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Friday, 8 June 2018

Critical Periods in the Biology of Autism – Not to miss the Boat



This blog has shown that great things are possible just by fine-tuning a full-sized autistic brain, during childhood. In the case of our reader Roger, we are reminded that in adulthood the correct intervention can have profound results.


It is never too late.

Nonetheless, it is clear that the sooner you intervene with biology, the better the end result should be.
There is a concept of Critical Periods (also called sensitive periods) where it seems the maturation of a young brain is particularly vulnerable to both environmental and genetic insults. During these periods if you intervene pharmacologically you might make permanent life-changing modifications to the brain.  The recurring theme in Critical Periods in autism is a disturbed excitatory-inhibitory (E/I) balance. This is the same E/I imbalance discussed in depth in this blog. 
Some conditions that may lead to autism are detected before birth, such as Down Syndrome (DS) and many others could be. Surprisingly, there is now an experimental DS therapy that commences prior to birth. 
Emerging tests, such as one using an EEG, can predict with some accuracy which babies will develop autism.



When is it too late?
I think it is never too late to intervene in the biology of autism, but the sooner you do so the more productive it will be.
The sequence of Critical Periods starts before birth, with gestational weeks 10–24, highlighted in one paper. Birth itself is a critical period, as discussed by Ben Ari. By 12 months the autistic brain has already measurably overgrown, but this process continues to three years old. One researcher, Knut Wittkowski, believes that a therapy given during the second year of life can redirect future severe autism towards an Asperger’s-like outcome.
After the age of six, critical brain development has mostly been completed, except for synaptic pruning that occurs gradually during adolescence.

Cortical circuits in the brain are refined by experience during critical periods early in postnatal life. Critical periods are regulated by the balance of excitatory and inhibitory (E/I) neurotransmission in the brain during development. There is now increasing evidence of E/I imbalance in autism, a complex genetic neurodevelopmental disorder diagnosed by abnormal socialization, impaired communication, and repetitive behaviors or restricted interests. The underlying cause is still largely unknown and there is no fully effective treatment or cure. We propose that alteration of the expression and/or timing of critical period circuit refinement in primary sensory brain areas may significantly contribute to autistic phenotypes, including cognitive and behavioral impairments. Dissection of the cellular and molecular mechanisms governing well-established critical periods represents a powerful tool to identify new potential therapeutic targets to restore normal plasticity and function in affected neuronal circuits.








Figure 1: Possible critical period alterations in autism. The solid black curve represents the normal expression of a critical period, with a distinct onset and closure and characteristic duration. Onset could be precocious or delayed. Duration could be increased or decreased. Degree of plasticity could be increased or decreased. Finally, the critical period could fail to open or close.


The variable nature of E/I imbalance and altered plasticity in autism animal models suggests that the disruption of critical periods in autism is likely heterogeneous, in some cases resulting in excessive plasticity and in others, insufficient plasticity. This could be due to disruption of the mechanisms governing either the onset or closing of critical periods Figure 1, and both could be detrimental to functioning. A brain that is too plastic at the wrong times could result in noisy and unstable processing. On the other hand, a brain that lacks plasticity early in life might remain hyper- or hypoconnected and unresponsive to environmental changes early in life. A situation could also arise where plasticity is at an optimal level in some systems and an aberrant level in other systems, which could the case in Asperger and/or Savant syndrome.

Autism is diagnosed exclusively by cognitive behavioral symptoms, but there are likely underlying problems arising at lower-level stages of processing. By first understanding the development of primary senses in autism, a cumulative chain reaction of abnormalities could be prevented early on and save consequent behavior. In the long run, a collaborative multilevel analysis of different brain regions over development and in different animal models of autism is of paramount importance. Hypothesis-driven efforts may then have a wider implication for the diagnosis and treatment of neurodevelopmental disorders in general. We are now in the position to adopt a mouse model to human multi level analysis approach to test well-defined, mechanistic hypothesis and to discover new therapeutic interventions to restore normal cortical function.


