ASD variants - (mis and missed) diagnoses. Calcium ion channel dysfunctions Cav1.1, 1.2, 1.3 and 1.4

This post serves to introduce some ideas relevant to a post that is will shortly arrive on calcium ion channel dysfunctions (Cav1.1, 1.2, 1.3 and 1.4).

As we have seen, nearly all behavioral and psychiatric disorders are just diagnosed based on observation.  Only in very rare cases is the underlying biological problem diagnosed.  So it is fair to say that these are not accurate medical diagnoses.

Under the wide umbrella term of ASD are likely hundreds of thousands of  discrete variants, since ASD generally results from the combination of multiple hits/dysfunctions.  A single one of these dysfunctions is usually not enough to trigger autism, but some may indeed trigger something else noticeable.  A small number of individual hits, like Fragile-X and Retts can trigger autism, but these are the exception.

Mis and Missed diagnoses

One reader of this blog received a diagnosis for his child as “late onset regressive autism or possible childhood disintegrative disorder”.  Neither of these options is very good, since you are talking about an entirely typical child who, after the age of four, begins to regress and lose his acquired skills.

After a long struggle, he found the biological diagnosis, which is mitochondrial disease.  After a few months of the Richard Kelley (from Johns Hopkins), therapy the regression was halted and now new skills are again being acquired.

This is another example of how unacceptable simple observational diagnoses are.  What would have happened if the reader had not stumbled upon this blog and then later sought out help from the leading experts (just look on my Dean’s list)?

Attention Deficit Disorder (ADHD)

ADHD is very commonly diagnosed in the US, much more so than in other countries.  More severe cases of ADHD look much like ASD, which is why I call them autism-lite.

Another group of ADHD may indeed be purely behavioral – too much time with smart phones, iPads and video games.  This is supported by the fact that the data on incidence of ADHD shows that a large group of children with ADHD, “grow out of it”, or were misdiagnosed in the first place.

However, it does look like there is another group of ADHD which is biological, but may be different to autism.  On this subject I will bring you the comments of Dr. Manuel Casanova, a neurologist and along with that, thoughtful and knowledgeable about autism. 

Then we have the recurring clinical trials on high EPA/DHA fish oil, which really do show an effect in most trials in ADHD, but fail in most trials in autism.  This will be developed further in the later post on calcium channels.  The suggested view is that either the vitamin A, or the omega 3 oil, is somehow helping and even perhaps some people have a problem absorbing some types of vitamin A.  I was always unconvinced by this. 

However, it has now been shown that the EPA in fish oil has an effect on certain L-type calcium channels.  If you had a mild dysfunction (channelopathy) of one of the L-type calcium channels, then a big enough dose of EPA might have an effect on them.  This becomes more interesting when you learn that some doctors in the US think that dyslexia is another autism-lite.

One suggested cause of dyslexia is visual deficit that makes reading difficult, but it also accompanied by a difficulty seeing in the dark.  This night blindness is known to be caused by vitamin A deficiency (or an inability to absorb it properly) and also by an ion channel dysfunction in Cav1.4.

It appears that the high EPA fish oil would increase vitamin A and also affect the function of Cav1.4.  The calcium ion channel Ca1.4 is widely expressed in your eyes.

Another interesting point is that it is thought that a dysfunction in one type of Calcium channel will often affect the function of others.  This is important because when you look at the effect of dysfunctions in these channels you will a listing including:-

·        Autism (Timothy Sydrome)

·        Mood disorder

·        Depression

·        Bipolar

As well as things like

·        Night blindness

·        Heart defects (Timothy Sydrome)

We also should note that many people (without autism) with sight problems claim improvement from taking high EPA fish oil.

Dyslexia

Dyslexia is the most common learning disability. It affects about 3 to 7 percent of people. While it is diagnosed more often in males, some believed it affects males and females equally. Up to 20 percent of the population may have some degree of symptoms

Dyslexia and attention deficit hyperactivity disorder (ADHD) commonly occur together; about 15 percent of people with dyslexia also have ADHD and 35 percent of those with ADHD have dyslexia.

The causes appear to be genetic and epigenetic. For example the gene KIAA0319

People usually think of dyslexia only in children, but that may be because many adults do not read very much.  Or do they "grow out of it".

ADHD

“It affects about 6–7% of children when diagnosed via the DSM-IV criteria and 1–2% when diagnosed via the ICD-10 criteria.  Rates are similar between countries and depend mostly on how it is diagnosed. ADHD is diagnosed approximately three times more in boys than in girls. About 30–50% of people diagnosed in childhood continue to have symptoms into adulthood.”

So it would seem that most people “grow out” of ADHD 

Dr. Manuel Casanova

Dr. Manuel Casanova is a neurologist and along with that is clever, thoughtful and knowledagable about autism.  He looks at measurable anatomical differences and how these may be related to behaviour.  So he is more into the consequences of unchangeable differences in brains.

