Matching Pathology with Behaviours in Autism

 
I think the wrong people are in charge of autism research; forensic scientists or even air-crash investigators might do much better.

We have seen in this blog that many drugs have a positive effect in specific types of autism. In many, but not all cases, the mechanism of that drug and its effect on the pathology of autism is understood. 

If you have followed an ABA programme, you will know that an experienced autism therapist would very easily be able to give a long list of behavioral issues that occur in varying combinations among her clients.

From reading the research, it is clear that the people who understand the biology, often do not understand the psychology and the behavioral issues they are trying to treat - but perhaps they should.  Only then can you target treatments for specific problems.  There can be no single drug for autism, but there can be a drug for obsessive behaviours, and another for self-injury.  You cannot say a low dose of X helps with social cognition, but for aggression you need a high dose of X.  To me at least, this is complete nonsense and shows a complete failure to understand the underlying psychology.

Just as most people struggle with all the jargon of biochemistry, I suppose the medical researchers fail to grasp the nuances of the psychologists’ jargon.  We need to match both sides, because we need science to solve a complex problem that presents itself in hard to describe, odd behaviours and not as nice neat equation to solve.

It is difficult to accurately describe and quantify the behavioral issues of a child with ASD.  It is very hard for a parent, but it is definitely possible for a psychologist using tools like ABBLS and others.  Then you can move towards seeing precisely what behavioral effects a drug has and stop expecting improvements in areas that are completely unrelated.

Having produced the list of deficit areas you can then try and understand the underlying pathology as to why a drug is effective.

I make no claims to have great expertise in this area, but it looks like nobody else does either.

Here are some examples:

Obsessions

Obsessive compulsive behaviours are well known to affect some people with autism.  This is a type of behaviour that most people would understand and would notice if they saw it, although they might find it hard to quantify.

Oxidative stress is a measurable pathological condition that is present in some people with autism.  Oxidative stress exists in other medical conditions and has a known therapy, an antioxidant like NAC.

By chance, it was found that treating someone with obsessive compulsive behaviours with NAC, greatly reduced those behaviours.

In the case of people with autism and obsessive compulsive behaviours, it would be good to know if other deficit areas were also impacted.  Clearly, taking away the obsessive compulsive behaviours, you would expect to see a general improvement, since the person is now much calmer and better able to function and so many behaviours should improve to a certain extent.  But does NAC reduce head banging and other SIB?  I think not.

So we can then conclude that oxidative stress triggers obsessive compulsive behaviours and NAC should be prescribed.  Oxidative stress may exist to a lesser degree in subjects that do not (yet) display obsessive behaviours.

 

Anxiety

I have not tried to treat anxiety in autism, but many people have.  Anxiety lies on the axis running from happy to depressed.  By raising the level of serotonin in the brain you move from depressed towards happy.  The antidepressant Prozac is given to many children with ASD to reduce anxiety. Prozac is a selective serotonin reuptake inhibitor (SSRI).

The problem with such drugs is their side effects and use can result in dependency.  If that was not the case, the advice would be simple.

I think a better and safer way exists to raise brain serotonin levels in autism.

Seizures and SIB

Not all people with SIB (Self-injurious Behavior) have seizures, but I expect many people with seizures have SIB.  Both conditions appear to be channelopathies (ion channel/transporter dysfunctions); but there is more to it than that, what triggers the channelopathy?  It would seem that in both cases the message comes via inflammatory signalling from the vagus nerve.  So to treat these conditions you can block the inflammatory signalling (vagus nerve stimulation), or you can treat the resulting ion channel/transporter dysfunction in the brain; doing both may be quite unnecessary.

If you have neither seizures nor SIB, then using any of the above therapies would be of little effect.

Many open questions remain

All is not clear; for example, where does hyperactivity fit in?  Where does anger fit in?  Is anger just a mild version of SIB?  It is extreme anxiety?  Is it something entirely different?

An interesting finding of mine was that showing affection appears to be pathologically related to self-confidence and lack of inhibition.  The pathology linking them appears to be neuroinflammation, or rather the control of it.