Let us see what Ben-Ari has to say on this subject


Birth is associated with a neuroprotective, oxytocin-mediated abrupt excitatory-to-inhibitory GABA shift that is abolished in autism, and its restoration attenuates the disorder in offspring. In this Opinion article, I discuss the links between birth-related stressful mechanisms, persistent excitatory GABA actions, perturbed network oscillations and autism. I propose that birth (parturition) is a critical period that confirms, attenuates or aggravates the deleterious effects of intrauterine genetic or environmental insults.
Birth is associated with a neuroprotective, oxytocin-mediated abrupt excitatory-to-inhibitory GABA shift that is abolished in autism, and its restoration attenuates the disorder in offspring. In this Opinion article, I discuss the links between birth-related stressful mechanisms, persistent excitatory GABA actions, perturbed network oscillations and autism. I propose that birth (parturition) is a critical period that confirms, attenuates or aggravates the deleterious effects of intrauterine genetic or environmental insults.

Cerebellar research has focused principally on adult motor function. However, the cerebellum also maintains abundant connections with nonmotor brain regions throughout postnatal life. Here we review evidence that the cerebellum may guide the maturation of remote nonmotor neural circuitry and influence cognitive development, with a focus on its relationship with autism. Specific cerebellar zones influence neocortical substrates for social interaction, and we propose that sensitive-period disruption of such internal brain communication can account for autism’s key features.
Three recent computational studies have used aggregated gene expression patterns to ask when and where ASD genes are expressed. Some ASD susceptibility genes show a high degree of coexpression with one another in mouse and human brain, allowing the identification of specific gene networks or “cliques”. ASD-related coexpression networks have been found during two distinct periods of development. First, during human gestational weeks 10–24 and mouse postnatal days 0–10 (P0–P10), expression occurs in a broadly defined somato-motor-frontal region (especially in layer 5/6 cortical projection neurons  and other layers. Second, in humans from neonatal to age 6, cerebellar network expression is strong, particularly in the cerebellar granule cell layer
Taken together, these patterns identify two regions where genetically driven ASD-related developmental programs can go off track: the second-trimester frontal/somatomotor neocortex and the perinatal/postnatal cerebellar cortex. Based on gene ontology classification, many of the coexpressed ASD susceptibility genes are involved in synaptic plasticity, development, and neuronal differentiation, indicating disruptions in neural circuit formation and plasticity as targets for investigation.
Long-term compensation is unlikely only in cerebellar agenesis, in which motor function remains underdeveloped throughout life. Thus, the cerebellum is compensatable with respect to motor functions, but cognitive and social functions are specifically vulnerable to early-life perturbation of cerebellum—suggesting a sensitive-period mechanism.

In infants who later go on to develop autism, increased net brain growth is apparent by age 1, as quantified by increased head circumference. Extreme head growth is associated with the most severe clinical signs of autism. In volumetric MRI measurements, ASD brains grow faster on average than neurotypical brains in the first two postnatal years. By age 2.5, brain overgrowth is visible as enlargement of neocortical gray and white matter in frontal, temporal, and cingulate cortex. Since this abnormal growth comes after the time of neurogenesis, volume differences are likely to arise either from disruption of progressive (growth) or regressive (pruning) events. Disruption to either of these processes could account for perturbations in the trajectory of gross volume changes. Additional contributions could also come from changes in glial volume or number. Finally, overgrowth in ASD brains is followed by premature arrest of brain growth after age 4. These abnormalities would be expected from defects in plasticity mechanisms—for example, dendritic growth and pruning or axonal branching.

Such a deficit in sensitive-period circuit refinement could arise in two ways. First, inappropriate input, as originally described by Hubel and Wiesel, could fail to instruct developing circuitry through Hebbian plasticity mechanisms. This could occur if subcortical structures, including the cerebellum, were perturbed. For example, reduced numbers of Purkinje cells, which are inhibitory, could allow abnormally high levels of firing by deep-nuclear projection neurons. Second, plasticity mechanisms themselves could be perturbed by specific alleles of the genes that govern those mechanisms. Both cases amount to a failure of postnatal experience to have its normal effects on the neocortex. Such a failure could contribute to the blunting of regional differences in gene expression across neocortical regions that is seen in autistic subjects.