If you start looking at ion channels and transporters as being key drivers in behaviour then you have the chance to make alterations.  We saw that the same applies to fine tuning the function and indeed structure of key neurotransmitter receptors.

In lay terms, Manuel is showing how brains are indeed “hardwired” differently in many cases of autism, ADHD and even dyslexia.  This might reinforce the old view that really it is “case closed” and nothing more can be done.

However the really clever scientists looking in greater depth show us that notwithstanding some structural variation, much of the problem lies in the aspects of the brain that can be modified and indeed some are constantly in a state of change, for example the shape of dendritric spines and indeed the very substructure of those  GABA_A receptors.

He groups dyslexia with ADHD and sees them as fundamentally different to autsim.  Having said that, Manuel tells us that attention disorders may be found in close to 30% of autistic individuals

 He has his own blog.

Dyslexia, Attention Deficit Hyperactivity Disorder and Autism

I suggest you read his full article, but here are some excerpts:-

“Claiming that there is comorbidity across neurodevelopmental disorders based on a single behavioral symptom negates many aspects of the individuality of each condition. In this regard, there are marked differences in the cognitive styles of dyslexic or ADHD individuals and those within the autism spectrum. Dyslexics enjoy a top-down cognitive style, tend to be holistically-oriented and have a gestalt processing bias (e.g., they see the forest but lose track of the individual trees). They are considered to have strong central coherence and excel in synthesizing sensory or cognitive experiences. Individuals within the autism spectrum enjoy a bottom-up cognitive style which makes them detail-oriented. Thus, contrary to dyslexic/ADHD subjects, ASD individuals see the tree but tend to lose sight of the forrest. In addition, they have a local processing bias with weak central coherence and appear to be good analyzers.”

“The above related differences in cognitive style appear to have anatomical correlates. As compared to neurotypicals, dyslexics tend to have smaller brain volumes with a concomitant striking increase in the size of their corpus callosum (the white matter projections that join homologous areas in both cerebral hemispheres). In addition, they have a simplification of their convolutional pattern and their cortical modules for information processing (minicolumns) are wider than expected. We find completely the opposite in patients within the autism spectrum.”

Yet more labels

Since we will be looking at calcium channels and one thing that does affect them is EPA, we should look at another label, dyspraxia, which also is reportedy  affected by fatty acids.

  

Fatty Acids in Dyslexia, Dyspraxia, ADHD and the Autistic Spectrum

Here is the link     Dyslexia, dyspraxia, ADHD and the autistic spectrum

What is Dyspraxia, also known as Developmental Coordination Disorder (DCD) ?

Dyspraxia, also known as Developmental coordination disorder (DCD), is is a chronic neurological disorder beginning in childhood that can affect planning of movements and co-ordination as a result of brain messages not being accurately transmitted to the body.

People with developmental coordination disorder sometimes have difficulty moderating the amount of sensory information that their body is constantly sending them, so as a result dyspraxics are prone to sensory overload and panic attacks.
Many dyspraxics struggle to distinguish left from right, even as adults, and have extremely poor sense of direction generally.

Moderate to extreme difficulty doing physical tasks is experienced by some dyspraxics, and fatigue is common because so much extra energy is expended while trying to execute physical movements correctly. Some (but not all) dyspraxics suffer from hypotonia, low muscle tone, which like DCD can detrimentally affect balance.

Gross motor control

Whole body movement, motor coordination, and body image issues mean that major developmental targets including walking, running, climbing and jumping can be affected. The difficulties vary from person to person and can include the following:

• Poor timing
• Poor balance (sometimes even falling over in mid-step). Tripping over one's own feet is also common.
• Difficulty combining movements into a controlled sequence.
• Difficulty remembering the next movement in a sequence.
• Problems with spatial awareness, or proprioception.
• Some people with developmental coordination disorder have trouble picking up and holding onto simple objects such as pencils, owing to poor muscle tone and/or proprioception.
• This disorder can cause an individual to be clumsy to the point of knocking things over and bumping into people accidentally.
• Some people with developmental coordination disorder have difficulty in determining left from right.
• Cross-laterality, ambidexterity, and a shift in the preferred hand are also common in people with developmental coordination disorder.
• Problems with chewing foods.

Fine motor control

Fine-motor problems can cause difficulty with a wide variety of other tasks such as using a knife and fork, fastening buttons and shoelaces, cooking, brushing one's teeth, styling one's hair, shaving, applying cosmetics, opening jars and packets, locking and unlocking doors, and doing housework.