 

 

The Vagus Nerve and Autism

It is good to know that there are some brilliant minds out there, willing to cross disciplines.  A case in point is Professor Stephen Porges, a neuroscientist with particular interests in understanding the neurobiology of social behavior.  He is a Professor in the Department of Psychiatry and the Director of the Brain-Body Center in the College of Medicine at the University of Illinois at Chicago.  He has an equally clever wife who is a world leader in the role of neuropeptides oxytocin and vasopressin in social cognition.
You would want to think twice before inviting this couple round for dinner, unless you had spent the day before boning up on your science. 

Porges is best known for his Polyvagal Theory.  The Wikipedia article does not really do justice to the theory.  Here are two highly cited papers:-

The polyvagal theory: phylogenetic substrates of a social nervous system (2001)

The Polyvagal Theory: phylogenetic contributions to social behavior (2003)

He has only written one paper on autism, it is certainly not a light read but it shows a brilliant mind.

The vagus: A mediator of behavioural and visceral features associated with autism 

This paper is actually a chapter in a book and can be accessed via Google Books.

His paper explains odd autistic behaviours in terms of the functioning of the vagus nerve.  For example, the neural mechanism for making eye contact is shared with those needed to listen to the human voice.  So if you struggle to make eye contact, you will struggle to listen to what somebody is saying to you.  We can infer that if your ABA program trains you to make eye contact, you will likely become a better listener in the process.  Also, don’t talk to somebody unless you are facing them.

He comments on the regulation of the gut, the vagus and the immune system, vagal regulation of the HPA axis, all with reference to ASD.

Having read his paper you really will need no more convincing to go tune up your child’s vagus nerve. 

Tuning up the Vagus Nerve

Unlike Professor Porges, I like to simplify things so you do not read them more than once.  Clearly Kevin Tracey and Porges are the experts on the vagus nerve, but they do not go as far as telling you what you really want to know – how to improve its function using today's technology.  Fortunately, there is plenty of research on the Cholinergic System, of which the vagus nerve is part.  The following paper is a good example:-

Cholinergic Activity in Autism: Abnormalities in the Cerebral Cortex and Basal Forebrain

You may recall from my earlier post Biomarkers in Autism: The Cholinergic system, that there are two types of cholinergeric receptors, nicotinic and muscarinic.  This paper is telling us how in autism these receptors are fewer in number than normal and the ones that are there, are not working (binding) as they should.

So this goes some way to perhaps explain why so many odd behaviours can be tracked back to the autistic vagus nerve; it is damaged.

In his paper, Porges is basically telling you to go try a vagus nerve stimulator, of the kind that already exists for epilepsy (see photo above) and Kevin Tracey is developing for arthritis (another inflammatory condition).  Right now this is not very feasible, but chemical stimulation of the vagus nerve does not look beyond the wit of man, using currently available technology.


 

More on anti-histamines in Autism and introducing H4

In my previous posts on histamine, you would have read that I found that Claritin appeared to reduce autistic behaviours.  Once I had got to the bottom of what was going on, I found out that histamine has a long record of stimulating challenging behaviour in all children.  It also became clear that typical anti-histamines (H1 antagonists) are all slightly different and one may be effective in one person and ineffective in another.  Each one tends to have additional secondary effects.

It now appears that the secondary effect of certain H1 antagonists may actually be more important than the primary intended effect of reducing itchy eyes and runny noses.

There are three generations of H1 drugs.  The fastest working and most potent is still the first generation, the second generation are non-drowsy derivatives of the first generation.  The third generation are the active metabolite of the second generation.  As you will see in today’s central paper, the third generation probably does not warrant the tittle.  For many users they may be just expensive versions of the second generation drug.