Sensitive Periods for Cognitive and Social Function

Higher sensory capabilities are thought to undergo sensitive periods once lower sensory structures have matured. A similar principle is likely to apply to cognitive functions. One illustrative example is the ontogeny of reading. In early readers, activated brain regions are distributed on both sides of the neocortex and cerebellum. Between childhood and adolescence, these regions come to exclude auditory regions, leaving a more focused, largely left-hemisphere network that includes the visual word form area. Notably, in readers who first learn to read as adults, activity patterns are more bilaterally distributed  and are reminiscent of literate children starting to read, indicating that adult circuitry has considerably less capacity for refinement

The chart below is interesting; be careful with baby's head during birth. 




Risk ratios for ASD for a variety of probable genetic (light blue) and environmental (dark blue) factors. Risk ratios were taken directly from the literature except for the largest four risks, which were calculated relative to the U.S. general-population risk. At 36×, cerebellar injury carries the largest single nonheritable risk. For explanation of other risks, see text.










Critical Periods and the Immune System  
There is more to Critical Periods than just an excitatory-inhibitory (E/I) imbalance. We have seen in earlier posts that the immune system needs to be "calibrated" very early in life. If this does not occur correctly, the baby grows up with an immune system that does not respond only to genuine threats, but is over-activated and attacks the healthy body; this results in auto-immune disease. Autism can in part be considered an auto-immune disease.   The critical period to calibrate your immune system is during pregnancy and in the first months of life.
This is why having a pet indoors during pregnancy reduces asthma rates in the child. Giving babies probiotics also has been shown to reduce immune conditions and also conditions like ADHD and milder autism.
Giving the same probiotics to older children does not have the disease-changing benefit; the Critical Period to set up the immune system has past. The only work around, shown effective in MS, is to reboot the immune system and start again, using a bone marrow transplant. 
A possible link between early probiotic intervention and the risk of neuropsychiatric disorders later in childhood: a randomized trial
Seventy-five infants who were randomized to receive Lactobacillus rhamnosus GG (ATCC 53103) or placebo during the first 6 mo of life were followed-up for 13 y. Gut microbiota was assessed at the age of 3 wk, 3, 6, 12, 18, 24 mo, and 13 y using fluorescein in situ hybridization (FISH) and qPCR, and indirectly by determining the blood group secretor type at the age of 13 y. The diagnoses of attention deficit hyperactivity disorder (ADHD) and Asperger syndrome (AS) by a child neurologist or psychiatrist were based on ICD-10 diagnostic criteria.

RESULTS:


At the age of 13 y, ADHD or AS was diagnosed in 6/35 (17.1%) children in the placebo and none in the probiotic group (P = 0.008). The mean (SD) numbers of Bifidobacterium species bacteria in feces during the first 6 mo of life was lower in affected children 8.26 (1.24) log cells/g than in healthy children 9.12 (0.64) log cells/g; P = 0.03.

CONCLUSION:


Probiotic supplementation early in life may reduce the risk of neuropsychiatric disorder development later in childhood possible by mechanisms not limited to gut microbiota composition.
 
Critical Period E/I Intervention
We already have mouse research showing how early intervention can achieve permanent disease-changing benefits as suggested in the above papers. The paper below concerns a model of Fragile-X.


Sensory perturbations in visual, auditory and tactile perception are core problems in fragile X syndrome (FXS). In the Fmr1 knockout mouse model of FXS, the maturation of synapses and circuits during critical period (CP) development in the somatosensory cortex is delayed, but it is unclear how this contributes to altered tactile sensory processing in the mature CNS. Here we demonstrate that inhibiting the juvenile chloride co-transporter NKCC1, which contributes to altered chloride homeostasis in developing cortical neurons of FXS mice, rectifies the chloride imbalance in layer IV somatosensory cortex neurons and corrects the development of thalamocortical excitatory synapses during the CP. Comparison of protein abundances demonstrated that NKCC1 inhibition during early development caused a broad remodeling of the proteome in the barrel cortex. In addition, the abnormally large size of whisker-evoked cortical maps in adult Fmr1 knockout mice was corrected by rectifying the chloride imbalance during the early CP. These data demonstrate that correcting the disrupted driving force through GABAA receptors during the CP in cortical neurons restores their synaptic development, has an unexpectedly large effect on differentially expressed proteins, and produces a long-lasting correction of somatosensory circuit function in FXS mice.