Difficulties with fine motor co-ordination lead to problems with handwriting, which may be due to either ideational or ideo-motor difficulties. Problems associated with this area may include:

• Learning basic movement patterns.
• Developing a desired writing speed.
• Establishing the correct pencil grip
• The acquisition of graphemes – e.g. the letters of the Latin alphabet, as well as numbers.
• 
  

Associated disorders

People who have developmental coordination disorder may also have one or more of these co-morbid problems:

• Attention deficit hyperactivity disorder (ADHD) (inattention, hyperactivity, impulsive behaviour).
• Dyscalculia (difficulty with mathematics),
• Dysgraphia (an inability to write neatly and/or draw),
• Dyslexia (difficulty with reading and spelling),
• Hypotonia (low muscle tone)
• Sensory processing disorder
• Specific language impairment (SLI)
• Visual perception deficits

Dysjustabouteverything (DJE)

If you consider the early years of classic autism, you will see that, in many cases, it includes all of the above disorders, even hypertonia.

But some people are otherwise pretty much typical/normal, are diagnosed with a single disorder like dyscalculia.

The problem is that these are all just observational diagnoses.  Does something biological underlie and connect them?  I think it does.

An autistic person’s struggles with mathematics may be more to do with a problem of understanding the language used to explain it.  This is why, in many cases, they struggle to move beyond counting.  Special methods of teaching maths have been created for such people, but they only take you to an elementary level.

If you have Asperger’s, you have no problem with the language used to explain the concepts or to frame the questions.  Some people with Asperger’s excel at mathematics.

The same is true for dysgraphia, autistic people tend to have very scruffy handwriting, but does this mean that they have dysgraphia? 

Hypotonia is an interesting one.  Many parents report low muscle tone and indeed DAN doctors actually treat it (apparently with Creatine).  I think hypotonia, if present in autism, is likely to be connected to the disruption in the various growth factors that has occurred and this itself may related to GABA_B dysfunctions. (I mentioned this connection in an earlier post).  In Monty, aged 11 with ASD, when he was a baby he had Hypertonia.  He was big and all muscle.  As he got older he slid down from the 80-90^Th percentile to the 20^th percentile.  This fits one very distinct pattern of classic autism.

In the case of Monty, almost all the earlier signs of Dysjustabouteverything have now vanished.  Is this always the case?  Why would that happen in some people and not others?  Did his Polypill interventions play a role?

To investigate

What we need to know is whether there is a common link between all these various “dys-disorders”.

Probably in some (mis/over-diagnosed) people there is no link; but in others there may well be.

In some people there really is a link.  I did not tell you that my old “favourite”, hypokalemic periodic paralysis (HPP), can be caused by a Cav1.1 dysfunction.  HPP-lite is something called hypokalemic sensory overload.  In a little experiment I demonstrated that autistic sensory overload can be just hypokalemic sensory overload.  You just need 250 mg of potassium and a disturbing noise or light to illustrate it.  This is also a symptom of what they call Dyspraxia.

So Cav1.1 associates with HPP (hypokalemic periodic paralysis) and by my inference, sensory overload and some hypotonia;  Cav1.2 associates directly with autism (Timothy Syndrome) and bipolar; Cav1.3 associates with mood disorders, depression, bipolar; Cav1.4 associates with night blindness and perhaps some dyslexia.

A dysfunction in one L-type channel (Cav1.1, Cav1.2, Cav1.3 and Cav1.4) can apparently cause dysfunction in the others.  This surprised me.

So if you have autism, is not surprising if you appear afraid of the dark, feel depressed, experience sensory overload and are not very muscular.

The good news is that much of this appears to be treatable.

For the scientists among you:-

CACNB2    

Voltage-dependent L-type calcium channel subunit beta-2 is a protein that in humans is encoded by the CACNB2 gene

http://www.ebi.ac.uk/interpro/entry/IPR005444

Mutation in the CACNB2 gene are associated with Brugada syndrome, autism, attention deficit-hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder, and schizophrenia.

I did forget to remind readers that I see the label schizophrenia as just another name for adult onset autism.

So it is no surprise that adults with autism have a 22 times higher chance of also being diagnosed with schizophrenia compared to non-ASD people.  Note bipolar, OCD etc; and this does not include all those adults with autism who get forgotten.

Source:  Adults with autism are at risk for host of health problems

Conclusion

I am not suggesting “medicalizing” people with dyslexia, or indeed most with ADHD. 

However, it might be useful for somebody affected to know if Cav1.1 to 1.4 were dysfunctional, then at critical moments, like exam time at school, you could indeed give them some extra help.

People with dyslexia, and I presume other “dys-disorders” do often get given extra time at school for exams.  People with ADHD are often entitled to financial benefits in developed countries, and it has been suggested that these countries are the ones with high incidence of diagnosis.  In the US 11% of children and 4.4% of adults have a diagnosis.   ADHD has been medicalized in the U.S. since the 1960s.  In the UK, 3.62% of boys and 0.85% of girls have an ADHD diagnosis.  In France less than 0.5% of children are taking medication for ADHD.

Here is a nice quote:-

Why Are ADHD Rates 20 Times Higher in the U.S. Than in  France?

