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Wednesday, 23 December 2015

“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:-




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.









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.

GABAA 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 EGABA,  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?











18 comments:

  1. Feel free to delete this post. While looking around in a journal for a particular article on serotonin, I came across this paper you might be interested in. At least read the abstract:

    Early Postnatal Switch in GABAAR α Subunits in the Reticular Thalamic Nucleus

    http://jn.physiology.org/content/early/2015/12/02/jn.00905.2015

    It discusses clonazepram among many other things. It is low-level scientific stuff and it deals with mice and not humans so discussing it here would probably not be of much interest to people, but I thought it would interest you.

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  2. To further elaborate on all of this, with respect to serotonin, it can have very different effects on the brain depending on whether there is intact inhibition. A recent paper by a group out of Case Western Reserve:

    http://jn.physiology.org/content/early/2015/11/20/jn.00996.2014

    After reading the abstract (the full paper isn't available to me yet through alternative means) and then reading one of the group's earlier papers that this research builds upon

    http://www.case.edu/med/galanlab/pdf/Puzerey_Decker_Galan_JNeurophys2014.pdf

    The general ideas here that they have are that traditionally serotonin has been thought of only as an inhibitory neurotransmitter in that it was believed only inhibitory neurons had serotonin receptors. Of course things are far more complicated than that and their research suggests many pyramidal (excitatory) cells also have serotonin receptors. Furthermore, they suggest specifically that 5-HT3 receptors promote neural noise in the brain for the purposes of increasing general cortical excitability. Of course in autism, excess neural noise is a hallmark symptom as well. 5-HT2 receptors when overstimulated also produce bursts of beta activity that can lead to seizures as well when inhibition in the brain is compromised (as is with autism). 5-HT1 receptors seem to be inhibitory, and they don't even get into really discussing the many other types of serotonin receptors because their research is limited to these three.

    Long story short is that they believe serotonin should be considered excitatory because of the effects they noticed from fluoxetine (Prozac), especially once they chemically ablated inhibition and its effect in inducing seizure like activity. The bigger takeaway here is that people with compromised GABA systems (much if not just about all of the autistic population) may be made much worse by many SSRI's if the GABA dysfunction is not addressed concurrently. Of course there is plenty of research suggesting what generally happens when you deplete the brain of serotonin in autistic individuals (symptoms tend to worsen), so this looks like a receptor issue that will require new drugs or maybe a combination of drugs with one will antagonize the 5-HT3 and 5-HT2 receptors but another that will agonize the 5-HT1 receptors.

    In another note, I read another study this week discussing the use of mianserin a 5-HT5 antagonist and atypical antidepressant in worms where they got a dramatic life extension effect from the drug:

    http://elifesciences.org/content/4/e08833

    What is relevant here is that they drilled down into the mechanisms and they found that a process they called "transcriptional drift" is attenuated via mianserin which has the secondary effect of affecting "stress, innate immunity, aging and the xenobiotic response". Perhaps serotonin signaling throughout the body could be causing a lot of the seemingly random symptoms in autism, many of which are associated with age-related decline.

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  3. Well, I just found out the hard way that our good old FDA here in the states is playing politics again and have effectively banned Picamilon:

    https://blog.priceplow.com/supplement-news/picamilon-fda

    Which is ridiculous because to date there have been no recorded deaths from Picamilon overdose ever and it is not habit forming either because of how excess GABA is rapidly excreted from the brain (true GABA prodrugs are another story as is alcohol of course).

    I mean, if they want to ban a real GABA agonist that does actual major damage to people and society then they should ban alcohol which actually is addicting and does lots of other nasty stuff to your body and brain unless you imbibe in very, very small quantities (which next to no drinkers actually do).

    This is of course not too surprising for a whole host of reasons. The FDA a decade or so ago banned ephedrine which was used in the most effective weight loss stack that reached mass market appeal (the ECA stack of Ephedra, Caffeine, and Aspirin). A few reported cases out of 10's of millions of people who had no complications whatsoever (if you have a heart condition you shouldn't drink 10 cups of coffee either) and they ban its use, even though you could reasonably argue that this action may have killed more than a million Americans indirectly via obesity and the complications thereof (Type II diabetes/obesity/cardiovascular disease/dementia). Millions of people used the weight loss stack successfully and then it was gone and now a decade or so later there is a lot of science with regards to how so-called beige fat cells work and thermogenesis that the media cynically talks about as a new frontier for weight loss and diabetes treatment. I mean, I know about thermogenesis for weight loss back when I was 13 years old (I am 40 now) when I read about a study done via autopsy of Norwegian loggers which concluded chronic cold stress could create brown fat.

