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Sunday, 8 November 2015

The Brain is Hypothermic in Mitochondrial Disease, but is it in Autism?


Having noted in the previous post something as simple, and measurable, as reduced blood flow in the brain exists in autism, I decided to dig a little deeper.

Not only can you measure blood flow in specific regions of the brain, but using Magnetic Resonance Spectroscopy you can measure the temperature of the brain.

Intense heat production is an essential feature of normal brain energetics; most of the energy used for brain functioning is eventually released as heat.  In the brain, heat is produced mostly by mitochondrial oxidative chemical reactions. Most of the energy required for brain activity is generated from the net chemical reaction of oxygen and glucose; some of this energy (33%) is immediately dissipated into heat, and the rest (67%) is used to synthesize ATP. The final ATP hydrolysis releases part of the energy back to the system as heat.

Note that your core temperature is not the same as your brain temperature.


Brain temperature Tbr should be near constant

Increases in Cerebral Blood Flow reduce Tbr and increases in brain metabolism increase Tbr.

Neuronal activity is temperature dependent, with neuronal firing increasing with increased temperature.  Many other functions in the brain are temperature dependent.

When your brain gets too hot febrile seizures can be the result, caused by excessive neuronal firing.


Mitochondrial Disease

Since heat in the brain is produced mostly by mitochondrial oxidative chemical reactions, when mitochondrial disease is present, it would be expected that there would be less heat and therefore a lower Brain temperature Tbr.  This time biology is indeed logical and this is the case.  People with mitochondrial disease have measurably colder brains.




We sought to study brain temperature in patients with mitochondrial diseases in different functional states compared with healthy participants. Brain temperature and mitochondrial function were monitored in the visual cortex and the centrum semiovale at rest and during and after visual stimulation in seven individuals with mitochondrial diseases (n=5 with mitochondrial DNA mutations and n=2 with nuclear DNA mutations) and in 14 age- and sex-matched healthy control participants using a combined approach of visual stimulation, proton magnetic resonance spectroscopy (MRS), and phosphorus MRS. Brain temperature in control participants exhibited small changes during visual stimulation and a consistent increase, together with an increase in high-energy phosphate content, after visual stimulation. Brain temperature was persistently lower in individuals with mitochondrial diseases than in healthy participants at rest, during activation, and during recovery, without significant changes from one state to another and with a decrease in the high-energy phosphate content. The lowest brain temperature was observed in the patient with the most deranged mitochondrial function. In patients with mitochondrial diseases, the brain is hypothermic because of malfunctioning oxidative phosphorylation. Neuronal activity is reduced at rest, during physiologic brain stimulation, and after stimulation.


The question is whether this lower brain temperature, in itself, leads to changes in brain function/performance and hence mood, behaviours and cognition.



Mitochondrial Disease in Autism

There are various types of mitochondrial disorder in autism and, confusingly, different terminology is used for similar biological conditions.  Regressive autism triggered by a viral illness, fever, or in some cases a reaction to a vaccine is likely mitochondria-related.

I have covered Dr Kelley from Johns Hopkins ideas on this subject, but there are others.  Here are some other perspectives:-







Fever Effect in Autism

It is well documented that in many people with autism their symptoms subside when they are sick and have a fever.  This is the so-called “fever effect”.  It only applies to some people with autism and in a small number the effect can be dramatic.

There are numerous unproven theories.









  