“it makes perfect sense to me that French children don't need medications to control their behavior because they learn self-control early in their lives. The children grow up in families in which the rules are well-understood, and a clear family hierarchy is firmly in place.

In French families, as Druckerman describes them, parents are firmly in charge of their kids—instead of the American family style, in which the situation is all too often vice versa.”

In the case of ADHD, it looks like the French have got it right; but not sadly for autism.

Knowing many different nationalities, I can certainly confirm that French parenting is much tougher than the UK or US variety.  The UK variety is very similar to the US, but without the liberal use of drugs for ADHD or indeed autism.

In tough cases of ADHD, that even French parenting cannot control, perhaps it really is a calcium channelopathy.  Perhaps in these cases a mild calcium channel blocker like fish oil, or indeed Olive Leaf Extract may be potent enough, so you could use these daily without the need for any prescription medication.

In any case, Verapamil, if shown effective, looks a much safer bet than the usual ADHD stimulants like Ritalin.  If your ADHD was caused by calcium channel dysfunction, it would likely later appear elsewhere in your body; all those years on stimulants would not have helped you.

Recall that Verapamil can also be effective in bipolar.

What does Cancer Risk and Autism tell us?

Today’s post is a short one.

As you look deeper into how the body functions you come across many, only recently understood, pathways.  In reality these are still “works in progress”, but some will eventually lead to a better understanding of diseases like cancer, diabetes, Parkinson’s, Alzheimer’s and, eventually, many types of autism.

Within this blog we have seen how many common diseases share some underpinnings with autism.  As a result these diseases appear more commonly in people with autism, and so they get called comorbidities.

Some comorbidities get talked about quite a lot, things like epilepsy and MR/intellectual impairment.

For me the really interesting ones and the ones that might actual lead you to some therapeutic implication.  In this respect, allergies (food and airborne) have proved to be the most useful.

Not far behind are heart disease, diabetes and cancer.

In Paul Whiteley’s blog he recently highlighted a study showing how heart disease was increased in autism.  This has been noted before and I believe leads back to calcium channels, known to be dysfunctional in autism.  One particular channel is called Cav1.2 and it is widely expressed in the brain and the heart.  In earlier posts I have covered this channelopathy from the point of view of autism.  Not surprisingly, if you have Cav1.2 dysfunction in the brain, it might very well occur elsewhere.

There are little genetic errors called Single Nucleotide Polymorphisms, or SNPs.  In the CACNA1C gene there are 12,932 known SNPs.  Some of the most common ones are associated with autism, bipolar and schizophrenia.

You can look up this gene, or any other one, and see for yourself.

Genecards database

If you read the gene description above, the idea that heart disease is comorbid with autism is no surprise. 

The lower red arrow points at hypokalemic periodic paralysis.  This has appeared many times on this blog, along with Hypokalemic Sensory Overload.  I discovered long ago that there is a potassium ion channel dysfunction in autism; it appears to be behind the odd sensory overload experienced by many with autism and also in some people with ADHD.  What is interesting is that this dysfunction co-occurs with CACNA1C dysfunctions.

Cancer and Autism

The science behind cancer is complex and so as not to research it in vain, it is useful to know that there is solid evidence linking autism and cancer.

The following study of 8,438 people with autism, compared their incidence of cancer with the incidence in the general population

To understand the jargon first read this excerpt from a fact sheet on cancer statistics:

Fact Sheet: Explanation of Standardized Incidence Ratios

How an SIR Is Calculated

The expected number is calculated by multiplying each age-specific cancer incidence rate of the reference population by each age-specific population of the community in question and then adding up the results. If the observed number of cancer cases equals the expected number, the SIR is 1. If more cases are observed than expected, the SIR is greater than 1. If fewer cases are observed than expected, the SIR is less than 1.

Examples:

60 observed cases / 30 expected cases: the SIR is 60/30 = 2.0

Since 2.0 is 100% greater than 1.0, the SIR indicates an excess of 100%.

45 observed cases / 30 expected cases: the SIR is 45/30 = 1.5

Since 1.5 is 50% greater than 1.0, the SIR indicates an excess of 50%.

30 observed cases / 30 expected cases: the SIR is 30/30 = 1.0

A SIR of 1 would indicate no increase or decrease.

Here is the autism study:-

Risk of Cancer in Children, Adolescents, and Young Adults with Autistic Disorder

Objectives

To investigate whether individuals with autism have an increased risk for cancer relative to the general population.

Study design

We enrolled patients with autistic disorder from the Taiwan National Health Insurance database in years 1997-2011. A total of 8438 patients diagnosed with autism were retrieved from the Registry for Catastrophic Illness Patients database. The diagnosis of cancers was also based on the certificate of catastrophic illness, which requires histological confirmation. The risk of cancer among the autism cohort was determined with a standardized incidence ratio (SIR).

