Oxidative Stress, Central Hypothyroidism, Autism and You

   Warsaw University of Life Sciences, Source: Wikipedia

Regular readers of this blog will have noticed there are some strange things going on related to endocrinology in the autistic brain; in effect there are low levels of certain critical hormones.

We saw in research from the Harvard Medical School that it seemed that oxidative stress in the brain affected the level of a key enzyme D2 (iodothyronine deiodinase type 2).  D2 has an important role; it converts the passive thyroid pro-hormone T4,  into the active thyroid hormone T3.  Without enough T3, you are said to be hypothyroid.  When the brain is affected, it is called central hypothyroidism.

As T3 is essential for cellular metabolism, growth and differentiation, and thus critical for brain development, thyroid deficiency during embryonic or early postnatal periods would likely lead to developmental abnormalities, including autism.

Now we have some follow up research from Harvard and Warsaw University.  The paper is more readable than many scientific papers, so click on the full version below.

DISRUPTED BRAIN THYROID HORMONE HOMEOSTASIS AND ALTERED THYROID HORMONE-DEPENDENT BRAIN GENE EXPRESSION IN AUTISM SPECTRUM DISORDERS

“While the mechanism responsible for the decrease in brain T3 levels in ASD is unclear, the relationship between T3 and Hg (mercury) should not be that easily dismissed.

Our recent animal study of perinatal mercury exposure in rats supports the possibility that the environmental toxicants can affect brain deiodinases and thus affect brain TH (thyroid hormone) status even in absence of systemic hormonal deregulation

Total Hg levels were determined in human postmortem cerebellar and brain stem samples derived from both male and female ASD cases. The results of this analysis, presented in Fig. 4 as the male and female combined data, indicate no significant difference in Hg levels between control and ASD cases in either the brainstem or the cerebellar samples.

Thus, changes in oxidative stress levels reported here could also modulate D2 activity. It is of interest that TH regulates GSH levels in the developing brain and treatment of astrocyte cultures with TH results in increased GSH levels and improved antioxidant defense, suggesting that TH plays a positive role in maintaining GSH homeostasis and protecting the brain from oxidative stress. Thus lower T3 levels in ASD brain may exacerbate the oxidative stress.

The results presented here suggest that putamen is the brain region that exhibits not only an increase in oxidative stress and a decrease in T3 levels, but also most prominent changes in gene expression in ASD. Interestingly, the putamen's main function is to regulate movements and influence reinforcement and implicit learning, processes that rely on interaction with the environment; abnormal sensory reactions are part of autistic pathology. Thus, present study further implicates this brain region in autistic pathology.

Decreased brain TH levels and changes in gene expression in ASD brains, suggested by the present study, are likely to impact the developing brain and have clinical implications. It has been previously observed that deficiency of T3 during early postnatal periods impacts basic stages of development i.e. neurogenesis, cell migration of, and synaptogenesis that could contribute to downstream functional and structural damages observed in ASD brains. At this point, because the instability of D2 in the postmortem tissue and lack of detectable D3 activity we can only speculate on the molecular mechanisms involved in decreased TH in ASD brains. However, present data suggest that the role of TH in ASD pathology should not be dismissed prematurely and certainly requires further study, especially since correction of TH deficiency may offer new therapies.

Our results showed, for the first time, brain region-specific decrease in TH levels in the cortical regions of ASD male cases. Data reported here, although derived from a limited sample size, suggest the possibility of brain region-specific disruption of TH homeostasis in autistic brain. Furthermore, brain region-specific changes in TH-dependent gene expression reported here suggest disruption of gene expression that could possibly impact the developing brain and contribute to the autistic pathology. While the postmortem instability of brain deiodinases precluded further molecular studies, the role of TH in ASD pathology and TH-based new therapies warrant future studies.

The expression of several thyroid hormone (TH)-dependent genes was altered in ASD. Data reported here suggest the possibility of brain region-specific disruption of TH homeostasis and gene expression in autism. “

Conclusion

We know that T3 is reduced in the autistic brain.  This may be because oxidative stress has reduced the level of the enzyme D2, but we cannot be sure, because the brain samples are old and D2 will decay with time.

The authors clearly hope that thyroid hormone-based therapies for autism will emerge.  Autistic people are likely to be euthyroid, so in their blood the thyroid levels are just fine; it is just in the brain the level of T3 is low. A successful therapy would raise the level of T3 in the brain, without affecting the level of T3 in the blood.

Reducing oxidative stress (if present) can only do good.  This is easily done with N-acetylcysteine (NAC).  If giving NAC reduces stimming/stereotypy, then the odds are that you have oxidative stress.  Oxidative stress appears to be chronic, it never goes away; you can treat it, but you cannot cure it.  We also saw this is the asthma research, where smokers were resistant to asthma drugs.  Even decades after ceasing to smoke, oxidative stress lingered and reduced the effectiveness of drugs.  In asthma the treatment for oxidative stress is NAC.

If you want a diagnostic test to establish central hypothyroidism (without any injections), this is easy.  Just give a small dose of T3 for a few days.  Before the thyroid has time to reduce its natural thyroid output, there will be a temporary increase in brain T3 levels.  If behavior improves notably for a day or two and then reverts, you have established a case of central hypothyroidism and seen how it affects behavior.

The scientific method of determining central hypothyroidism uses a test called the TRH stimulation test; but you do not get to see how behavior changes when T3 increases in the brain.

Also, note again that while mercury is definitely very bad for you, the study showed that the brains of people with autism had no more mercury than the control group.

We also see that while oxidative stress may cause a reduction in brain T3 levels, low T3 levels promote further oxidative stress.  So it is a self-perpetuating process.  This brings us back again to my venn diagram, where everything is inter-related. 

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.