Mefenamic Acid (Ponstan)
The other potentially disease changing therapy mentioned in this blog is Mefenamic Acid, which is available OTC in many countries as Ponstan. Knut Wittkowski, is developing his idea that the cascade of damaging events that occur in severe autism after birth can be reduced by Mefenamic Acid. He is proposing this as a medium term therapy, just until key stages in brain maturation have been completed.
In effect his idea is to shift a trajectory set to severe autism to one of mild autism.
We could call it a potential trajectory changing therapy.
His start-up company is called Asdera.

Asdera's Vision is to Prevent Mutism in Autism  http://www.asdera.com

Among the  more than 60,000 US children who develop autism spectrum disorders (ASD) every year, 20,000 become nonverbal and will have to rely on assisted living for the rest of their life. Genetics (http://www.nature.com/articles/tp2013124) suggest that mutism is to autism what pneumonia is to the common cold – more severe than the underlying condition (“Asperger’s”), but easily treatable by an exceptionally safe drug given to high risk children during the 2nd year of life to prevent disruption of active language development (DALD) from causing life-long lack of language and intellectual disability”

The Mainstream view of the Critical Period in Autism 
Monty was diagnosed in 2006 with autism by a neurodevelopmental pediatrician; one thing she told us was that up until the age of 6, remarkable improvement is possible, in some people. She recommended applying PECS (Picture Exchange Communication System) and TEACCH, using speech therapists and occupational therapists and hope for the best.
The US and Canada are unusual in diagnosing autism at two years of age, more typical is the advice below from Hong Kong:-


Research has indicated that the golden treatment period for autism is between age 0 to age 6, because the development of cognitive, coordinative, sensory and social skills in children within that age group is the quickest.
Children who are suspected to be autistic should receive assessment before age 4 or 4.5. Once diagnosed with the disorder, the child should receive professional training which lasts for at least two years before primary one.

Conclusion
I find it encouraging how in the decade since my son was diagnosed with autism we have gone from finding partially-effective experimental therapies to now having some researchers thinking about the time dimension (longitudinally). When do you need to intervene to make the greatest impact and can you do this even before symptoms have manifested themselves?

Our English neurodevelopment paediatrician from 2006 might see this as a pipe dream, but the authors of today’s first paper from Boston Children’s Hospital are already thinking along the right lines.  

The only risk is that minor brain changes possibly caused by a disruption in the E/I balance probably do produce those highly intelligent Asperger’s types who function perfectly well.  If you identified their odd EEG at 3 months of age and intervened, you might produce a social, rather than nerdy child, but no longer quite as intelligent.
If you can avoid the 0.3% of children having severe autism, which is Knut’s objective, I think you would have done well.                                                                          
I would agree with Courchesne (the previous post about brain overgrowth in autism) that by the time most autism intervention start the autistic brain has already neared adult size; he rather suggests that by then it is game over, it clearly is not. You have not missed the boat, even intervening in adulthood, it is just that the final destination will be different. 

As regards prevention of future autism (and ADHD), buy a dog before starting a family and from birth add a mix of probiotic bacteria to the baby's diet.      
       


         Not a bad destination





28 comments:

  1. @Tyler

    Peter has told me that you have a recipy for the biogaia gastrus yoghurt to increase the yield, would you mind giving me the link or the recipy itself on how to do it.

    Thanks

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    1. It is not yogurt, but more like kefir. I tried the yogurt route and it was very irregular, likely because of contamination from reusing culture (i.e. you take some of your yogurt and use it as the starter culture for your next batch just like with kefir).

      So what I settled with which is what I do today is I fill up a pyrex/glass container with 24 ounces of skim milk and then microwave it for 8 minutes (this will cause it to boil). You do this to kill any bacteria or other microorganisms in the milk, even though the milk has been pasteurized already. Once it has been boiled, I put the milk in a mason jar and seal it with a plastic lid and then put it in the freezer for an hour to cool the milk to a lukewarm temperature (100-130 degrees). I do this twice since I have four children as each mason jar's contents I split between two of my children (2 mason jars with 24 ounces of milk for four children). Once the mason jar(s) have cooled down a bit after an hour, I take one Biogaia Gastrus tablet and split it in two and put each half in each mason jar. This means it will cost me a dollar a day for all 4 children (3 have an autism diagnosis) as that is about the cost per tablet of Biogaia Gastrus. Then I put the mason jars on a shelf and let them fermend for around 24 hours. The next day you should have a consistency that is thicker than milk but not clumpy. If it is clumpy, it means it is overfermented and you might want to cool the milk a little longer in the freezer first or else make sure the ambient temperature in the house is not too high. Clumpiness means the milk is going under a second fermentation which produces a higher amount of alcohol and tastes pretty horrible as well.

