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Showing posts with label Cortisol. Show all posts
Showing posts with label Cortisol. Show all posts

Thursday, 6 June 2013

The Singing Statin, the BCL-2 Gene and Epigenetics

This post has something for both the casual reader and the scientists among you.  Today I will start with the science.

Epigenetics

Epigenetics are chemical markers that can appear on your DNA as the result of some environmental exposure, like diet or stress.  Methylation is a type of epigenetic change in which methyl groups are added to DNA and switch on or off the underlying gene.  This can have severe consequences depending on which gene is affected.

Identical Twins

It seems that if one identical twin has autism, there is a 70% chance that the other twin will be autistic.  In 30% of the cases the twin is neurotypical.  Researchers have very cleverly started to analyse pairs of twins from this 30% group and look for epigenetic marks.  This would highlight genetic causes of autism.

Apoptosis

Apoptosis is a tricky word to spell, for somebody like me, but is actually something quite simple; it is programmed cell death.  Apoptosis happens in all of us, all day long.  If it gets out of control, it becomes bad and something called atrophy will occur.  Too little apoptosis can result in irregular cell growth and cancer.

 
Candidate Genes

Using the epigenetics approach, in 2010 a study was published that identified two “candidate” genes linked to autism.  They were BCL-2 and RORA.

According to that study, BCL-2 is an anti-apoptotic protein located in the outer mitochondrial membrane that is important for cell survival under a variety of stressful conditions.  In other words BCL-2 inhibits cell death.

According to another source, BCL-2 is “one of the foremost anti-apoptotic molecules”.

A very recent study has identified more such genes, using the same approach.
 
If you are really interested in the genetics of autism, there is actually a database of all the indicated genes, maintained by the Simons Foundation.

  
BCL-2 and autism

Going back to 2001, researchers had already noted that the autistic brain was deficient in BCL-2 and they suggested that:-

“These results indicate for the first time that autistic cerebellum may be vulnerable to pro-apoptotic stimuli and to neuronal atrophy as a consequence of decreased BCL-2 levels.”


As we have already learned, in the autistic brain the important Purkinje Cells are reduced in number by half due to atrophy.  If BCL-2 can indeed reduce this excessive apoptosis, it should be a friend indeed.

 
Stimulating production of Bcl-2

Fortunately the clever people working with Professor Wood, at the University of Minnesota, have been studying cholesterol regulation in the brain for some time.  Here is what they have been up to:-

“The lab has recently made the novel discovery that statins both in vivo and in vitro stimulate gene expression and protein levels of one of the foremost anti-apoptotic molecules, Bcl-2. Currently, studies are focused on mechanisms of statin-induction of Bcl-2”

Or in plainer English, statin drugs increase your level of BCL-2 and so reduce cell death.
 

 
The Singing Statin

Now we have finished with the pure science and we move back to the practical world of applied science.

Monty, aged 9, has been taking atorvastatin for a few weeks.  After day one, he developed the urge to play the piano outside of lesson time.  Every day since, he has played more and more.  Now his piano teacher says she thinks he has absolute pitch.  It turns out that this is far more common in the autistic population and there is a great deal of research that has been done on this and music/autism in general.  Here is a short article on the subject.

Now in an earlier post we established the importance of the stress hormone cortisol and also the interesting finding that you can reduce it by singing.  Then I got people asking about, “what about just listening to music” or “what about playing an instrument”.  I did not do the research, but I think nothing works like a good sing.

So yesterday I was delighted to hear that Monty has started to sing spontaneously in his room.  He put on his Mozart CD and started to sing, with his own lyrics and not just in English, but also in his second language.

I have to thank Mr Pfizer and in fact Mr Bruce Roth for bringing us Atorvastatin (called Lipitor or Sortis, depending on where you live).  Mr Roth invented it in 1985.

Perhaps BCL-2 could be better named the Singing Gene?
 
 
 

Wednesday, 17 April 2013

Cortisol, AVP, Oxytocin - Part II Stress Reactivity Model

I think today's post is going to be one of my better efforts.  We are continuing with the theme of Cortisol, depression and stress; but we are going to add two further chemicals, both "social neuropeptides".

