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 T_br should be near constant

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

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 T_br.  This time biology is indeed logical and this is the case.  People with mitochondrial disease have measurably colder brains.

The brain is hypothermic in patients with mitochondrial diseases

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:-

Has Your Child with Autistic Symptoms Been Properly Screened for a Subset of  Mitochondrial Disease Known as OXPHOS?

Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis

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.

A Study of Behaviors Associated with Fever in Children with Autism/PDD

Hyperthermia and the amelioration of autism symptoms 

  

Hyperthermia and the Improvement of Autism Spectrum Disorder (ASD) Symptoms

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 T_br 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 T_br.  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 T_br ?  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:-

Antipurinergic therapy corrects the autism-like features in the poly(IC) mouse model.

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 T_br 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 T_br.

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 T_br, as well as broader autism.

Autism Flare-Ups & Leaky Blood Brain Barrier

As I discussed in an earlier post, autism flare-ups occur regularly in the lives of many autistic children.  The cause might be a pollen allergy, food allergy or indeed an illness that does not cause a fever.

That last part might sound odd, but fever actually reduces autistic behaviours.  This has been noted and documented by many, but never conclusively explained.  Lots of parents have noticed and one even created a blog about it, but they have not explained it.

To investigate the fever effect, you first need to understand thermoregulation, the process by which the body sets and maintains its temperature and the role played by of the HPA axis (hypothalamic-pituitary-adrenal axis).  The simplified explanation is that the body initiates a fever as part of its defence mechanism to the threat that has been detected, like an infection of some kind.  Certain hormones are released so as to raise and then maintain a steady higher temperature; they include TRH, ACTH, AVP, PRL and TSH. It occurred to me that if you could identify which hormone increase was behind the reduction in autistic behaviours during fever, you would be on to something really useful.  This is something that is very poorly covered in the literature and so it is very difficult to prove anything.  My hunch is that TRH is the one and I am looking into ways to prove it.  I wrote an early post all about TRH, which I believe, for other reasons could have great therapeutic value in autism. 

The Peter Hypothesis of TRH-induced Behavioural Homeostatis in Autism

Back to flare ups …

 

Sickness involving stress/inflammation, but without fever, makes autistic behaviours worse.  Stress and inflammation have been shown in research to make the Blood Brain Barrier (BBB) more permeable.  In an earlier post we discovered that histamine itself increases the permeability of the BBB.

If you want to read up on the BBB, here is some heavy reading:-

The Blood-Brain Barrier/Neurovascular Unit in Health and Disease

The other observation that seems not to get documented in the literature is the effect of a new cause of stress/inflammation on any previously existing or dormant ones.  This is very relevant in autism since part of the brain is known to be in a near permanent state of inflammation/stress.  So if a new site of inflammation/stress elsewhere in the body will “re-ignite” other weak sites around the body (including the brain) then we have a problem.  Just as we showed that pollen and food allergies sparked autism flare ups, so can a viral infection.

Because there is no temperature, you may hardly notice the virus. Most parents think their kids are only really sick if they have a temperature.

These observations actually apply to all of us.  My son Monty, aged 10 with ASD, currently has a virus that does not cause a fever.  I know all about it, because I subsequently caught it from him.  Having caught it myself, I see why it would affect Monty’s behaviour.  It goes on far longer than a common cold, but outwardly after a day sneezing and a runny nose there is little to notice.  Since I am now focused on autism flare up and comorbidities, I am taking a lot of notice.  I can see that in my own body sites of previous inflammation do indeed flare up.  Like many people, I occasionally suffer from GERD, which you might know better as “heartburn”.  This causes inflammation to the oesophagus and when it occurs you can actually feel it, as I can while writing this.

Imagine you have a brain with chronic neuroinflammation, even if you are taking steps to put out that fire (NAC and statins) along comes a wave of inflammatory cytokines released elsewhere in the body and they act to reignite the inflammation in the brain again.

