention in autism sometimes stop working ?

We have seen in this blog that several apparently different, but interconnected, conditions seem to mediate autism, at least in some people:-

• Oxidative stress
• Neuroinflammation
• Channelopathies
• Hormonal dysfunction
• Immune system "over-activation"

So if you now look again at the True Self graphic

Oxidative stress, if present, will manifest itself as stereotypy and in the graphic it will close the valve a little blocking the true self.  In hard science, the oxidative stress will also reduce the level of the thyroid hormone T3 in the brain.  We saw this in research from Harvard that showed that the oxidative stress reduces the level of the enzyme D2 that converts the pro-hormone T4 into T3.  So both the blue valve and the green valve close.

In similar fashion both neuro-inflammation and channelopathies affect both the nervous system and the hormonal system. 

This might explain the fact that sleeping patterns, appetite, emotions, empathy, self-confidence are all sometimes impaired in autism.  To some extent, these impairments seem to be reversible.

In the only real case of autism that I have to contend with, the most important factor seems to be, the sometimes over-activated, immune system.  I am presuming it is just affecting the nervous system.  In this case, the blue valve to the left can shut completely; the Observable Self is then a totally different person to the True Self.  It also means that even though the other valves upstream may be wide open, it is all to no avail.

So when my autism drugs "stopped working" it was because further down stream there was an insurmountable problem.  Even NIKE and Avis had little effect.   

In the children for whom none of these drugs show any effect, I suspect either the immune system is involved, or in their type of autism, there are other additional factors at play.


A Note on ABA


ABA (Applied Behavioral Analysis) is not the subject of this blog, but it would be more than worthy.  When well implemented, ABA is a powerful resource and not only for small children.  The general public perception of ABA rather misses the point, it is actually more a philosophy applicable life-long.

We once had an excellent young ABA consultant trained at the New England Centre for Children, in Massachusetts.  I was surprised to hear from her about the support still being given to older adults; the adult and their buddy (ABA assistant) would even go on short trips, like to Las Vegas.

We are now using ABA to develop conversational skills.  An example is giving Monty, aged 10 with ASD, the task in break time at school, to go and initiate five conversations with the potential reward of his favourite candy.  This might sound very staged, but he goes around the school looking for kids to talk to, some of whom he has never spoken to before, initiates the conversation, looks over his shoulder to check his assistant has noticed, plays a bit and then finds someone else to talk to.  He did not take the easy option and just find the nearest five kids and say "Hi, how are you".  I was surprised how well this worked.

Later you can fade the reinforcer, so that he works for praise and not candy.  You can also gradually increase the target of five conversations.  You can then also extend the requirement to have more stages to and fro, in the conversation.  It may sound very odd to do this, but the end result will be learning to make social conversation, which would be natural in other kids.  

What people do not realize is just how much ABA is needed and that it is not just like having a music lesson, it is more like a religion.  If everyone who interacts with the child consistently applies the principles, much can be achieved.  If ABA is just a lesson the child goes to and then comes home, it is not a surprise that very much less is achieved.

If you talk to the parent of a child who has persevered with ABA for years, you will see just how committed they became.  If you prefer sport as an analogy, it is just like a would-be professional tennis player, who practices every day from the early hours.  It is an obsession, but if you want to compete at a high level, you just have to do it.

Where we live there is no ABA school, but there is a Novak Djokovic tennis academy, in fact they came to visit Monty's school last week.  I think Novak would definitely understand the NIKE and Avis effects, he probably would not think ABA was odd at all.









 

Clonazepam Dosage and Effectiveness in Autism

Much research is based on experiments with mice rather than humans, for obvious reasons.  This was the case with Dr Catterall’s recent successful trials of a long established drug called Clonazepam, in two mouse models of autism.

Well, it turns out that his findings are applicable to humans.

With a dosage of around 1mcg/kg (that is micrograms per kilo) twice a day, the same kind of positive behavioural/cognitive changes Catterall found in mice are indeed evident in some humans.

The question remains as to the long term effect of using this drug; in very much higher doses, there are negative consequences.

Comparison with dosage for other conditions

·        As a treatment for seizures, the maximum dosage in children for 0.2 mg/kg/day

·        As a treatment for panic/anxiety the typical adult dose is 1mg with maximum of 4 mg

·        For bipolar disorder in adults the maximum dose is a hefty 20 mg

Clonazepam use in the above conditions is associated with both tolerance (gradually needing a higher dosage to maintain effectiveness) and being habit forming (addictive).

The autism dose appears to be just one hundredth of the maximum pediatric anti-seizure dose and is perhaps too low to cause problems. 

 

Increase in Serotonin

Not only does Clonazepam affect the neurotransmitter GABA, but it has a known secondary effect on serotonin, the “happy hormone”, which appears to be low in the autistic brain.

In the US the trade name is Klonopin and it appears to be called “K-pin” among those who abuse it, for the happy effect.

In most of the rest of the world it is called Rivotril.

 

Just how dangerous is Danger Mouse?  (in tiny doses)

Nobody knows.

For the science, click below:-

Channelopathies in Autism - Treating Nav1.1 with Clonazepan