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.

Autism, Schizophrenia, MR, 5 Overlapping Genes and Epigenetic Dysfunction

In a recent post I raised the issue of maybe we should be looking at the schizophrenia research, given that the condition appears very closely related to ASD.  Then I got rather side tracked by MR (Mental Retardation), now known as Intellectual Disability, in polite society.  Since schizophrenia is adult-onset, I thought it might attract some serious research; indeed it does.  

It turns out there may have been more sense than you thought, in my making “connections” between autism, schizophrenia and MR.

A striking study has just been published from Trinity College, Dublin.  It draws these three conditions together using genes and makes a remarkable conclusion regarding epigenetics.  Epigenetic change has already been highlighted as a key process behind the development of autism. 

The full paper is not openly available, but below is the abstract and here is a press release from the University. 

De novo mutations in schizophrenia implicate chromatin remodelling and support agenetic overlap with autism and intellectual disability

An excellent lay person’s summary is available in this article:-

A Single Genetic Variation Is Shared By People With Schizophrenia ,Autism, And Intellectual Disability

 

Scientists believe some cases of schizophrenia are caused by gene mutations passed from parents to children with environmental factors exacerbating the effects of such mutations. Yet researchers also believe some cases of the mental disorder may be caused by de novo genetic mutations (DNMs). DNMs are new defects in genes that occur only in offspring — in such cases, neither parent possesses the same defects as the child. These mutations are simple copying errors caused during mechanical DNA replication. They occur infrequently in every human being during sperm and egg development, but typically they have no overall impact on human health.

However, when de novo mutations occur in a gene or genes indispensable for normal development they have devastating consequences. For this reason, McCombie and his colleagues, in an ongoing collaboration with Dr. Aiden Corvin of Trinity College, Dublin, hypothesized there may some special link between schizophrenia and DNMs.

For the current study, then, the team enlisted the help of 42 “trio” families in which the child, but neither parent, was diagnosed with schizophrenia and/or psychosis. They also enrolled 15 trio families with a history of psychosis. Then they set to work, searching for de novo mutations. What did they discover?

Among the 42 affected children in the study, they discovered de novo mutations in three genes: AUTS2, CDH8, and MECP2. (In prior genetic studies, mutations on these very same genes have been identified in people with autism.) Two other mutated genes found in the participants — HUWE1 and TRAPPC9 — have been similarly linked to people with intellectual disability.  Of these five "overlapping" genes, three — CHD8, MECP2 and HUWE1 — play a role in what scientists call the epigenetic regulation of transcription. That is, these three genes are involved in a complex molecular process that determines when and which genes are switched on or switched off.

"There's a growing awareness of the importance of epigenetic regulation during brain development, as well as in cognition in the mature brain," said Dr. Shane McCarthy, a CSHL research investigator and lead author of the new study. This regulation is the reason why the team’s discovery is so important — normal brain development depends on these genes. With this study, then, de novo mutations of these genes have been linked to not just schizophrenia but autism and intellectual disability as well.

Conclusion

This is actually all very important.  Epigenetics is a mechanism whereby the environment can affect your genes (flipping a specific gene, from on to off, or off to on).  Epigenetic changes can be inherited and so pass through the generations.  In theory, it can potentially be reversed.  Epigenetic change is not a good thing; but it seems that in people with autism, key genes have mutated that make them more prone to such epigenetic change.  So this might explain why people with autism are prone to so many other things (comorbidities) as well.  It might also explain why they are autistic in the first place; they were already at risk, but in addition they were more vulnerable to any kind of environmental insult.  The number of environmental insults is increasing in modern society and we are slowly accumulating some of the epigenetic flaws of our ancestors.  This might explain the increase in autism, particularly in modern societies, where environmental insults are more likely.

The other interesting point is that the five overlapping genes related to autism, MR and schizophrenia in the study are all new mutations; they were not inherited from the parents.  Many parents, and indeed pseudo-experts with their therapy “protocols”, often suggest that autism is nothing to do with genetics and they look for other factors to "blame", like heavy metals.  Parents clearly do not want to feel autism was their “fault”.  As this study shows, these five critical genetic causes are not inherited, they are just the result of imperfections in the copying process.  So in the case of these five genes, parents can accept the scientific evidence without any feeling of guilt. 

People with autism, but no MR, should probably count themselves very lucky indeed.