In healthy neurotypical people the brain is better protected from such inflammatory cytokines due to a more effective Blood Brain Barrier (BBB).  In autism there is plenty of evidence pointing to a more permeable BBB.

You cannot stop your child getting pollen allergies, though you might well adjust diet to avoid food allergies; but can you do anything to keep those pro-inflammatory cytokines out of the brain?

We know for a fact that certain substances weaken the BBB; we just need to find the neuro-protective ones that can strengthen the BBB.  Such substances do indeed exist.  A common issue than arises is that what works in the test tube (in vitro) does not always work in humans (in vivo) and also what works in rodents (the typical laboratory test subject) may not apply to humans.

Other diseases linked to leaky BBB - Multiple Sclerosis & Alzheimer’s

The best known disease long thought to be caused by a breakdown in the BBB is multiple sclerosis.  People with MS and those trying to help them have a big interest in what might protect the BBB.

I found it interesting that recent research shows that Alzheimer’s disease is also triggered by a failure in the BBB.  

Alzheimer's protein damages blood brain barrier

Alzheimer's disease: A breach in the blood–brain barrier

Alterations in brain blood vessels in mice precede the neural dysfunction associated with Alzheimer's disease. The finding highlights potential targets for drug development.

Alzheimer’s disease (AD) is well researched/funded since it is the leading cause of dementia.  It is characterised by both oxidative stress and neuroinflammation, as is autism.  Drugs developed for AD that target strengthening the BBB or reducing stress/inflammation in the brain would be good targets to trial in autism.

Substances neuro-protective to the BBB.

If you look in the literature you struggle to find much research on strengthening the BBB.  Much more frequent reference is made to “neuro-protective” ,which is something good but subtly different.

  

Mast cell stabilizers.

                         

Mast cell stabilizer drugs work to prevent allergy cells called mast cells from breaking open and releasing chemicals that help cause inflammation.

 

Commonly used mast cell stabilizers in medicine include  the drugs Cromoglicic acid and   Ketotifen.  These drugs are used in treating allergies and asthma. Both these drugs have been covered in earlier posts and at least Ketotifen is used in autism. Some researchers suggest that truly effective mast cell stabilizers for humans do not exist.  It is suggested that mast cell stabilizers would be highly protective of the BBB.

Lipoic Acid

It has been stated that Lipoic acid is protective of the BBB, also known as  Alpha lipoic acid and thioctacid; it is another antioxidant.  I have also mentioned it previously in this blog.

Thioctacid is prescribed by doctors to patients with diabetic polyneuropathy in Germany and most East European countries.  It not only reduces symptoms of neuropathy but it also reduces the amount of insulin patients require.  It is given both intravenously and orally.  I am told that oral administration is effective, but research showed that IV has the strongest effect.

In autism some people in the US take advantage of its metal-chelating properties.  All anti-oxidants have should have metal-chelating properties, by the way.

 

Here is a study from the world of Multiple Sclerosis, into the protective properties of Lipoic Acid.

Lipoic Acid Affects Cellular Migration into the Central Nervous System and Stabilizes Blood-Brain Barrier Integrity

In the following research NAC was combined with Lipoic Acid to reverse memory impairment and oxidative stress in the brain.

The antioxidants α-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8  mice

These results support the hypothesis that oxidative stress can lead to cognitive dysfunction and provide evidence for a therapeutic role for antioxidants

From Iran, I found a hypothesis about lipoic acid reducing inflammation in autism. 

Gold nanoparticles and lipoic acid as a novel anti-inflammatory treatment for autism, a hypothesis

Anti-oxidants as neuroprotectors

Anti-oxidants will indirectly strengthen the BBB, since they reduce the oxidants that damage the BBB.  Are all anti-oxidants equal?  There is an argument that you should match the anti-oxidant to the oxidant.  The most powerful anti-oxidant available seems to be NAC, and I am already using it.  My second choice would be L-carnitine, since there has been at least one positive clinical trial in autism.