    Anyways, I am just ranting now and we Americans pretty much all hate our government for different reasons so saying I am mad about this action would be an understatement. Pretty soon, our FDA will ban vitamins just like in the EU.

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  4. Hello Peter,

    Over the last couple of months our child has been exhibiting bouts of prolonged unexplained giggling and laughter. He's been doing it at school and home and it's becoming very problematic. It's become obvious to us that he can't control it.

    In your research, have you come across any probable causes or remedies that we could look into?

    Many thanks.

    Regards,
    D&G

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    Replies
    1. Yes.It sounds like it might be gelastic seizure.It may be caused by a benign brain tumor
      http://www.epilepsy.com/learn/types-seizures/gelastic-and-dacrystic-seizures

      Or something else.

      http://www.disabled-world.com/health/neurology/epilepsy/gelastic.php

      Delete
    2. D&G, this is not a problem we have experienced. I have read other people with this issue and it is one of the things the DAN doctors in the US do treat. So on that basis, look on autismweb, which seems to have lots of people using DAN therapies.

      Delete
    3. Hi D&G

      Following from what Roger Kulp has suggested: our son has also exhibited those types of behaviours. We have been worried for some time about the possibility of them being gelastic seizures. As you live in Australia (so I understand it), I hope Peter will not mind if I provide some basic information about our experiences and discoveries.

      Our son Morgan will be getting an MRI in May 2016. That will represent a wait of just over two years in Melbourne’s public hospital system since we first received a referral from our GP. Depending upon the demands on your State or Territory’s public health system, I suggest it might be significantly quicker to suck up the expense and get an MRI done privately. (Had I known it would take so long, I would have done the same. In any event Morgan has had a privately-arranged sleep-deprived EEG.)

      I am putting quite large amounts of hope in the MRI turning up something that might be treatable. Here in Melbourne, pioneering surgery for treating hypothalamic hamartomas has been developed by Professor Jeffrey Rosenfeld (see http://www.med.monash.edu.au/surgery/alfred/staff/hod-rosenfeld.html). Hamartomas and other brain abnormalities can be treated using gamma knives, of which there is one at Macquarie University Hospital in New South Wales (see http://muh.org.au/Services-Specialties/Gamma-Knife/About-Gamma-Knife/About-Us). Of course conventional surgery can also be used.

      If it turns out Morgan suffered brain injury at birth similar to that experienced by some people with cerebral palsy or stroke, then perhaps the new etanercept treatments will help him (see for example http://www.news-medical.net/news/20121101/Single-dose-of-etanercept-can-improve-chronic-neurological-dysfunction-from-stroke-or-TBI.aspx. Regarding trials in Queensland, see http://strokerecoverytrialfund.org/clinical-trial-information/ and https://www.griffith.edu.au/health/menzies-health-institute-queensland/research/stroke).

      In the meantime, one of the things that has most helped Morgan has been a ketogenic/ low GI diet, which mimics some epilepsy drug treatment. Amongst the behaviours that disappear when on the diet are the endless late night giggling while lying in the dark, and the day time silly giggling triggered by just about anything. It is hard – we give him a break at Christmas – but not as hard as day to day living with a huge six year old who can’t learn or understand anything. Alexandria

      Delete
    4. Alexandria,

      Thanks for your interest and response.

      We too placed a high degree of hope in an MRI revealing something tangible to focus on. With the support of our pediatrician we undertook MRI scanning 18 months ago which revealed nothing of significance for us that could be related to his symptoms.

      I will look into the the references you mention. Many thanks for taking the time providing them.

      On Peter's suggestion I looked at some of the Dan therapies and the Ketogenic diet. We've sought to eliminate any added sugar from his diet as eating for him has always triggered unconventional behaviour. We also commenced him on a pharmacy pro-biotic.

      Our child is unquestionably better on an empty stomach in comparison. The best way I can describe it is that eating has an 'alcoholic-like' delerious effect on his behaviour. Our child has always eschewed sweets. Which child eschews sweets? Is this significant?