      Once you have the fermented Biogaia Gastrus milk, you can mix its contents in a smoothie or else drink it plain if you want. For my kids I add sucralose for taste and also add in Vitamin D, a teaspoon of 50/50 barley flour and potato starch mix, inulin, and either vanilla extract or unsweetened chocolate (they have their preferences).

      I do this everyday pretty much and it is laborious, but two of my kids had behavior issues so bad in kindergarten and first grade that I was worried they would be kicked out of school, and this particular intervention pretty much reversed all of their problems within two weeks. The scientific reasoning for this intervention is a long discussion I have posted about before on this blog but it is in the realm of inheriting a poor microbiome from their mother as all four of my kids were delivered by Caesarian section. My more severe child with autism I also believe benefits from this.

      I also have no idea if me doing this intervention until they are 18 will be necessary, but the research on prebiotics/probiotics I have seen to date suggests any benefits derived are temporary and therefore need to be administered chronically. I don't want to have anymore trips to the principal's office anymore in having to defend my kids for their crazy impulsive actions that I can't explain to a school administrator in science terms that will go over his head anyways and just question his authority, so I continue with this intervention daily and hope for the best.

      Last but not least, the variables might need to be adjusted for you based upon the strength of your microwave and how cool your freezer is. You don't want the milk too hot or else it will kill the probiotic bacteria, but you don't want it too cold to start or else it won't divide either because lactobacillus bacteria prefer temperatures around 100 degrees.

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    2. Also, I meant to say I add in a tablespoon, not a teaspoon of barley flour/potato starch. You can add in as much as you want, but the drink can get too thick if you add in too much supplemental fiber. Inulin should also be spread around evenly when you put it in (like via a shaker), because it will clump together otherwise which is not what you want.

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    3. Tyler are you aware of this detailed thread that there is on longecity on exactly this subject?:

      https://www.longecity.org/forum/topic/70456-lactobacillus-reuteri-atcc-pta-6475-most-potent-thing-ever/page-7

      A poster even commented today (and these guys are knowledgable):

      "He (refering to the person who posted before him) is making assumptions on how inulin increases the growth of the bacteria. The strains in Gastrus DO NOT FERMENT INULIN, as shown in the study posted here earlier. Even when inulin is fully hydrolyzed by other micro-organisms in vivo, they can barely ferment the fructose. I expect at least that he did a plate count of one batch with and one without inulin with to support his claim. "

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    4. The inulin is not for the Biogaia Gastrus, but rather as a general prebiotic for the rest of the microbiome since you need to eat a huge amount of high-fiber vegetables (by western standards) to get enough soluble fiber in your diet to keep your intestines healthy. Supplementing soluble fiber, though not a perfect solution, I feel is a good solution to a severe lack of fiber in the western diet. If you can't get your kids to eat a decent sized salad with pretty much every meal, you should probably consider supplementing some soluble fiber (this is just my opinion based upon all the research I have seen on the topic).

      Inulin is probably the most widely studied prebiotic in the literature that I have come across. Is it the best prebiotic? Well that is an open question, but the research I have seen suggests fiber variety (like how many different plant sources you have in your diet) is more important than quality or quantity.

      Last but not least, I have read many threads on Longecity, but you have to realize it is really only a good place to farm for ideas and not a place to accept what is said as actual truth. Also, many of the people who post there (especially in the last few years) come up with ideas they present as facts everyone should accept at face value or else anyone who disagrees with them is deemed someone who is a "corporate shill", or else "drinks the kool-aid", or whatever if you disagree with them. So the result is a lot of the more knowledgeable posters don't post anymore because they don't have the energy or time to fight back against the echo chamber. The site is well-moderated but even then it can subsume to groupthink at times.

      If you come across an interesting thread, you will often find people drawing conclusions from cherry-picking scientific abstracts to support their strongly held position, so in that case I will just get the full papers directly and then make up my own mind about the topic.