Background:  The observation that some ASD patients manifest clinical improvement in response to fever suggests that symptoms may be modulated by immune-inflammatory factors.  The febrile hypothesis of ASD stems from this observation, and could be due to (1) the direct effect of temperature; (2) a resulting change in the immune inflammatory system function associated with the infection of fever; and/or (3) an increase in the functionality of a previously dysfunctional locus coeruleus-noradrenergic (LC-NA) system.  
Objectives:  To assess the effect of hyperthermia on ASD symptoms.
Methods:  We completed a double blind crossover study of 15 children with ASD (5 to 17 years) using two treatment conditions, hyperthermia condition (102°F) and control condition (98°F) in a HydroWorx aquatic therapy pool.  Five children with ASD without fever response acted as controls, completing only the hyperthermia condition, to ensure safety and feasibility.  Safety measures and Social Responsiveness Scale (SRS) were collected.  Ten patients with ASD and history of fever response were enrolled and received both treatment conditions.  Vital signs, temperature monitoring and clinical observations were completed throughout their time in the pool.  Parents completed the SRS and RBS-R.  Pupillometry biomarker and buccal swabs for DNA and RNA extraction were collected pre and post pool entry. 
Results:  Ten subjects with ASD and a history of fever response were enrolled and completed the hyperthermia condition (102°F) and control condition (98°F) at the aquatic therapy pool.  Improvement during the hyperthermia condition (102°F) was observed in social cognition, using the Social Responsiveness Scale (SRS) total raw score (p = 0.0430) and the SRS Social Behavior subscale raw scores (p = 0.0750); repetitive behaviors, using the Repetitive Behavior Scale-Revised (RBS; p =0.0603) and the SRS Restricted and Repetitive Behavior subscale (p = 0.0146); and on global improvement, using the Clinical Global Impression Scale-Improvement (CGI-I; p=0.0070). 
Conclusions:  This study demonstrates the feasibility of observing the direct effect of temperature in children with ASD, both with and without a history of febrile response, and provides preliminary data on the relationship between body temperature and changes in social and behavioral measures. It explores the direct effects of temperature on ASD symptoms, and offers a window into understanding mechanisms involved in improvement in ASD symptoms during fever episodes.  Behavior changes observed for each child were similar to those observed by parents during febrile episodes, including increased cooperation, communication and social reciprocity and decreased hyperactivity and inappropriate vocalizations. This study is important for the development of translational models on the mechanism of symptom improvement and the identification of novel targets for therapeutic development.



Why not measure Brain temperature Tbr in a large number of people with Autism?

The above study at the “Albert Einstein” medical school involved putting people in hot tubs to warm them up and then measuring their autistic symptoms. You would have thought it would have occurred to them to quickly pop upstairs to the MRI to measure brain temperature Tbr.  I do not think you need to be an Einstein to think of that.

Perhaps the people that exhibit the fever effect are the ones with low brain temperature Tbr ?  That would seem well worth checking.

It also is logical to just warm up the part of the body that will affect behaviour.


Hypothermia in Mouse Models

If you look up hypothermia and autism you again encounter Robert Naviaux, from University of California San Diego, and not much else.  Naviaux is a very clever researcher, but more importantly he just does not give up.  He is doggedly pursuing his antipurinergic therapy for autism.

It turns out that hypothermia is a feature of the maternal immune activation (MIA) mouse model of autism that he is using in his research.

Indeed his antipurinergic therapy corrects this hypothermia.








From:-


Relative hypothermia is a long-term feature of the Poly(IC) MIA Model. This is the lower line (PICSAL), when treated with Suramin, you get the yellow line PICSUR, with a higher body temperature similar to that of the regular mice (blue lines)  When they gave Suramin to regular mice (dark blue line) the was no overall change in body temperature.

So we know that in at least one major mouse model of autism, hypothermia is known feature.  Did anyone measure it in the others?



Conclusion

If raising Tbr improves autism symptoms so much, in some people, then why not just figure out a clever way to increase it?

Raising blood flow apparently should lower Tbr.

There are likely numerous options like increasing the oxygen level in the blood, which might be expected to increase heat production, for example using Diamox (Acetazolamid). 

Reducing heat loss by wearing a wooly hat, should marginally raise brain temperature, unless the brain then compensates for this.

Since the illicit drug MDMA, or ecstasy, is already known to raise brain temperature, there probably are ways to develop a safe drug therapy to achieve a small increase in brain temperature.  
  

Hopefully Naviaux will find a safe antipurinergic therapy, which might also be used in people with low Tbr, as well as broader autism.




10 comments:

  1. Does cocoa flavonoids increasing circulation -- does that raise blood flow or lower blood flow? If it raises blood flow --isn't that bad for this hypothermia -- or good?

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    1. Cocoa flavonoids should increase circulation.

      The science says that, all other things being equal, increased circulation should cool the brain down. Blood is both fuel and coolant.

      You might think that in someone where energy production in the brain was impaired, giving more "fuel", in the form of blood, might increase energy production and so raise the temperature.

