Leukemia, IL-6 IL-10 and an Autism Flare-up

   

Leukemia/Leukaemia  is cancer that begins in the bone marrow and result in high numbers of abnormal white blood cells.

I received a comment on this blog a long time ago from a parent whose child had initially responded well to some of the autism therapies suggested on this blog. Later on all the therapies stopped working.  That child also has leukemia.

We now know this is a common event when you start treating autism, some comorbidity arises that blocks the effects of those therapies.  In my son’s case it is a simple pollen allergy, but it can be all kinds of inflammatory conditions such as colitis, IBS, IBD, GERD, celiac disease, juvenile arthritis, mastocytosis etc.  This list goes on, but now I know why it includes leukemia.

I do not consider epilepsy, or indeed cognitive dysfunction, as comorbidities.  Epilepsy is periodic extreme neuronal hyper-excitability, whereas in much autism there is chronic neuronal hyper-excitability.  Not surprisingly, chronic neuronal hyper-excitability can develop to periodic extreme neuronal hyper-excitability.  So I see epilepsy as a natural progression from childhood autism, but one that perhaps could and should be prevented.

Earlier on writing this blog I thought that genetics and cancer pathways would be beyond its scope, but in apparent absence of anyone much else publicizing the connections with autism I revised my view.

It has been known since 1930 that leukemia is comorbid with Down Syndrome (DS).  DS is caused by caused by the presence of all, or part of a third copy of chromosome 21 this leads to over expression of 300+ genes.  DS is usually easy to diagnose based on physical appearance .  The gene over-expression frequently leads to autistic behaviors and somewhat less frequently to various types of leukemia and in later years early onset Alzheimer’s.  The good news is that DS  children with acute myeloid leukemia (AML), and in particular the acute megakaryocytic leukemia (AMkL) subtype, have exceptionally high cure rates.

The particular gene that is over-expressed in DS and can cause leukemia is called HMGN1.

DS is increasingly rare in Europe, but quite common in the US due to differences in parental choice regarding the termination of pregnancies identified as high risk of Down Syndrome.

I think it only fair to consider leukemia as a possible comorbidity of autism, since may people with DS do indeed exhibit autistic behaviors.

There is no quality data to say how common leukemia is in non-DS autism.

 

Leukemia and Cytokines IL-6 and IL-10

I do consider the pro-inflammatory cytokine IL-6 to be public enemy number one of autism, while the anti-inflammatory cytokine is a potential friend.

There are different types of Leukemia, but it appears that IL-6 and IL-10 play a key role and at least in acute myeloid leukemia can predict the outcome.  Generally speaking leukemia is associated with elevated IL-6 and in particular when there is a relapse.

Acute myeloid leukemia (AML) blast cells frequently produce interleukin-6 (IL-6) 

“Serum levels of Interleukin-6 can be used as prognostic serum markers at diagnosis of adults acute myeloid leukemia and it could be used as follow up parameters for early detection of relapse stage”

Cytokine profiles in acute myeloid leukemia patients at diagnosis: survival is inversely correlated with IL-6 and directly correlated with IL-10 levels

An aberrant production of the pro-inflammatory cytokines IL-6 and TNF-α and the anti-inflammatory cytokine IL-10 is observed in AML patients. Low levels of IL-6 and high levels of IL-10 represent favorable prognostic factors for survival in AML patients. These results support the idea that cytokine deregulation may be useful as a marker for predicting clinical evolution in AML patients.

So we can infer that a leukemia relapse will likely lead to a worsening of autism driven by an elevation in the level of the pro-inflammatory cytokine IL-6.  This would account for why the autism drugs “stopped working” in the case of our reader.

We could then ponder that a therapy that reduces IL-6 and increases IL-10 might help keep some types of leukemia in remission.

This is altering the Th1/Th2 balance which was the target of our reader Alli from Switzerland who did decide to spend many hours reading the oncology research to understand all those cellular signaling pathways.

For those interested in why DS increases the risk of leukemia, scientists at the Dana-Farber Institute in Boston have figured this out, at least in the case of one common form of Leukemia.

Link between Down syndrome, leukemia uncovered

If only some more of the clever people studied autism.