Results

During the observation period, cancer occurred in 20 individuals with autism, which was significantly higher than a total number of expected cancers with a SIR estimate of 1.94 (95% CI 1.18-2.99). The number of cancer in males was greater than the expected number with a SIR of 1.95 (1.11-3.16), but no excess risk was found for females with a SIR of 1.91 (0.52-4.88). Cancer developed more than expected in individuals age 15-19 years with the SIR of 3.58 (1.44-7.38), but did not differ in other age range groups. The number of cancers of genitourinary system was significantly in excess of the expected number (SIR 4.15; 95% CI 1.13-10.65), and increased risk was found in ovarian cancer with SIR of 9.21 (1.12-33.29).

Conclusions

Our study demonstrated that patients with autistic disorder have an increased risk of cancer.

So, overall, the risk of all cancers is about twice as high if you have autism.  

Certain cancers are particularly high risk and understanding why this is the case might lead to a better understanding of the “pathways” leading to some types of autism. Due to the rarity of some cancers, like ovarian, one might need to validate the result; note the (1.12-33.29) range for ovarian cancer.

Rather than worry about this risk, we should use these observations to understand and treat autism.

Just as we can counter the elevated risk of heart disease we can do the same for cancer.

Clearly the cancer pathways that will soon be appearing in this blog are relevant to autism.  But in the meantime anyone can reduce their cancer risk by ensuring a high level of antioxidants in their body.  People at higher risk are those with low levels of antioxidants, which include almost all older people and people of all ages with autism.

A vast wealth of information already exists showing the chemo-protective effect of antioxidants.  Cancer clearly generally results from multiple hits, and you may be unlucky to have a single gene that “ups” your risk.  By upping your antioxidant intake you can slash one risk, in this multiple step process.

It does not seem to matter which potent antioxidant you take, but you do need enough of it.  They are all slightly different and most likely a mix of several will yield the best result.

My current favourites are:-

·        NAC (N-acetyl cysteine)

·        ALA (Alpha lipoic acid) - Nrf2 activator

·        Sulforaphane – Nrf2 activator

·        Cocoa Flavanols

·        Lycopene (cooked tomato)

These should reduce both the risk of cancer risk and heart disease.

Other antioxidants mentioned in this blog include:-

·        L-Carnosine

·        Silibinin – Nrf2 activator

·        Selenium

One should be aware that avoiding cancer and treating an existing cancer are different tasks.  Once a cancer has developed, some antioxidants can interfere with the body’s own response mechanism.

My focus is preventative “medicine”.

We saw in an earlier post how children at risk of developing asthma could be identified by their atopic dermatitis.  By treating these children with a cheap mast cell stabilizer called Ketotifen, a trial showed how it was possible to avoid the onset of asthma.

I suspect that the same thing might be possible with epilepsy.  We saw in an earlier post that the first epileptic attack make a (epigenetic?) change, and thereafter there is a greatly increased risk of future seizures.

Other interesting preventative interventions, include statins to avoid Parkinson’s disease and Verapamil to avoid the onset of Type II diabetes.

I did explain all this to the European Medicines Agency some months ago, the idea of treating the comorbidities of autism BEFORE they occur.  Perhaps an idea before its time?

The Peter Hypothesis of TRH-induced Behavioural Homeostatis in Autism

This is a repost  from last year - the original got deleted.  TRH is another area that you will not find much if you Google "autism plus ......".  But, since writing this post, I did find other people using it for various neurological conditions.  It is another hormone/drug that seems to have a good effect when used in very small doses.










Abstract

Based on observation of a single boy with autism, thorough desk research, and one simple experiment, it is hypothesized that the hormone TRH (thyrotropin-releasing hormone) can induce a brief period of behavioural homeostatis.  During this period, behaviours appear to be modified to near normal.  It is further hypothesized that a TRH analog, Taltirelin, could induce prolonged periods of behavioural homeostatis.

Due to the very short half-life of TRH in plasma, it is necessary to use an analog of TRH.  The proposed TRH analog is Taltirelin hydrate, already licensed for human use since 2000 in Japan, under the trade name Ceredist.  Not only does Taltirelin hydrate have a substantially longer half-life, but it is also it induces a dramatically lower stimulating effect on the thyroid.

It has already been established (Ben-Ari, Lemmonier, Peter) that autistic behaviours are mediated by malfunctions in channelopathy. Ben-Ari’s work focused on the chloride importer NKCC1 and the chloride exporter KCC2. 

Peter drew parallels between the Autistic Sensory Overload (ASO), frequently observed in autism, and the channelopathy diseases hypokalemic periodic paralysis (HypoPP) and Hypokalemic Sensory Overstimulation (HypoSO).  Experimental evidence (Peter) supported the connection, since administration of oral potassium was shown to be a remedy in ASO, as it has already been proved to be in HypoSO and  HypoPP.