      On the flip side, just because some of the people might come up with eccentric ideas does not mean they are wrong, even if they defend those ideas with irrational fervor. In my particular case, if I find it interesting, I read them and try and follow the rabbit hole to wherever it goes (time permitting) and make up my own mind after all of that.

      Nevertheless, back to the original comment you made, I can see how you might have assumed that the supplemental fiber (potato starch/barley flour/inulin) was intended to be synergistic with the Biogaia Gastrus, even though that was never the case. Probiotics as far as we understand at this time, generally just run their course through the digestive tract and do not permanently colonize or alter the gut microbiome, at least not without the aid of several rounds of very strong antibiotics which should only be used in rare circumstances for otherwise impossible to treat diseases of the intestinal tract. This field of scientific study really didn't exist two decades ago and has really exploded since then, so maybe everything I say now will be proven to be untrue in the future, but for now you should assume probiotics need to be given chronically and that just like with prebiotics, variety seems to be better than quantity or quality.

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    5. Fair points you make there and yes I noticed that aswell on longecity, there was a fiercy discussion on that thread (especially first 4 pages or so) on the optimal growth medium.

      With regards to inulin, I have tried it myself from bulkpowders before (as standalone and when I was experimenting with clostridicum butyricum), what I remember from it is that inulin is one of the best (if not the best) prebiotic to increase butyrate in the gut.

      I will try your recipy, Ive also seen yoghurt machines, would this save a lot of time if I think the batch with the milk was a success?

      Also you mention freezer, im assuming you mean the refridgerator? Also you use a thermometer? And isnt making a very very large batch all at once going to save more time?

      Thanks a lot so far!

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    6. No I did mean freezer for 1 hour as the milk is boiling hot at first. The freezer just speeds up the time it takes to lower the temperature to the point that the Biogaia Gastrus strains won't be killed from excessive heat.

      Also, the bacteria are a live culture so they will keep fermenting until they exhaust their food source, then other bacteria will use the previous bacteria as a food source as it breaks down so this is why you usually make kefir daily. I just found through trial and error that the method I posted worked for making a new batch each day. You can try a yogurt maker or other methods, just make sure you try and sterilize the milk first before fermenting unless you want to grow a bunch of bacteria that will make you sick.

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    7. Thanks Tyler for all the help so far, after running out on gastrus and it arriving today the difference is very very noticable. Literally took 4 tablets this morning on the empty along with 750mg agmatine and yep a very good day! Im so much more open to social conversations too and they actually seem to give me energy instead of draining me. I did a very big order 8x 30 tablets so it should last ages, atleast untill I find out how to properly do the batches like you as im sure it will take some effort at first to get it right.

      As far as milk concers, do you get bio yoghurt? or regular milk at the supermarket?

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    8. I just use regular skim milk. People who make kefir usually recommend using whole milk, but the Lactobacillus bacteria have little use for the fatty acids as best I know so it does not really matter. I also don't think organic matters much or not since you will be boiling the milk anyways. As you well know there are different grades of pasteurization and high heat will degrade some of the vitamins, but in our particular case we don't care about any of that since the goal is to ferment a good yield of probiotic bacteria, plus you can just take a multivitamin or else drink some extra milk out of a glass if you want to.

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  2. Peter, the post on critical periods is a refreshing and encouraging reminder to carers of ASD children to keep digging and fighting because scientists and treating doctors don't agree: never give up regardless of what developmental window has supposedly 'closed.' That being said, - question 1 - could you elaborate more on the practicalities of activating GABARs needed for the adolescent period of synaptic pruning??? and question 2 - returning to bumetanide - we shifted to morning dose only of either 1.5 or 2.0 mg (no more bedwetting) -- however I am stuck on comparing the options for enhancing BBB transmission and effectiveness. I've read about the probenecid, potassium bromide, diamox, and cinnamon options presented in the blog. But how is one to compare them critically. While Diamox and Probenecid are available online here without a prescription - a big advantage - isn't it true that Diamox will add to the risk of hypokalemia, so while it could help ramp up bumex effect, it might complicate the medical picture. That would suggest probenecid is better if equally effective. As to potassium bromide, after many months wait I was finally able to obtain some from Germany (so relieve it finally was possible) but I have not started because trying to understand the concern over 'half life' in the body. And, do we have a critical comparison between potassium bromide and, say, probenecid? Thanks as ever for sharing your observations from review of the scientific research and promoting this forum for other knowledgeable people also to share. -- Mira