Treating KCC2 Down-Regulation in Autism, Rett/Down Syndromes, Epilepsy and Neuronal Trauma ?

In this composite image, a human nerve cell derived from a patient with Rett syndrome shows significantly decreased levels of KCC2 compared to a control cell.  This will be equally true of about 50% people with classic autism, people with Down syndrome, many with TBI and many with epilepsy

In a recent post I highlighted an idea from the epilepsy research to treat a common phenomenon also found in much classic autism.  Neurons are in an immature state with too much intracellular chloride, the transporter that brings it in, called NKCC1, is over-expressed and the one that takes it out, KCC2, is under-expressed.  The net result is high levels of intracellular chloride and this leaves the brain in an over-excited state (GABA working in reverse) reducing cognitive function and with a reduced threshold to seizures.

The epilepsy research noted that increased BDNF is one factor that down regulates KCC2, which would have taken chloride out of the cells.  So it was suggested to block BDNF, or something closely related called trkB.

Unfortunately there is no easy way to this.  But I did some more digging and found various other ways to upregulate KCC2.

There is indeed a clever safe way that may achieve this and it is a therapy that I have already suggested for other reasons, intranasal insulin.

BDNF is a neurotrophin and other neurothrophins also have the ability to regulate KCC2. IGF-1 is another such neurotrophin and we even have very recent experimental data showing its effect on KCC2.

Regular readers will know that several trials with IGF-1, or analogs thereof, are underway.

I actually am rather biased against IGF-1 as a therapy, since in my son’s case the level of IGF-1 in blood is already high.  So I do not want to inject him with IGF-1 or even give him an oral analog.

However by using intranasal insulin the effect would be just within the CNS and insulin binds at the same receptors as IGF-1. So if IGF-1 upregulates KCC2 so will insulin.

We know from extensive existing trial data and direct feedback from one researcher that intranasal insulin is well tolerated and has no effect outside the CNS.

So rather to my surprise there seems to be a safe, cheap way to treat KCC2 down-regulation and this would also be applicable in epilepsy, traumatic brain injury (TBI) and any other condition involving immature neurons or neuronal trauma. 

The Science

There is a very thorough recent review paper that looks at all the ways that KCC2 expression is regulated.

Current view on the functional regulation of the neuronal K⁺-Cl⁻ cotransporter KCC2

The epilepsy researchers consider trkB, top left in the figure below.  But just next to it is IGFR which can be activated by both insulin and IGF-1.

In Rett syndrome they are already using IGF-1 to modulate KCC2.  The research is done at Penn State.

As you can see in the figure the mechanism for IGF-1 and insulin is not the same as BNDF/trkb, but Penn State have already shown that IGF-1 works in vitro.

We saw in early posts regarding intranasal insulin that this was a safe way to deliver insulin to the brain without effects in the rest of the body.

So we know it is safe and in theory it should achieve the same thing that the Penn State researchers are trying to achieve.

Signaling pathways controlling KCC2 function. The regulation of KCC2 activity is mediated by many proteins including kinases and phosphatases. It affects either the steady state protein expression at the plasma membrane or the KCC2 protein recycling. All the different pathways are explained and discussed in the main text. The schematic drawings of KCC2 as well as other membrane molecules do not reflect their oligomeric structure. GRFα2, GDNF family receptor α2; BDNF, Brain-derived neurotrophic factor; TrKB, Tropomyosin receptor kinase B; Insulin, Insulin-like growth factor 1 (IGF-1); IGFR, Insulin-like growth factor 1 receptor; mGluR1, Group I metabotropic glutamate receptor; 5-HT-2A, 5-hydroxytryptamine (5-HT) type 2A receptor; mAChR, Muscarinic acetylcholine receptor; NMDAR, N-methyl-D-aspartate receptor; mZnR, Metabotropic zinc-sensing receptor (mZnR); GPR39, G-protein-coupled receptor (GPR39); ERK-1,2, Extracellular signal-regulated kinases 1, 2; PKC, Protein kinase C; Src-TK, cytosolic Scr tyrosine kinase; WNKs1–4, with-no-lysine [K] kinase 1–4; SPAK, Ste20p-related proline/alanine-rich kinase; OSR1, oxidative stress-responsive kinase -1; Tph, Tyrosine phosphatase; PP1, protein phosphatase 1; Egr4, Early growth response transcription factor 4; USF 1/2, Upstream stimulating factor 1, 2.