The effect of TRH on the central nervous system (CNS) is via receptors TRHR1 and TRHR2.  The exact function of TRHR1 and TRHR2  is not fully understood in the literature; but it appears to involve blocking the flow of K⁺ ions through certain channels.

Clearly only neurons with TRH receptors would be affected and it would be useful to study this in depth.

In the literature, TRH has been shown to have wide ranging benefits in numerous neurological disorders ranging from depression to motor neuron disease. The role of TRH was nicely summarized as “TRH broadly increases the coping capacity of the organism” and “the effects of TRH are not diagnosis specific, but neither are behavioural deficits.”

TRH has also even been demonstrated to help mitigate suicidal tendencies.  Suicide is currently a major problem in the US military.  In August 2012, a leading TRH researcher, Michael Kubek, from Indiana University was awarded a $3 million contract to develop a nasal spray that dispenses TRH. It is not clear whether it is TRH itself, or an analog.

Initial Observations

Having established that autism is at least partially reversible (Peter2012), an investigation was launched under the broad umbrella of Applied Neurological Analysis (Peter).  ANA combines real observations of odd behaviours in autism with the appliance of neuroscience from the literature.

The most important observation investigated was:-

      i.        Neurotypical behaviour during and following a period of extreme sensory exhilaration.

Two further observations were subsequently investigated:

     ii.        Reduction of autistic-like behaviours during fever

    iii.        Effect of oral potassium on Autistic Sensory Overload (ASO)

Neurotypical behaviour during and following extreme sensory exhilaration

This is an observation by Peter; I did not find any similar observations documented by others.  Only the carer would be able to note such behaviours and carers are highly prone to a lack of objectivity.

It was noted that whenever Monty was exposed to extremely windy and sunny conditions his behaviour and manner became decidedly neurotypical.  A perfect example is when riding on the open top deck of a city sightseeing tour bus; others include the open top deck of a large ferry boat crossing the open sea, or running along an exposed beach in windy conditions.

Being a keen photographer, I have learnt how to get great photos will good eye contact and happy facial expressions; this is not always easy with typical children, but is especially hard with an autistic child.  An autistic child like Monty, will not pose smiling for his photo.

Yet, if we go on the open top deck of a City tour bus, and I sit in the row in front of him, I can shoot great photos of Monty one after the other.  Even more interesting is that when the tour ends and we disembark, for a few minutes the neurotypical behaviour and mannerisms continue.

Last summer in Lisbon, Portugal, I had final proof, if it was needed.  The bus stopped, the tour was over and we were in Marques do Pombal Square.  Monty was with his Aunty and I was planning to take a few photos.  Then something totally bizarre happened; Monty walked towards me, stopped about 5 metres (15 feet) in front of me and posed for a photo.  This had never happened before and has not happened since.  He stood still and made a big grin with his mouth closed and the photo is unlike any other of the thousands that I have taken.

I have other less extreme examples, like swimming under water with Monty when I am rewarded with near constant direct eye contact; riding on a big motorbike or in a noisy/shaky old convertible Triumph Spitfire seems to have a similar effect.

Now to Applied Neurological Analysis

In late January 2013, I decided to turn detective and look for clues in the literature that would explain my observations.  It did not take me long.

I found a study from 1976 that investigated hormonal changes in an adult version of my son’s sensory exhilaration - parachute jumping.

Prolactin, thyrotropin, and growth hormone release during stress associated with parachute jumping (Noel Gl et al, May 1976, Aviat Space Environ Med)

I subsequently found a second, more recent and rigorous study of the same effect.

Hormonal Responses to Psychological Stress in Men Preparing for Skydiving (Chatterton RT et al 1997 Clinical Endocrinology and metabolism)

In both studies blood samples taken just after completing the parachute jump showed a spike in prolactin and growth hormone (GH).  The 1976 study also measured TSH, which also showed a spike; the 1997 study measured luteinizing hormone (LH) which also showed a spike.

Anterior Pituitary Gland and Hypothalamus Hormones

The anterior pituitary gland secretes at least eight hormones, of which six seem to be well understood

1.    Follicle stimulating hormone  (FSH)

2.    Luteinizing hormone (LH)

3.    Growth hormone (GH)

4.    Thyroid-stimulating hormone (TSH)

5.    Prolactin 

6.    Adrenocorticotropic hormone (ACTH)

7.    Beta-lipotropin

8.    Beta-endorpin

The basic roles of 1 to 6 seem understood.  Understanding of the role of prolactin, particularly in men, seems incomplete. The role 7 and 8 in human physiology remains unclear.

The anterior pituitary gland is itself is controlled by chemical messengers from the Hypothalamus.

It is not disputed that TSH is itself controlled by TRH (Thyrotropin-releasing Hormone) from the nearby hypothalamus.  In the textbooks (Vander’s Human Physiology 12^th Edition) Prolactin is controlled by Dopamine (DA), but in the footnotes and in the literature, Prolactin is actually controlled by TRH.  