      I went back to Zyrtec and again 'magic'. It just works - albeit for only approx 4-5 hours. It has the most positively significant effect on our child's behaviour out of everything he's taken. He also derives some benefit from ONLY a subclinical dose of Risperdal. It too I believe has an anti-histamine property - DAAO inhibition?. Examples are greater engagement, expression, imagination, interest. It's just obvious whe your child is doing better - and worse.

      I can't prove anything and these are only opinions based on observation but the effects are stark.

      Peter, what could be the mechanism behind the desirable effects of Zyrtec we see? I don't believe - although I could be mistaken - it's the sedative effects of the medication of 5ml twice a day. If it just ceased the laughing/giggling and he became more withdrawn, then I could easily say so, but it's the positive behaviours that are salient.

      Is there anything that could augment the benefits of the mechanism behind Zyrtec?

      I do also recall that on a course of antibiotics - Amoxocillin - our child again was significantly better after a few days. Is there a relation between the two. I'm trying to reconcile the success of these two and the effects of food on our child's behaviour and his autism phenotype.

      Is there a dysfunction in his gut? Yeast overgrowth? I believed this to be quackery at once stage because he's never really had constipation or diarrhoea but I may have dismissed more subtle signs such as significant bloating after meals and reflux.

      In summary, our child is taking the daily probiotic, pharmanac and sustained Nac, Zyrtec and biotin with the very occasional subclinical dose of Risperdal. Also the elimination of all added sugar. We've shifted our focus to a more gut-brain relationship centric one.

      This is most definately working now. We hope it lasts.


      Thanks again.

      Regards,
      D&G

      Delete
    5. Alexandria, did you try giving bumetanide to Morgan? It seems to help about 50% of people with an autism diagnosis. It looks like it can be prescribed in Australia. Some people are buying it online. Perhap D&G can connect you to his doctor who seems interested to prescribe it?

      Delete
    6. D&G, did you read about the hypoglycemic diet and autism? Perhaps this is the one for you.
      If Zyrec is effective, that might be the solution. There are more potent mast cell stabilizers, but maybe you do not need them. There must be some kind of allergic response going on.
      Antibiotics do seem to help some people with autism, but this may have nothing to do with the allergy or the effect of increased blood sugar after eating.
      You can even out peaks in blood sugar through diet and zyrtec is very well studied (i.e. safe) and OTC.
      You could try and find if your son has a specific food allergy. There are many tests, but they seem to be of questionable value. Perhaps see an immunologist and tell them about the zyrtec effect?

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    7. D&G, one dietary intervention you could employ (that I employ) in attenuating some of the potential histamine issues is perilla oil. It is high in many healthy fatty acids, but also has a lot of rosmarinic acid which acts as an anti-histamine through multiple mechanisms.

      Rosmarinic acid is also a GABA transaminase inhibitor which basically means it helps to inhibit production of the enzyme that metabolizes GABA. The slower GABA is metabolized, the more GABA you have in the brain. For rosmarinic acid alone, you can also instead do lemon balm.

      https://examine.com/supplements/perilla-oil/

      http://www.ncbi.nlm.nih.gov/pubmed/21239739

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    8. Hello D&G,
      My son also had odd behaviours or looked drunk/high after meals (with giggling, clumsiness, wierd eye movements and all things that would be funny if it was some guy in a party and not my 2 years old after diner).
      I was extremely sceptic of gluten and casein free diet, until I tried it. And when I say sceptic, I mean like had really good laughs reading some things... but now I know some things are quackery, and some aren't.
      As I didn't believe at the time it would make any difference, I went all out: no gluten and milk from the start, for 3 weeks. Then one week off diet as his (very scepitc) doctor requested we reintroduce the foods so blood tests for alergy could be performed. We endured a full week only because of the blood tests, because it was trully hell and absolutely heartbreaking to see my kid like that again.