The excellent paper  New anti histamines: a critical view is from Brazil, but it has an English version.  It is highly readable.  It tells of the specific secondary effects of certain second generation  H1 antagonists.   (She omits to mention the secondary effects of the first generation. Some people say Ketotifen is 1^st generation and other people say 2^nd generation, anyway it appears not to be sold in Brazil).  I suggest you read the paper, if you have a child with an ASD. The key section is this:

Antiallergic/anti-inflammatory effects

Originally, studies of the relative potencies of H1 antihistamines were based on the capacity of different compounds to competitively inhibit the H1 receptor binding of histamine, i.e. on their blocking effect on the receptor.⁸ Nevertheless, it has already been known for some time that, in addition to acting on H1 receptors, many H1 antihistamines, at appropriate doses, are capable of inhibiting not only the release of histamine by mast cells,^9,10 but also mast cell activation itself.¹¹ Some of them can even regulate the expression and/or release of cytokines, chemokines, adhesion molecules and inflammatory mediators.^5,8

Therefore, the antiallergic properties of H1 antihistamines are generally a reflection of their capacity to affect mast cell and basophil activity, inhibiting the release of preformed mediators such as histamine, tryptase, leukotrienes and others.⁸ Several second-generation H1 antihistamines have demonstrated antiallergic properties, irrespective of their interaction with the H1 receptor.^5,8

Chronic allergic inflammation resulting from the late-phase reaction, exhibits components that are similar to other forms of inflammation, including chemotaxis of inflammatory cells followed by activation and proliferation, with subsequent production and release of many chemical mediators. Among cells involved in allergic inflammation are: antigen-presenting cells (for example, macrophages), mast cells, basophils, T lymphocytes, epithelial/endothelial cells and eosinophils - major effectors of chronic inflammation. Cytokines, chemokines, inflammatory mediators and adhesion molecules also contribute to this process which ultimately leads to dysfunction of the affected organ.⁸

Many second-generation H1 antihistamines (particularly cetirizine) are capable of inhibiting the influx of eosinophils to the site of allergen challenge in sensitized individuals.^5,8 Studies have demonstrated that some of them can also alter adhesion molecules expression on epithelium and eosinophils, and reduce in vitro survival of eosinophils. Finally, some second-generation H1 antihistamines are capable, in vitro and in vivo, of altering the production of inflammatory cytokines (for example, TNF-a, IL-1b and IL-6) and the Th1/Th2 balance regulation cytokines (for example, IL-4 and IL-13).^5,8

Therefore, it is well established that, in addition to their effects on H1 receptors, many second-generation H1 antihistamines also manifest antiallergic and anti-inflammatory properties which differ depending upon their molecules and the experiments used for their evaluation.⁵

 

From my own experience, I have already replaced Claritine (Loratadine) with Cetirizine to see if it will remain active for longer.  Rather than working for 24 hours, Claritine is working for about 5 hours.

I thought Cetirizine might remain active for longer, but the main difference seems to be in how it works, rather than for how long it works.  With Cetirizine autistic behaviour has pretty much returned to where it was at the start of summer, before the allergy season.  With Claritine things improved greatly, but not all the way back to "normal".

Reading the paper and one of its references -

Compared pharmacological characteristics in humans of racemic cetirizine and levocetirizine, two histamine H1-receptorantagonists

makes me think that the expensive new  version of Cetirizine, called Levocetirizine, might be even better.  It happens to be available locally, but it is seven times as expensive.

The Brazilian paper does rather contradict some of what Dr Theoharides says about stabilizing mast cells.  You can choose who you think has got it right.  The good thing is that both Dr Inês Cristina Camelo-Nunes and Dr Theoharides seem very serious, objective people, which cannot be said about all the people offering their advice on the internet.

In fact, I found an interesting paper on the anti-inflammatory effects of the new version of Claritin, called Aerius/Clarinex (Desloratadine).

Antihistaminic, Anti-Inflammatory, and Antiallergic  Properties of the Nonsedating Second-Generation Antihistamine Desloratadine: A Review ofthe Evidence

It really seems to be the case of trying several antihistamines and selecting the one that works best for you.

 

The H4 Histamine Receptor and Inflammation

You may recall that there is a fourth histamine receptor, naturally called H4.

It was only recently discovered, as you might guess from the short entry in Wikipedia.  It seems that the H4 receptor plays a substantial role in the inflammatory response.  It is seen as playing a key role in conditions ranging from arthritis to asthma.

Here is a full text paper for those interested in the science:-

The role of histamine H4 receptor in immune and inflammatory disorders

 Here is a graphic from that paper:-

I wonder if that H4 is a ticking bomb in autism as well ?

Those more peaceful people among you will be less aware of what C4 is, and hence the sticks of H4 dynamite.