What cannot be disputed is that a spike in TSH can only be caused by a spike in TRH and most likely the spike in prolactin was also caused by the spike in TRH.

The role of TRH

As long ago as 1975 it was established in the literature (Shambaugh et al) that the hormone TRH had functions beyond the control of thyrotropin (TSH) synthesis and secretion and therefore control over the important thyroid gland.  40 years later many people remain unaware of this.

Also in 1975, at the 5th International Congress of the International Society of Psychoneuroendocrinology a remarkable paper was presented, by Arthur Prange from the University of North Carolina (interestingly in 2007 he was still publishing papers on this subject):-

Behavioural Effects of Hypothalamic Releasing Hormones in Animals and Men

In this paper he points out the rapid, though brief, antidepressant effect of TRH in humans.  He comments on the reduced thyroid-stimulating response to thyrotropin releasing hormone in people with depression.

He comments further:-

“We have not been astonished to find that the apparent benefits of TRH are not specific to a single diagnostic group.  TRH is hormone, not a drug.  It probably influences a variety of functions, the alteration of which have behavioral consequences that can reasonably be regarded as improvements, or aggravation, in any diagnostic entity in which that function is involved. 

The effects of TRH are not diagnosis specific but neither are behavioral deficits….”

And

“TRH broadly increases the coping capacity of the organism”

Reduced thyroid-stimulating response to thyrotropin releasing hormone in ASD

Not only is there a reduced thyroid-stimulating response to thyrotropin releasing hormone in depression, but also in most types of mental illness. In 1991 this was established to be the case in autism (Hashimoto et al).

In 2003 Gary et al (including Mr Prange) produced their own hypothesis regarding the role of TRH in Homeostatic Regulation.

In 2007 there was a follow up, this time Yarborough et al (including Mr Prange), but by now Yarborough has set up his own Micro-Pharma called TRH Therapeutics LLC, and patents start getting filed.

 

The short summary of the research is that TRH appears to be a kind of “wonder” hormone that could be used to treat mental illness of most types, brain/spine trauma etc.

Clinical reports of therapeutic benefits with TRH

·         Antidepressant effects in major depression

·         Behavioral vigilance/motivational EEG activation in depression

·         Therapeutic effects in amyotrophic lateral sclerosis/motoneuron disease

·         Anticonvulsant actions in certain intractable epilepsies

·         Therapeutic effects in Alzheimer’s disease

·         Attenuation of scopolamine-induced memory impairment

·         Protective effect on ECT impairment of delayed memory recall

·         Therapeutic effects in spinal muscular atrophy

·         Effective to reduce post-stroke pathogenic emotional liability

·         Decrease in schizophrenic psychotic symptoms

·         Antagonism of ethanol inebriation

·         Neurological improvements post-stroke and head trauma

·         Reversal of benzodiazepam-induced sedation

·         Improved cognition in short-duration alcoholism

·         Therapeutic effects in spinal cord injury

·         Metabolic improvements in protracted critical illness

·         Improves urinary bladder function in spinal shock

·         Stimulates respiration post-general anesthesia

·         Hemodynamic stimulation in vegetative or brain-dead patients

·         Increases cerebral blood flow in cerebellar atrophy and in childhood acute encephalitis or encephalopathy

·         Therapeutic effects in central pontine myelinosis

·         Improves ‘disturbances of consciousness’ post-brain trauma

·         Therapeutic effects in spinocerebellar degeneration

·         Attenuates mania and alcohol withdrawal dysphoria

·         Clinical benefit in juvenile Alexander disease

Some suggested clinical indications for TRH analogs

·         Depression, especially accompanied by hypersomnolence

·         Chronic fatigue syndromes

·         Excessive daytime sleepiness (including narcolepsy), neurasthenia,

·         and lethargy

·         Sedation secondary to drugs, chemotherapy, or radiation therapy

·         Sedative intoxication/respiratory distress (ER setting)

·         Recovery from general anesthesia

·         Attention deficit/hyperactive disorder

·         Disturbances of circadian rhythm (e.g. jet lag)

·         Bipolar affective disorder as a mood stabilizer

·         Anxiety disorders

·         Alzheimer’s disease and other dementias with cognition deficits

·         Seizure disorders

·         Motor neuron disorders

·         May be particularly effective as adjunctive therapy

 Reduction of autistic-like behaviours during fever

It has been observed (Peter) that autistic behaviours diminish during fever.  This phenomenon has recently been tested and proven by Curran (Behaviors associated with fever in children with autism spectrum disorders . Curran, L. 2007, Pedriatics).  In trying to explain the results, five mechanisms were proposed.  The fifth mechanism is “stimulation of the hypothalamic-pituitary-adrenal axis leading to modifications of neurotransmitter production and interaction”; the paper adds “should any of these mechanisms be proved to effect behaviour changes in individuals with ASDs, this would stimulate research on potential treatments focused on these pathways”.