      We are on the GFCF diet for about 18 months now.
      I strongly believe that without it, the supplements and other interventions wouldn't be effective. If nothing else he is healthier, and it shows.
      IMO its worth a try, even if only to mark it as tried and done with.
      The diet is not hard to follow once you realise there are plenty of naturally gluten free foods available, but not many industrialized stuff though, so some home cooking is almost inevitable.
      The difficult part was convincing his school to respect the diet for the first week, but the improvement was so visible they supported it later on.
      Besides the diet, we currently give him NAC, carnosine and the mitochondrial supplements (see post http://epiphanyasd.blogspot.rs/search/label/Regressive%20autism).
      My kid did not respond to sulforaphane, and responds well to ibuprophen and sytrinol wich I use only eventually.
      Blood and urine tests seems to indicate mito dysfunction (no official diagnosis though), but is negative for celiac desease, EEG was "borderline" normal and MRI normal.

      I can't offer you anything that Peter hasn't already published somewhere in this blog, but this was my experience so far. I hope it helps.

      Regards,

      J.


      Delete
    9. J – great to know you have had success with the GFCF diet. It was the very first therapy we tried after our diagnosis. After three weeks, not a thing had changed. Morgan was also subsequently dairy free for a year, also with no discernible changes (for positive or negative). However after three weeks on the Modified Atkins diet, he exhibited spontaneous imitative play for the first time. This history is the reason I am the annoying crazy woman banging on about ketogenic diets at every ASD gathering …

      D&G – thanks for your reply. I know I’m putting too much hope in finding something curable through the MRI, but we must do it anyway (especially now that Morgan has experienced his first, hopefully only, epileptic episode). My belief – hope? – is that Morgan only “really” has Asperger’s (and perhaps ADD/ ADHD), but that his birth trauma caused a treatable brain injury that resulted in his ID and some motor impairments.

      If I can just put in a plug once more for the Modified Atkins/ ketogenic diet … truly, it can be done without a dietician, if you are sensible: we did it. Morgan sounds a little like J’s and D&G’s child: after eating apples or bread it is like he is a happy drunk. (I recollect some of his annoying and anti-social behaviours began about six weeks after starting to transition to solid foods, most of which were carbohydrates.) Anyway, if you want a dietician and live in Melbourne, there is one who specialises in keto diets. I can dig up her details if anyone wants them. Also, as for eschewing sweets … a dentist recently told me many of the ASD kids he encounters do not like sweets. I do not think this is a coincidence.

      Peter – we haven’t tried Bumetanide but have tried Lasix. I’ve just now posted a bit more about this in my reply to your question about Diamox under your article dated 7 December 2015. The Lasix didn’t work, so I doubt the Bumetanide would either. But I am thinking about retrying the Lasix therapy, based on your suggestions in the article above. Alexandria

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  5. I see no other way to contact you,but I just thought you would like to know about this blog I found.Each entry is about a different type of inherited immune condition that manifests as autism.And yes,CFD/FRAs is one of them.

    http://www.preventautism.com/Analysis-of-Recent-Literature.aspx

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  6. This press release and its corresponding paper on rats and humans, shows a definite connection between function of GABA (I/E) and epilepsy. To me, it also explains how epilepsy can cause autism and how autism (or rather excitatory GABA) can cause epilepsy in the long rum. The main point could also be the importance to treat this downwards spiral in order to prevent further damage. Epileptiform activity should be taken more seriously and bumetanide given to prevent (and not only treat) epilepsy.
    https://www.helsinki.fi/en/news/new-mechanism-underlying-epilepsy-found

    Peter, this is what you have written about more than once.

    /Ling

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    Replies
    1. Ling, I do think bumetanide should reduce the chance of developing epilepsy. This is very hard to prove, until many hundreds of kids take bumetanide long term.

      The researchers were not so keen about my suggestion. I think this is because someone started taking bumetanide and then developed seizures, but that could be entirely coincidental.

      I think it is common sense that bumetanide should give some protection from developing seizures.

      Delete
    2. Last Friday we stopped Bumetanide, which we have been giving for almost 6 months at 0.5mg 2x/day. Son became touchy and emotional. He grew eyebags, which he used to have before Bumetanide but we never connected their disappearance with Bumetanide. On Sunday, we put him back on Bumetanide, and the touchiness and eyebags were gone within 1 hour. I am not sure if it was due to effect on GABA or simply reducing fluid retention and pressure in the scull. In Russia, children who are just diagnosed with autism or other neurological problems are checked for pressure inside skull and prescribed diuretics to relieve the pressure. That could be the secondary or main mechanism of action of Bumetanide. If anyone else noticed disappearing eyebags on Bumetanide, please respond.

      Delete

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