The Penn State research on using IGF-1 to increase KCC2 in Rett Syndrome

Discovery of a new drug target could lead to novel treatment for severe autism

The researchers also showed that treating diseased nerve cells with insulin-like growth factor 1 (IGF1) elevated the level of KCC2 and corrected the function of the GABA neurotransmitter. IGF1 is a molecule that has been shown to alleviate symptoms in a mouse model of Rett Syndrome and is the subject of an ongoing phase-2 clinical trial for the treatment of the disease in humans.

"The finding that IGF1 can rescue the impaired KCC2 level in Rett neurons is important not only because it provides an explanation for the action of IGF1," said Xin Tang, a graduate student in Chen's Lab and the first-listed author of the paper, "but also because it opens the possibility of finding more small molecules that can act on KCC2 to treat Rett syndrome and other autism spectrum disorders."

More Melatonin?

As Agnieszka pointed out in the previous post it appears that extremely high doses of melatonin can increase KCC2 in traumatic brain injury (TBI). In this example BDNF was increased by the therapy, so I think TBI may be a specific case.  In most autism BDNF starts out elevated and in epilepsy, seizures are known to increase BDNF and that process is seen as down regulating KCC2 expression.  So in much autism and epilepsy you want less BDNF.

Melatonin attenuates neuronal apoptosis through up-regulation of K+ -Cl- cotransporter KCC2 expression following traumatic brain injury in rats

Compared with the vehicle group, melatonin treatment altered the down-regulation of KCC2 expression in both mRNA and protein levels after TBI. Also, melatonin treatment increased the protein levels of brain-derived neurotrophic factor (BDNF) and phosphorylated extracellular signal-regulated kinase (p-ERK). Simultaneously, melatonin administration ameliorated cortical neuronal apoptosis, reduced brain edema, and attenuated neurological deficits after TBI. In conclusion, our findings suggested that melatonin restores KCC2 expression, inhibits neuronal apoptosis and attenuates secondary brain injury after TBI, partially through activation of BDNF/ERK pathway.

More Science

There is plenty more science on this subject.

It is suggested that in addition to IGF-1/insulin it may be necessary to involve Protein tyrosine kinase (PTK).

Insulin-Like Growth Factor 1 and a Cytosolic Tyrosine Kinase Activate Chloride Outward Transport during Maturation of Hippocampal Neurons

Protein tyrosine kinase (PTK) phosphorylation is considered a key biochemical event in numerous cellular processes, including proliferation, growth, and differentiation, and has also been implicated in synaptogenesis. Protein tyrosine kinases are subdivided into the cytosolic nonreceptor family and the transmembrane growth factor receptor family, which includes receptors for insulin and insulin-like growth factor (IGF-1). The maturation of postsynaptic inhibition may require both a cytoplasmic PTK, which increases GABA_A receptor-mediated currents, and insulin, which was shown to induce a rapid translocation of GABA_A receptors from intracellular compartments to the plasma membrane. KCC2 is also known to have a C-terminal PTK consensus site. Therefore, the maturation of postsynaptic inhibition may, in addition to other mechanisms, also involve the effects of PTK and insulin acting on KCC2.

Development and regulation of chloride homeostasis in the central nervous system

Conclusion

I would infer from all this science that intranasal insulin is likely to increase KCC2 expression in the brain, certainly worthy of investigation.

Protein tyrosine kinase (PTK) phosphorylation is considered a key biochemical event in numerous cellular processes.  This might be a limiting factor on the effectiveness of insulin in raising KCC2.  This would then add yet more complexity.

Protein kinases are enzymes that add a phosphate(PO₄) group to a protein, and can modulate its function.  A protein kinase inhibitor is a type of enzyme inhibitor that blocks the action of one or more protein kinases.

Abnormal protein tyrosine kinases (PTKs) cause many human leukaemias, so there is research into PTK inhibitors (PTK-Is).