Well I am no Endocrinologist, but it would seem to me that TRH is most definitely involved in stimulation of the hypothalamic-pituitary-adrenal axis and I think I have proved (along with Mr Prange) that TRH affects behaviour changes in autism.

Effect of oral potassium on Autistic Sensory Overload (ASO)

One of the most glaring of autistic behaviours (Peter) is the apparent hypersensitivity to loud sound in general and certain sounds in particular. An autistic child will often cover his ears with his palms or index fingers.  There are many other noted sensory problems and entire books and indeed businesses have created around so-called Sensory Integration Therapy and Auditory Integration Training. Gomes (Auditory Hypersensitivity in Children and Teenagers with Autistic Spectrum Disorder. Gomes, E. 2004, Arq Neuropsiquiatr.)  has investigated auditory hypersensitivity in autism and concluded that, that the behavioral manifestations to sounds are not associated to hypersensitivity of the auditory pathways, but rather to difficulties in the upper processing at the level of the cerebral cortex, involving systems that usually are impaired in autistic spectrum patients, such as the limbic system. Identical results occur with other changes in sensitivity and their associated behaviors, as fear and reality distortions, which are complex interactions originated from upper processings, instead of specific hypersensitive pathways.

There is a known condition called Hypokalemic Sensory Overstimulation (HypoSO) with virtually identical symptoms.

“Hypokalemic sensory overstimulation is a condition characterized by similarities to ion channel disorders such as hypokalemic periodic paralysis. The symptoms of hypokalemic sensory overstimulation and that of sensory integration disorder and attention deficit disorder are quite the same. The relation between the three conditions is yet to be established” (Illnessopedia)

The sensory overstimulation in HypoSO goes away abruptly after taking an oral dose of potassium.

A study by Segal (Hypokalemic Sensory Overstimulation. Segal, M. 2007, Journal of Child Neurology) of two generations of a family with symptoms of sensory overstimulation draws parallels to subtypes of attention deficit disorder that have a peripheral sensory cause and suggests the possibility of novel forms of therapy.

It could be hypothesized that in autism the endogenous level of TRH is reduced this in turn reduces the blockade of K+ channels that linked to TRH receptors. This ion channel dysfunction then induces a kind of hypokalemic sensory overload.  This clearly needs further research.

It would be reasonable to test sound hypersensitivity when trialling oral TRH analog on autistic subjects. Indeed it would be useful to test for sound hypersensitivity in autistic subjects before and after giving an oral dose of potassium.  

Update

Between 7-11 March 2013 we did our own trial with oral potassium and we published the result on my blog.

http://epiphanyasd.blogspot.com/2013/03/nom-de-guerre-mon-frere-manchopathy.html

We demonstrated that an oral dose of potassium reduced sound sensitivity in our autistic subject, but not in his “normal” brother. QED

TRH in practice

Due to its very short half-life (5 minutes in plasma) there has not been much clinical use of TRH.  It was used to test thyroid function, before a modern test was developed.

Researchers seem to have done plenty of self-experimentation.

TRH has also been demonstrated to help mitigate suicidal tendencies.  Suicide is currently a major problem in the US military.  In August 2012, a leading TRH researcher, Michael Kubek, from Indiana University was awarded a $3 million contract to develop a nasal spray that dispenses TRH. It is not clear whether it is TRH itself or an analog.  Prior to this funding Kubek, had grants from an Epilepsy charity for his TRH research.  Kubek has been researching TRH much of his career.

The most interesting case is in Japan, where TRH was used for many years as a therapy for the degenerative disease Spinocerebellar Ataxia (SCA).  This disease (perhaps like ASD) has multiple types, each of which could be considered a disease in its own right.

In Japan there are approximately 30,000 patients with SCA.  Whereas in Western medicine this disease is seen as untreatable, in Japan, the Mitsubishi Tanabe Pharma Corporation developed an oral analog of TRH to replace the previous injections of TRH into the spine. The TRH analog is Taltirelin hydrate and the trade name Ceredist.  It has been licensed for use since 2000.  The drug is very slightly different to the hormone TRH, but these advantages are extremely important:-

·         Much longer half-life (a few hours as opposed to a few minutes)

·         Can cross both through the gut and blood brain barrier, allowing for an oral tablet

·         Substantially (50x ?) reduced releasing impact on the Anterior Pituitary Gland, so that TSH is not overproduced and the thyroid does not become overactive and hyperthyroidism is therefore avoided.

I did already contact the Mitsubishi Tanabe Pharma Corporation in Japan and Mr Junya Namba wrote back saying that Ceredist is only available in Japan.

I also obtained from Japan the Post-Marketing Surveillance of Ceredist Tablets on Spinocerebellar Degeneration (in Japanese).  The drug was well tolerated.

Taltirelin hydrate is currently produced and sold freely as a generic chemical.