A prospective double-blind, randomized clinical trial of levocarnitine to treat autism spectrum disorders

It works in a quite different way to NAC and it also has an effect on the mitochondria.  As you saw above, there is also a case to be made for alpha lipoic acid (ALA), as an antioxidant.  In the research combinations of antioxidants have been trialled, just not for autism.  In an ideal world, some research would be carried out comparing the effectiveness of different combinations of NAC, Carnitine and ALA.

Interestingly as with lipoic acid, L-carnitine improves insulin response in diabetics.

I found this Alzheimer’s research interesting.  It tested NAC, carnitine and SAMe.  SAMe is used in to treat many neurological conditions, including ADHD, which I view as autism-lite.  It is also used to treat seizures, a major comorbidity of autism.

Effects ofdietary supplementation with N-acetyl cysteine, acetyl-L-carnitine andS-adenosyl methionine on cognitive performance and aggression in normal miceand mice expressing human ApoE4.

In addition to cognitive impairment, behavioral changes such as aggressive behavior, depression, and psychosis accompany Alzheimer's Disease. Such symptoms may arise due to imbalances in neurotransmitters rather than overt neurodegeneration. Herein, we demonstrate that combined administration of N-acetyl cysteine (an antioxidant and glutathione precursor that protects against A beta neurotoxicity), acetyl-L-carnitine (which raises ATP levels, protects mitochondria, and buffers A beta neurotoxicity), and S-adenosylmethionine (which facilitates glutathione usage and maintains acetylcholine levels) enhanced or maintain cognitive function, and attenuated or prevented aggression, in mouse models of aging and neurodegeneration. Enhancement of cognitive function was rapidly reversed upon withdrawal of the formulation and restored following additional rounds supplementation. Behavioral abnormalities correlated with a decline in acetylcholine, which was also prevented by this nutriceutical combination, suggesting that neurotransmitter imbalance may contribute to their manifestation. Treatment with this nutriceutical combination was able to compensate for lack of dietary folate and vitamin E, coupled with administration of dietary iron as a pro-oxidant (which collectively increase homocysteine and oxidative damage to brain tissue), indicating that it provided antioxidant neuroprotection. Maintenance of neurotransmitter levels and prevention of oxidative damage underscore the efficacy of a therapeutic approach that utilizes a combination of neuroprotective agents.

Statins

Statins are claimed to increase the integrity of the BBB.  I am already convinced of the benefit of Atorvastatin, for other reasons.

Flavonoids:  luteolin, Quercetin, Rutin

Dr Theoharides from Tufts University in Boston where he is Professor of Pharmacology, Internal Medicine (Allergy) and Biochemistry is a proponent of flavonoids to stabilize mast cells,  He favours a mix of luteolin, Quercetin, Rutin all mixed up in olive kernel oil.  He says it works far better than Ketotifen and cromolyn.  His mixture is marketed under the name Neuroprotek.

Mast stabilizers are claimed to reduce BBB permeability, so as a consequence these flavonoids should help

I initially found it odd that such a scientist was favouring natural extracts,  so I thought I would see what other neuro-protective extracts might be out there.

Naturally occurring neuro-protectants

The internet is full of natural remedies and most have little supporting evidence.  Here are two that I found interesting.

Blueberries

These are both very tasty, available and remarkably good for you; nobody is exactly sure why.  They seem to slow down cognitive decline in older people, reduce neuroinflammation and promote cell survival.

Antioxidant and neuroprotective properties of blueberry polyphenols: a critical review

Over the last 10 years an increasing scientific interest has developed about polyphenols, which are very abundant in blueberries, as they have been seen to produce favourable effects related to neuroprotection and linked to a possible decrease of age-related cognitive and motor decline, as shown by the improvement of such functions in animal models with a supplemented diet. Such effects could not only be explained through a purely antioxidant action but also through more complex mechanisms related to inflammation, genic expression, and regulation of cell survival

Blueberry supplemented diet reverses age-related decline in hippocampal HSP70 neuroprotection.