      So I think it is not certain what would happen to brain temperature in someone with an "autism" diagnosis.

      In a totally healthy typical person, it looks like blood flow would increase and the temperature would fall. Energy conversion in the brain would stay the same. I expect this fall is tiny in magnitude.

      The studies show that the overall effect of cocoa in people with heart conditions and memory loss is positive. I expect the same will be later found to be true in diabetes. One day, hopefully, somebody will study autism and schizophrenia.

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  2. This is a very interesting article.
    Heating plays an important role in autism and most parents have noticed, not only during fever periods, but also when the temperature in their environment changes. Their relationship with heating looks pathological and it can change mood and behaviour.
    My son has a small heater beside his bed and switches it on when he wants to get up. He also has a hair drier which uses in other ways rather than drying his hair. When in cold weather the first thing he needs is a hat.
    Petroula

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    Replies
    1. I also think that a hat is a very simple thing that people could try. The hair dryer is another interesting idea.

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    2. Anonymous,I would like to know if your son feels cold all the time,even in Summer.I often have that problem.Your son might have have a cardiomyopathy like I do,These can be mitochondrial,genetic,or due to infections,or autoimmune/inflammatory.Some of the symptoms can include low blood pressure,and reduced cardiac output.My symptoms started in my teens.

      Peter,as I told you,I have found out through whole exome sequencing,I have a very rare chromosomal disorder,but I have severe mitochondrial dysfunction,as measured by two buccal studies.I have had many acute infections,especially pneumonia and encephalitis-like infection.All have caused equally severe regressions.Once you really start to investigate syndromic autism,and get to the bottom of these cases,they can be more complex than you think.I currently have seven diagnoses,counting autism.ASD,nonverbal learning disorder,Severe MTHFR Deficiency,,Megaloblastic Anemia,Cerebral Folate Deficiency,mitochondrial dysfunction,and Ataxia-telangiectasia-like-disorder.

      Delete
  3. Peter your articles are so interesting. Thank you.

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  4. Maybe 5 years ago I read about a device called "The Glove" which I believe was developed at Stanford and used on the Stanford football team which helped cool core body temperature which happens to be one of the main limiting factors in exercise performance (as well as mental performance as well). What it essentially was is a pressurized metal glove you put your hands in that cools the blood in your veins as it returns to the heart. Simply dunking yourself with a gatorade jug of ice will instead cause your body to respond to the change in temperature and start pumping more blood to your core organs and less to the periphery (muscles, skin, etc.) which is undesirable when it comes to athletics. Perhaps this device or a similar contraption could test for this hypothermic response.

    Another tidbit you might want to look into is the mammalian dive reflex. Basically, the carotid arteries open up and pump more blood to your brain when your face is dunked in cold water (like when you are going to dive underwater). In terms of simple ways to pump more blood to the brain (at least acutely) this is one way to do it, though I am not so sure how you would get an autistic child child to comply willingly.

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  5. Yes, they are -- hope you know how much we all appreciate all your work and making a difference in our children's (and our families) lives! Thanks! Marian

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  6. Hi Peter,

    We seem to have the opposite problem here. My daughter's brain appears to run hotter. A hat, extra warm water on the head, standing near a hot open oven, even a sweater in a warm room in winter, all tend to provoke seizures. I also read that in people with tbi, the brain runs a few degrees hotter. During a fever, at around 101F, she becomes very vulnerable to seizures. We hate fevers here, and thanks to verapamil, we have not had one in a year.

    What can I posit here, that she probably does not have mitochondrial disorder? It definitely makes sense that there is not enough blood flow.

    I will probably start her on the cocoa pretty soon, its just so very expensive. Have you seen any specific changes with it?

    Thank you.

    ReplyDelete
    Replies
    1. Cocoavia is very expensive, the ACTICOA product is cheaper.

      I would check and see if it does any good first. I did look around and found that country of origin is important. Indonesian Cocoa has naturally a high flavanol content. There is one company that produces cocoa at low temperatures over there, run by some Americans. You can buy it in the US, just google:-

      Big Tree Farms Cacao

      If the Cocoavia works, I would try the above cacao and see if is has the same effect.

      The specif change is good mood. I think other changes would take time and be more subjective.

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