The reason than today's post is worth reading is that it will bridge neurobiology and neuropsychology.   For me at least, psychology is light reading whereas biology needs more thought and understanding.  A social neuropeptide is a nice term not invented by me; it seems to come from Dr Stein from the University of Cape Town.

Rather than understand everything about human hormones, we are just trying to understand stress and coping mechanisms, so that we can reduce or  just better manage autistic behaviours. 


Cortisol

Cortisol is a hormone that is very easy to measure; saliva samples will do just fine.  Cortisol levels, or changes in cortisol levels, tell us about how the body is coping with emotion stress.  We are not talking about oxidative stress, but clearly there is direct linkage between the two.

We know that cortisol is a hormonal body clock (it maintains diurnal rhythms), cortisol levels should peak 30 minutes after waking, decline rapidly in the morning and then reach its lowest level in the evening.  This is well illustrated in the figure below, from an excellent study by Vahdettin Bayazit from Turkey.  He was studying the effect of exercise and stress on cortisol levels.


 

Children with ASD are known to have atypical response to stress and some have dysregulation of diurnal rhythms and abnormally high evening cortisol levels.  Among children with ASD there are significant individual differences, so the level of dysregulation is variable.  Note that many children with ASD have sleeping disorders; not surprising really if their body clock is malfunctioning.


 
In Bayazit's study he comments:-
"The more unexpected finding was that the evening values (of cortisol) for the children with autism tended to be consistently elevated in comparison with the neurotypical group."
I do not find this result surprising; in fact I would expect it.
 
He goes on to tell us that it is known that older children with depression have altered hormone levels, including hypersecretion of cortisol in the evening.
 
Now back to a stressful event.  In Turkey, a group of high functioning children with ASD were given a public speaking task; their heart rates and saliva cortisol were measured, before, after and during this "stressful event".
 
 
 
 
All we need to note is that the stress tended to cause a spike in cortisol level.


Stress Reactivity Model

Now we combine biology with psychology.  I took an existing model from an excellent book called "The neuropsychology of Autism".  Chapter 22 has a paper by Suma Jacob et al; she provided the biology and I just added the psychology (the opposite of what you might have expected)
 
 
 
 


This model shows how the equilibrium in managing stress is hopefully maintained.

The two little interlopers on the chart above, oxytocin and AVP are social neuropeptides.  Oxytocin is seen as beneficial; it reduces stress levels and gives a feeling of wellbeing.  AVP (Arginine Vasopressin) works in conjunction with CRH (Cortisol Releasing Hormone) to control the release of cortisol.  AVP seems to work in a "bad" way, in that it exaggerates/magnifies natural changes in cortisol.  So if you have a lot of AVP, a small spike in cortisol would become a big spike in cortisol.

Both AVP and cortisol have numerous other functions in the body. For example AVP is also known as the antidiuretic hormone (ADH) and a version of it is used in therapy in extreme cases of bedwetting by children. Whoever designed the human body was either short of chemicals, or likes to play practical jokes.

We already learned in Part I, that you can reduce your own level of cortisol just by singing.  It is reassuring to know that you do not always need drugs.  There are in fact other ways that you can maintain your own homeostatis and reduce cortisol.

A clever clinical psychologist from the University of Zurich, called Markus Heinrichs,  has provided us with an excellent study that compares the effect of social support vs oxytocin as regulators of stress.  What he did was to create two groups of people, in one group each subject brought along their best friend; the other group all came alone.  Then each subject was put through this stressful process:-


"During the introduction to the TSST (Trier Social Stress Test) they were then told that they would be required to give a 5-min mock job interview to an unknown panel (consisting of one man and one woman) on personal suitability for a job and to enumerate their strengths and qualifications in an unstructured manner, followed by 5 min of mental arithmetic performed out loud. To increase task engagement, the job description was matched to each participant, taking into consideration his own individual goals and aspirations. The panel of evaluators were presented as experts in the evaluation of nonverbal behavior."