Withania Somnifera, also known as Ashwagandha

On the surface, this ages old Indian medical remedy looks interesting, not least because one study showed it could reverse Alzheimer’s Disease.  It is claimed to do many things, including protecting the BBB.

Withania somnifera reverses Alzheimer's disease pathology

Indeed it is an ingredient used in some supplements used for autism and if you Google it, you will parents recommending it.

Not being a regular to such types of “medicine” I did some research and found that you should buy the actual root rather than the ground up bits available in capsules.  The logic being that they put the leftovers in the capsules and that the capsules may give an overly concentrated dose, as compared to the tea version. 

With root you make a kind of herbal tea.  It is actually very easy and quite inexpensive; indeed the root seems easier to find than the capsules.  In keeping with my self-experimentation approach, I brewed up a batch of Withania somnifera tea and gave it a try.  Well there genuinely is an effect; you do feel different, although I would not call it “better”.  The problem is, as I learnt a couple of hours later, that it can, and does, irritate the gastrointestinal tract.  Maybe my brew was too strong or maybe I am just sensitive to it.  On WEBMD they list the following side effects:-

ASHWAGANDHA Side Effects & Safety

Ashwagandha is POSSIBLY SAFE when taken by mouth short-term. The long-term safety of ashwagandha is not known. Large doses of ashwagandha might cause stomach upset, diarrhoea, and vomiting.

It’s not known whether it’s safe to apply ashwagandha directly to the skin.

Special Precautions & Warnings:

Pregnancy and breast-feeding: Do not use ashwagandha if you are pregnant. It is rated LIKELY UNSAFE during pregnancy. There is some evidence that ashwagandha might cause miscarriages. Not enough is known about the use of ashwagandha during breast-feeding. Stay on the safe side and avoid use.

Stomach ulcers: Ashwagandha can irritate the gastrointestinal (GI) tract. Don’t use ashwagandha if you have a stomach ulcer.

“Auto-immune diseases” such as multiple sclerosis (MS), lupus (systemic lupus erythematosus, SLE), rheumatoid arthritis (RA), or other conditions: Ashwagandha might cause the immune system to become more active, and this could increase the symptoms of auto-immune diseases. If you have one of these conditions, it’s best to avoid using ashwagandha.

Surgery: Ashwagandha may slow down the central nervous system. Healthcare providers worry that anaesthesia and other medications during and after surgery might increase this effect. Stop taking ashwagandha at least 2 weeks before a scheduled surgery.

Since Ashwagandha can make the immune system more active, it would seem unsuitable for autism, which we have established in this blog is linked to an already overactive immune system.

Conclusion

Finding a remedy to permeability of the blood brain barrier (BBB), was never going to be simple, if it was, then multiple sclerosis and Alzheimer’s disease would have already  become curable.  But, knowing what weakens the BBB does help explain why autism flare-ups occur, and in turns this helps us to minimize them.

I think I will stick with the blueberries and steer clear of the Ashwagandha, at least until I have to worry about Alzheimer’s.  The L-carnitine is getting a trial as a supplemental anti-oxidant and mitochondria protector, as will Dr Theoharides’ somewhat expensive Neuroprotek.  Alpha lipoic acid is now in third position in my anti-oxidant league table and will be studied further.   NAC remains in pole position as antioxidant proven to reduce autistic behaviours.  The very inexpensive Ketotifen may have capabilities above and beyond those accepted by Theoharides, as suggested by the fact that it has the remarkable ability to prevent the onset of asthma in the at risk group.

I wrote an earlier post on flavonoids.  These are good parts of fruits that you usually miss out on in juices, since they are concentrated in the skins.  Indeed though olive oil contains beneficial flavonoids, many remain in the stone/kernel in the centre,  It was of interest to me that Theoharides uses olive kernel oil rather than regular olive oil to bind his Neuroprotek together.  All berries seem to be particularly good for you, including cranberries, blackberries, blueberries, billberries and raspberries. I think these flavonoids are likely more about promoting your general health than any autism breakthrough.