As we know from Abha Chauhan’s mammoth book, oxidative stress controls the activities of PTK.

Longitude, Latitude & Epilepsy in Autism

It is not always easy to decide which subjects to study, never mind if you have autism.

For Monty, aged 12 with autism, it has been me choosing what he studies.  At the beginning it was rather overwhelming for his 1:1 assistant, because there was so much to learn and never enough time.  It takes years to learn very simple things that typical kids just pick up naturally.

One big change after three and half years of Polypill use, is that Monty follows the standard academic curriculum, albeit for kids two years his junior.

An excellent but not very user friendly curriculum/skill list is in a book called ABLLS (assessment of basic language and learning skills).  It is both a curriculum and an assessment tool.  It covers all the very basic skills that kids need as a foundation for future learning.

We were working from this list of simple skills for four years, until the age of eight.  These are skills most kids effortlessly pick up in the first three or four years of life.

After you have mastered those simple skills what do you teach next to someone with classic autism?

I did my research and concluded the generally accepted answer is “not much”.

One phrase I still recall was a mother writing “our kids don’t need to learn longitude and latitude”, because this is going to go way over their heads.

It seems that for kids entirely non-verbal at three, about 10% have some maturational dysfunction that self-corrects by six, leaving just minor tics or perhaps mild "quirky" autism. Most of the remaining 90% end up "graduating" high school with an academic level of a four to seven year old.  A small number do better.  

A few years after ABLLS and Monty has mastered X,Y coordinates, even using negative numbers and identifying objects using Northwest, Southeast etc.

Regular readers will be aware that Monty’s recent academic development did not happen spontaneously, nor through ABA, it came from pharmacotherapy (drugs) and is reversible (hopefully not entirely).

Burden of proof

In spite of all this change it would be hard to prove what has caused it. Fortunately I do not need to.

Monty is still autistic, just less so and is now educable. That is a really big deal to me, but not to others. 

If you could convert 100% of kids with autism into outgoing, talkative, social, intelligent, typical kids then people would take note.  No therapy will ever deliver this. Just to confuse the issue, 10% will indeed "recover" without any intervention at all, which then is used to justify all kinds of interventions that those people used.

Have I measured Monty’s IQ?  No I have not.  A lady from California asked me why not, because over there they have excellent autism services, even assisted employment and sheltered housing but it is rationed based on things including IQ. 

One doctor reader of this blog suggested that some of the drug interventions in this blog will also reduce the development of seizures and therefore reduce the rate of premature death in autism; “surely we should tell people about this”.  I had a sense of déjà vu.

It is clear that in treating the excitatory/inhibitory imbalance that underlies much autism and also treating other channelopathies, you should also be avoiding some of the neuronal hyper-excitability that is epilepsy.

So treating autism should reduce death from seizures that reduce life expectancy in severe autism to just 40 years old.

This is all true and a year or so back I did suggest this to the Bumetanide researchers.  There was little interest and some skepticism. 

In fact there is a great deal of epilepsy research and some does indeed overlap with autism research.  One key area is Cation Chloride Cotransporters (CCCs), where the same type of immature neurons found in autism are found in epilepsy. Another is elevated BDNF (brain-derived neurotropic factor); in epilepsy, seizures trigger an increase in BDNF which then reduces expression of KCC2 which then shifts neurons further towards immature (high intra-cellular chloride) worsening the excitatory/inhibitory imbalance and making the next seizure more likely.  A clever idea we can borrow from the under-utilized epilepsy research is to consider blocking BDNF, or trkB, as a means of increasing KCC2 expression.  This could be a useful adjunct therapy to bumetanide, which blocks NKCC1. We want less NKCC1 but more KCC2, to give lower levels of chloride inside the cells and then neurons can fire when they are supposed to.

It takes decades for research findings, like those in the above paragraph, to be translated across into therapies.

If you, or particularly a researcher, make a statement that is controversial and not backed by a big stack of evidence (based on human trials, not mouse trials) nobody is going to believe you.  Worse still, the next time you make a claim, they will be even less likely to believe you.