The subjects were typical males in their early 20s.  Half the subjects had social support of a friend being present, and then each group had either a placebo or had a dose of oxytocin.  Here are the results:-







The base case is the "No social support + placebo".  This shows the highest increase in cortisol (i.e. stress).  The calmest group had "social support + oxytocin".  Of great interest is that the "social support + placebo" ended up less stressed than the "no social support + oxytocin".

This experiment showed the clear positive effect of both social support and oxytocin.

So in the stress reactivity model (the blue one up top) I decided to add social support and singing.  Clearly there are plenty of other social/psychological strategies that would likely have a similar cortisol reducing effect. 


Another dose of cortisol will come shortly in Part III.






 

Sunday, 14 April 2013

Cortisol, AVP, Oxytocin - Part I Depression & Stress

Today starts a mini-series inspired by a reader’s comment about depression.  Angie, from Australia, pointed out that while the kids with ASD might not be depressed, many of the parents certainly are.  Not only will we address Angie’s point, but we will extend it a little and show how this can also help in our quest for the grail.

Many people have stressful lives, but some have discovered a special way to overcome this.  I was reading an English newspaper recently and there was an article about a celebrity cook, Nigella Lawson, who is very popular on the BBC.  While Jamie Oliver appears not to overindulge on his own cooking, it appears that Nigella does. Nigella was giving her tips to losing those excess pounds or kilograms.  The interesting part was not the treadmill in the spare room, but her comment about singing extremely loudly while using it.  
Here comes the science part.  Cortisol is an important hormone; and as we learnt previously when studying TRH, while a hormone may have a well-documented primary function, there may also have numerous additional effects.  The most important roles of cortisol are the activation of three metabolic pathways:-

1.    Generating glucose

2.    Anti-stress

3.    Anti-inflammation

The function that Nigella has stumbled upon is number two.  While we all need cortisol, too much is not good for you.
Cortisol is released in response to stress and while short term increases serve a valuable purpose, prolonged cortisol secretion, perhaps caused by chronic stress, can cause damaging physiological changes.
It would be nice if there was a way to reduce excess, stress-induced, cortisol and then you would feel calm, refreshed and ready to fight on.  While exercise is also very good for you, it is actually the singing that really makes Nigella feel good.

It is scientifically established that singing substantially reduces your level of cortisol, which in turn makes you feel much better.  Here is a link to simple study done in Angie’s home country and with the help of the Macquarie University Choir.
I could now tell you all about music therapy and its application in psychiatry.  If you are interested, do look into it; it is used to treat everything from autism to alcoholism.

In essence music is good for you; but it seems that making your own music is far more beneficial than just listening to other people.

Tip for parents
Follow Nigella’s example (and mine) and sing.
I will check to see if Angie does.


Back to ASD
Have you noticed that an autistic child is at their most stressed first thing in the morning?  I certainly have; this was particularly marked when Monty’s behaviour regressed.  My approach was and remains to have Monty through this possible trouble zone quickly; so once he is up, he should have breakfast, brush teeth and get dressed promptly. It proved an effective strategy.
I did wonder what the reason for this phenomenon was.  Originally, I thought it was just the fact that he had not eaten for a long time and so his blood sugar level had dropped.  This applies with all kids; if they have not eaten, they will get cranky.

Now I have an alternative explanation, and probably a better one. It is likely to do with the natural variation in cortisol levels in the blood that apparently peaks at about 8am and falls to a low for the day at bed time.  Wait to read more in Part II.

Autism, Depression and Suicidal Tendencies
It may not make cheerful reading, but one factor these three groups all have in common is dysregulation of the HPA, which is the Hypothalamic-Pituitary-Adrenal Axis.  There is also the well documented phenomenon of enhanced cortisol response to stress in children in autism. This will be continued in a science-heavy Part II and quite possibly will result in another hypothesis regarding a practical intervention.

Just to let you know, that my very long recent post about the TRH hypothesis has now gone for review to a clever and interested neuroscientist in the US.  I have a feeling that it will shortly be joined by my CRH (corticotropin releasing hormone) hypothesis; but maybe it should be called Angie’s CRH hypothesis?