So better under-promise but over deliver.  Start finally treating some autism and then watch in the next thirty years that epilepsy incidence falls and along with it SUDEP (Sudden Unexpected Death in Epilepsy).  Then you can say “I told you so, it was those Cation Chloride Cotransporter after all ”.

In spite of all the “evidence” that some autism is treatable, cognitive dysfunction is reversible, the world has not taken any notice.  Where is the undisputed concrete proof?  I just have to think “longitude and latitude”, that’s my proof.

So in reality while avoiding epilepsy should be a big deal for the parents, it is not for anyone else.  The current wisdom is keep your fingers crossed and hope that you are not in the one third that will develop epilepsy around puberty.  In some people this triggers an epigenetic change, opening the way to many future seizures.  For those who are interested:-

          Epigenetics and Epilepsy

If you follow 100 kids with autism on bumetanide for 10 years and found 5 developed seizures that would not be regarded as proof.

Based on my reading of the literature, you would expect 30+% of people with classic autism to develop epilepsy.  So if they had just 5 cases, I would see that as vindication, but it would not be seen as conclusive proof by others, just another paper to file and forget.

So the idea of prophylactic drug treatment to avoid the onset of epilepsy in autism is unlikely to catch on and is easy to rubbish.

Just like prophylactic use of drugs to avoid dementia, avoid type 2 diabetes or avoid the nasty side effects of type 1 diabetes, they will not enter the mainstream.

Conclusion

Setting low standards and targets will guarantee poor outcomes.  Aim to learn longitude and latitude, but it might be easier with a daily dose of bumetanide.

Some epilepsy is avoidable, some may not be, but if treating autism can also reduce the chance of epilepsy and SUDEP do you really need to wait for absolute evidence?

It is currently a matter of geography and google competence who is going to access effective pharmacotherapy.  For a change it is the poorer countries who have the advantage, since they have less rigid control over access to prescription medication.

I was just reading that the excellent New England Center for Children (NECC) charges up to $300,000 a year to educate kids with autism.  It is a great school and we employed a former teacher from there a few years ago, to help with our home program.  With something like 0.3% of all kids having serious autism, there needs to be a less expensive solution available to all.  

Spending $300,000 at NECC will almost definitely have a positive impact on one severely autistic child for one year.  Alternatively, for the same money, you could treat 480 kids with strict definition autism with my Polypill for one year.  It looks like around a half would respond very well.  Ideally you would spend $300,620 and have both the NECC and the Polypill; this is pretty much what was my target, but without leaving home.

 

Propranolol, Autism and Sodium Ion Channels Nav1.1, Nav1.2, Nav1.3 and Nav1.5

When writing this blog I frequently wonder what happened to all the very clever people; why are these full-time paid researchers often missing the obvious?

Boy with severe headache and ASD, awaiting Propranolol

The answer is, with a few notable exceptions (Catterall, Ben-Ari etc), the clever ones do not study autism, they study things that are much better defined, rare things like Angelman Syndrome and, recently, Pitt-Hopkins Syndrome.  These researchers seem much more rigorous.  For example:-

David Sweatt (Pitt Hopkins)

Pitt–Hopkins Syndrome: intellectual disability due to loss of TCF4-regulated gene transcription

Edwin Weeber (Angelman syndrome)

http://weeberlab.com/as.html

So autism is left to what might be termed the Baron Cohen brigade.

Propranolol

Propranolol is a medication of the beta blocker type.  It is used to treat high blood pressure, a number of types of irregular heart rate, thyrotoxicosis, performance anxiety, and essential tremors. It is used to prevent migraine headaches, and to prevent further heart problems in those with angina or previous heart attacks.

It is a nonselective beta blocker which works by blocking β-adrenergic receptors.

While once a first-line treatment for hypertension, they do not perform as well as other drugs, particularly in the elderly, and evidence is increasing that the most frequently used beta blockers at usual doses carry an unacceptable risk of provoking type 2 diabetes.

Beta blockers block the action of endogenous catecholamines epinephrine (adrenaline) and norepinephrine(noradrenaline) on adrenergic beta receptors, of the sympathetic nervous system, which mediates the fight-or-flight response. Some block all activation of β-adrenergic receptors and others are selective.

It is occasionally used to treat performance anxiety.   Given the effect (above) on the fight or flight response this is logical.

The sympathetic nervous system's primary process is to stimulate the body's fight-or-flight response. It is, however, constantly active at a basic level to maintain homeostasis.

Evidence to support the use in other anxiety disorders is poor.

But what the ever useful Wikipedia almost glosses over is the part I find more interesting:-

Propranolol blocks cardiac and neuronal voltage-gated sodium channels

  

Now we have to hope that cardiologists prescribing Propranolol are fully aware of the role of Nav1.5 in the heart and its role in heart rate.  This has nothing to do with it being a beta blocker.

Hopefully neurologists prescribing it for certain severe headaches understand the role of Nav1.1 in the brain.

It would not surprise me if they did not.

Propranolol earlier in this Blog

Earlier in this blog there are comments regarding the use of low doses of Propranolol to treat anxiety in autism.

Some people report it works wonders, while for others it did nothing.

  

Propranolol in Autism Research

A study was published recently and a reader drew my attention to it, but there have also been a few others.

Blood pressure medicine may improve conversational skills of individuals with autism

An hour after administration, the researchers had a structured conversation with the participants, scoring their performance on six social skills necessary to maintain a conversation: staying on topic, sharing information, reciprocity or shared conversation, transitions or interruptions, nonverbal communication and maintaining eye contact. The researchers found the total communication scores were significantly greater when the individual took propranolol compared to the placebo.

"Though more research is needed to study its effects after more than one dose, these preliminary results show a potential benefit of propranolol to improve the conversational and nonverbal skills of individuals with autism," said Beversdorf

  

Effect of propranolol on verbal problem solving in autism spectrum disorder

Effect of Propranolol on Functional Connectivity in Autism Spectrum Disorder—A Pilot Study

Back to Channelopathies

There are 24,000 human genes, but a much more manageable number of ion channels.  For each ion channel or transporter, there is a gene that expresses it.

When ion channels malfunction, it is called a channelopathy.  Channelopathies are quite well researched and very common in autism.  Early on in this blog I simplified idiopathic classic autism with the following chart.

I suspect that people with channelopathies (Nav1.1, Nav1,2, Nav1.3) caused by dysfunctions in the genes SCN1A, SCN2A, SCN3A are the ones that will most benefit from Propranolol.

I suspect those people will already suffer terrible headaches and/or seizures.

These three channelopathies have been known to be associated with autism for ten years.

Nav1.1 / SCN1A

http://ghr.nlm.nih.gov/gene/SCN1A

Migraine, other headaches

Epilepsy

Dravet syndrome

Regular readers will know that Professor Catterall is the expert on sodium channels and here he is again below

NaV1.1 channels and epilepsy

Nav1.2 / SCN2A

http://ghr.nlm.nih.gov/gene/SCN2A

Epileptic encephalopathy, early infantile, 11 (EIEE11): An autosomal dominant seizure disorder characterized by neonatal or infantile onset of refractory seizures with resultant delayed neurologic development and persistent neurologic abnormalities. Patients may progress to West syndrome, which is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG

Nav1.3 / SCN3A

neuronal hyperexcitability and epilepsy 

         Novel SCN3A variants associated with focal epilepsy in             children.

Nav1.5 / SCN5A

http://ghr.nlm.nih.gov/gene/SCN5A

Mainly heart conditions, since this ion channel is expressed mainly in the heart.

Brugada syndrome  Romano-Ward syndrome  etc

Autism and Nav1.1, Nav1.2, Nav1.3

For many years it has been known that the hundreds of variations in the genes SCN1A, SCN2A and SCN3A are associated with autism.  So we can consider them pretty well established autism genes.

Clearly any drug affecting expression of those genes, or affecting the ion channels they express, should be a target autism drug.

Sodium channels SCN1A,SCN2A and SCN3A in familial autism

Conclusion

Some people with autism and severe headaches, or epilepsy, have an underlying sodium channelopathy.  Sodium channel blockers are not as well understood/ developed as calcium channel blockers.

In some cases, but maybe not all, this should be detectable by genetic testing of the genes SCN1A, SCN2A and SCN3A.

If you live in a country that does not bother with genetic testing, you might want to fall back on trial and error and discuss Propranolol with your doctor.

Did all the people with Asperger’s, in the recent study, who became more conversational after a single dose of Propranolol, have problems with Nav1.1, Nav1.2 or Nav1.3 ?  I doubt it.  The other commonly known effects of Propranolol should also play a role.

But for a sub-set of people with Strictly Defined Autism, Propranolol might be hugely beneficial.  Perhaps Professor Catterall should investigate?

“More GABA” for Autism and Epilepsy? Not so Simple

Today’s post was prompted by Tyler highlighting a very recent paper from MIT and Harvard, with some interesting research on GABA in autism.  It also provides the occasion to include an interesting epilepsy therapy, which I encountered a while back.  This fits with my suggestion that the onset of much epilepsy in autism could be prevented.

In the MIT/Harvard study, they were looking into the excitatory/ inhibitory (E/I) imbalance found in ASD and schizophrenia. They used a non-invasive optical method to measure E/I imbalance and this did get some media coverage.  However, I am not sure this could be a diagnostic tool in very young children with classic autism, as was suggested; most such children would not cooperate.  It is not just a problem of being non-verbal, as was suggested in the media.

Indeed, due to the nature of the experiment, the researchers involved older subjects, with milder autism and none had MR/ID (IQ<70).  Being a trial done in the US, of the 20 autistic subjects, 11  were being treated with psychiatric medications: antidepressants (n = 8), antipsychotics (n = 2), antiepileptics (n = 4), and anxiolytics (n = 2).

The easy to read version is from the MIT website:-

Study finds altered brain chemistry in people with autism

The full version is here:-

Reduced GABAergic action in the Autistic Brain

They used something called Binocular Rivalry  as a proxy for  E/I imbalance.

During binocular rivalry, two images, one presented to each eye, vie for perceptual dominance as neuronal populations that are selective for each eye’s input suppress each other in alternation [16, 17]. The strength of perceptual suppression during rivalry is thought to depend on the balance of inhibitory and excitatory cortical dynamics [12–15] and may serve as a non-invasive perceptual marker of the putative perturbation in inhibitory signaling thought to characterize the autistic brain.

We therefore measured the dynamics of binocular rivalry in individuals with and without a diagnosis of autism (41 individuals, 20 with autism). As predicted, individuals with autism demonstrated a slower rate of binocular rivalry (switches per trial: controls = 8.68, autism = 4.19; F(1,37) = 16.52, hp 2 = 0.311, p = 0.001; Figure 1A), which was marked by reduced periods of perceptual suppression (proportion of each trial spent viewing a dominant percept, (dominant percept durations)/(dominant + mixed percept durations): controls = 0.69; autism = 0.55; F(1,36) = 7.27, hp 2 = 0.172, p = 0.011; Figure 1B). The strength of perceptual suppression inversely predicted clinical measures of autistic symptomatology (Autism Diagnostic Observation Schedule [ADOS]: Rs = 0.39, p = 0.027; Figure 1) and showed high test-retest reliability in a control experiment (R = 0.94, p < 0.001; see Supplemental Experimental Procedures and also [18]). These results replicate our previous findings in an independent sample of autistic individuals [11] and confirm rivalry disruptions as a robust behavioral marker of autism.

To test whether altered binocular rivalry dynamics in autism are linked to the reduced action of inhibitory (g-aminobutyric acid [GABA]) or excitatory (glutamate [Glx]) neurotransmitters in the brain, we measured the concentration of these neurotransmitters in visual cortex using magnetic resonance spectroscopy (MRS).

GABA and glutamate are predicted to contribute to different aspects of binocular rivalry dynamics: mutual inhibition between (GABA) and recurrent excitation within (glutamate) populations of neurons coding for the two oscillating percepts [14].

. Critically, reducing either mutual inhibition or recurrent excitation is predicted to reduce the strength of perceptual suppression during rivalry in one implementation of this model [14], mirroring the dynamics we observed in autism. We therefore considered each neurotransmitter separately to test whether inhibitory or excitatory signaling was selectively disrupted in the autistic brain.

As predicted by models of binocular rivalry, GABA concentrations in visual cortex strongly predicted rivalry dynamics in controls, where more GABA corresponded to longer periods of perceptual suppression (Rs = 0.62, p = 0.002; Figure 2B). However, this relationship was strikingly absent in individuals with autism (Rs = 0.02, p = 0.473; Figure 2B). The difference between the two correlations was significant (hp 2 = 0.167, p = 0.013; Figure 2C), indicating a reduced impact of GABA on perceptual suppression in the autistic brain.

GABA was working backwards

Importantly, this finding was specific to GABA: glutamate strongly predicted the dynamics of binocular rivalry in autism (Rs = 0.60, p = 0.004; Figure 2B), to the same degree as that found in controls.

Glumate is working just fine.

These findings suggest that alterations in the GABAergic signaling pathway may characterize autistic neurobiology. Consistent with prior evidence from animal and post-mortem studies, such dysfunction may arise from perturbations in key components of the GABAergic pathway beyond GABA levels, such as receptors [3–9] and inhibitory neuronal density

Together with the pivotal roles of GABA in canonical cortical computations [39] and neurodevelopment [40], these findings point to the GABAergic signaling pathway as a prime suspect in the neurobiology of this pervasive developmental disorder [41]

This study reconfirms what regular readers of this blog already knew.

Epilepsy

I thought it was positive that the MIT researchers suggested that the high level of epilepsy in autism and this E/I imbalance really must be connected.

I have been suggesting for some time that by correcting this E/I imbalance in children with autism, it is likely that the onset of epilepsy could be avoided (in some cases).

I did suggest this to one well known researcher who thought the idea of preventing the onset of epilepsy was not something that the medical community would accept as a concept.

I also raised the novel epilepsy therapy, below, to the same researcher who thought it also would never be considered.

The therapy was to use both bumetanide and potassium bromide to switch GABA back to inhibitory and then give a little boost using a GABA agonist.   

There are many types of epilepsy and some do not respond well to current treatments.  It would seem plausible that the autism-associated type of epilepsy might constitute a specific sub-type.

Combined effect of bumetanide, bromide, and GABAergic agonists: An alternative treatment for intractable seizures

Potassium Bromide was the original epilepsy therapy over a hundred years ago.  It is still used in Germany as a therapy.  Reports from a century ago suggest it has the same effect in autism as Bumetanide. (we saw this in my post on autism history). 

As you can see on Wikipedia there is a wide range of GABA agonists, but the only ones that would help in epilepsy and autism would be the ones that can cross the blood brain barrier.

GABA_A receptor Agonists

·         Bamaluzole

·         GABA

·         Gabamide

·         GABOB

·         Gaboxadol

·         Ibotenic acid

·         Isoguvacine

·         Isonipecotic acid

·         Muscimol

·         Phenibut

·         Picamilon

·         Progabide

·         Quisqualamine

·         SL 75102

·         Thiomuscimol

In an earlier post, we looked at the possible use of small doses of AEDs (anti-epileptic drugs).  One reader found that tiny dose of Valproate (known to raise GABA) had a positive effect when combines with Bumetanide.

In a recent comment one reader showed the same result by combing picamilon with bumetanide.

Both Picamilon and Valproate are having the effect proposed by the epilepsy researchers.

Potassium Bromide does have known side effects, but the idea of further boosting the effect of Bumetanide is interesting.  I have suggested before that this should also be possible using Diamox (Acetazolamide).  Diamox does not affect NKCC1 or E_GABA,  it affects the  Cl-/HCO3-exchanger AE3  to further affect Cl- levels.  

I did suggest this a long time ago in my posts on the GABAa receptor.  I am not the only one to realize this.

NKCC1 and AE3 Appear to Accumulate Chloride in Embryonic Motoneurons

   

Picamilon is well researched Russian drug, sold in other countries as a supplement.  It is a modified version of GABA that includes niacin; together it can cross the blood brain barrier (BBB).

So I think a better version of what the epilepsy researchers suggest might be:-

                           Bumetanide  +  Diamox  +  a touch of Picamilon

What would be the effect in autism?