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    1. Mira. Question 1, I think improving the E/I imbalance with bumetanide may improve adolescent synaptic pruning. Question 2, Probenecid was used in world war 2 to improve the effect of antibiotics, which were in short supply, the same mechanism also applies to bumetanide. The only question is what dose will be the optimal so as not to have any negative effects. There is no definitive research on optimizing bumetanide and there may never be. The best solution might just be a higher dose of bumetanide.

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    2. Mira, I've been using all these drugs with the exception of Probenecid.
      Diamox indeed decreased potassium level in my son, but only slightly and temporarily - at the beginning of the treatment. Not to the point of abnormal result.
      It required potassium supplement dose adjustment for long term use, but it was not something difficult or disturbing.

      For your information I was concerned about the use of two diuretics together and consulted pediatric nephrologist who didn't see any problem with this. The same about supplementation of high dose of potassium provided normal kidney function in a child.

      ---------

      Peter, does the chart above about the risk ratios for ASD suggest that MMR reduces autism risk??

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    3. Agnieszka, yes the chart indicates MMR vaccination reduces the risk of autism. I am not sure how reliable this data point is.

      Clearly, a 3 year old who catches M,M or R will increase their risk of "catching" autism as well, if they have a predisposition to mitochondrial disease.

      We already know that vaccinations themselves carry a small risk of adverse events and that is why, at least in the US, there is an industry funded compensation scheme. It evidently helps if one parent is a Johns Hopkins trained neurologist, when lodging a claim.

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    4. I will try to verify the chart data out of curiosity.

      Anyway, there would be a good question how to identify those at risk of "catching" autism and how to prevent the consequences of inflammatory insults.

      Btw I know a case of autism which is believed to be associated with R in the mother while pregnant.

      Back to bumetanide: Peter, did you use higher dose than 2mg/d which was considered optimal in the French trial?

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    5. Agnieszka, I currently use 2mg of bumetanide once a day, with a decaffeinated coffee flavanol as an OAT3 inhibitor. Last summer I did try 2mg before breakfast and 1 mg in the afternoon. Since we have no problem with K+, I do plan to try 3mg once a day.

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  3. Hi Peter, my son had a strong intestinal colic and in the urgency the passed him ketoprofen intravenously, they did a quick urine analysis and showed possible infection, the urine culture will be ready on monday.Yesterday I found Nitrofurantoin, it is a bactericidal nitrofuran antibiotic, it is completly absorbed in the upper intestinal tract and has no detrimental effect on gut flora. The mechanism of action is unique, it works by damaging bacterial dna. Faecal flora analysis didn´t show overgrowth resistant bacteria.50 mg at bedtime is safe for use long term, 12 months, as preventive treatment. I wanted to know if you have some information and what do you think.
    Valentina

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    1. Valentina, Nitrofurantion reaches high levels in urine and so is used to treat urinary tract infections. I do not expect it will have immunomodulating properties like Azithromycin. It can cause neuropathy.

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    2. Ok,thanks Peter, he has no infection, the same happened with The OAT test,all seems to be normal even though sometimes his behavior shows the contrary. May be histamine is something I should look closer.
      Valentina

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  4. Also in schizophrenia there are critical periods:

    "The existence of prenatal risk factors for schizophrenia, such as maternal infections, nutritional deficiency, obstetrical complications and stress, suggests that there is a developmental window of sensitivity in which a transient early insult leads to long-lasting developmental perturbations.
    In supporting of this notion, NMDAR antagonism during an equivalent period in rodents (first 2 post-natal weeks) induces long-lasting behavioural and cognitive disturbances that are relevant to the schizophrenia phenotype and which extend
    into adolescence and adulthood.
    Moreover, severe NMDAR blockade induces forebrain apoptosis in rats, but only when administered between the first and third postnatal week. A milder antagonism regime caused long-lasting behavioural changes and a specific longlasting decrease in cortical PVI numbers, mimicking a key pathological feature of
    schizophrenia"

    https://serval.unil.ch/resource/serval:BIB_0ECCF75A1F1F.P001/REF

    As my other post shows, sulphoraphane possibly has the ability to treat parts of the problem, and also NAC:

    "The causal relevance of oxidative stress was further strengthened by the demonstration that juvenile antioxidant treatment using N-Acetyl cysteine (NAC) prevents oxidative stress in a developmental rat model of schizophrenia (neonatal ventral hippocampal lesion (NVHL)) and, in doing so, inhibits the
    emergence of morphological, electrophysiological and behavioural deficits" (this was a reference to another paper)

    /Ling

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  5. Peter,you mention me right off the bat,but you don't mention why my autism responded so well to treatment,starting in my late 40s.I was one of the early patients found to have high levels of folate receptor alpha autoantibodies.I had a pair of MTHFR mutations,and more importantly,levels of homocysteine and methylmaonic acid,that were diagnostic of Severe MTHFR Deficiency and Homocystinuria.I still treat the homocysteine,because it's the only thing that controls my seizures.I also have a long family history of disorders associated with folate metabolism.I am aware that FRAAs are supposed to be very common with autism,and autism doctors hand out folinic acid like candy,whether it benefits patients or not,but true disorders of folate metabolism are a different matter.In my case,it may be part of a bigger picture,as I also have a pair of pathogenic mutations of a rare cancer gene,with double strand DNA breaks,and rearrangement on two chromososomes.This has been known to reprogram metabolic pathways,especially redox and folate.

    Our friend Dr. Ramaekers in Belgium,also discovered some forms of schizophrenia are due to folate receptor alpha autoantibodies,and respond very well to folinic acid treatment.
    https://s3.amazonaws.com/academia.edu.documents/43321523/Folinic_acid_treatment_for_schizophrenia20160303-31691-hlkgnk.pdf?AWSAccessKeyId=AKIAIWOWYYGZ2Y53UL3A&Expires=1528897456&Signature=eK6zc6RcZWj5UJNezqd%2BYmlUklk%3D&response-content-disposition=inline%3B%20filename%3DFolinic_acid_treatment_for_schizophrenia.pdf

    Schizophrenia patients are usually adults.Inborn metabolic disorders can be treated at any age.

    I also know a woman,whose autism was about a severe as mine,moderate to severe,who also reversed her autism,starting in her 40s,like I did.This woman did so by treating a mast cell disorder.It is probably the case,that older patients whose autism can be successfully treated,have a single clear cut medical cause for their autism.and targeted treatment will reverse it,no matter how old the patient is.

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  6. Some very interesting research relevant to several recent discussions on this blog suggests that noise, especially during sleeping, contributes to inflammation which eventually leads to vascular damage:

    Press Release:

    https://www.sciencedaily.com/releases/2018/06/180614095235.htm

    Paper:

    https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehy333/5037114

    Now if you are already from a compromised population of people with inflammation, oxidative stress, and vascular problems both in the periphery and CNS, this suggests that nighttime noise may make things much worse. Now it is not new that noise is bad for the brain while sleeping (white noise generators can help some people go to sleep but should not loop all night long), but this research shows one particular reason why and that a drug that activates the gene FOXO3 called Bepridil attenuates some of the negative effects on noise while sleeping.

    One can also speculate that if someones has a hypersensitivity to sound in the first place, such as the situation which is very common in autism, that noise while sleeping can be even more damaging to that person than someone with normal sound sensitivity.

    I know I am guilty of watching late night TV at times while the kids are asleep, but this makes me wonder whether some wireless headphones for my wife and I might be a good intervention since even though the kids sleep upstairs and the TV is in the living room, even if the TV is at low volume, you can still hear the sound of the television if your have decent hearing. How hard it happens to be for someone with hypersensitive hearing to filter out noise while sleeping is a hard question to answer, but I would assume that the more noise, the more you are going to get the negative vascular/inflammation effects mentioned in this paper.

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    1. Tyler, I can only comment on my own case, but I do find up I wake up very easily if my neighbours come home late at night despite them not making too much sound.

      Then again 23andme confirmed suspision that I have circadian rythm disruptions. Now atleast in Aspergers this is common. Lacking a proper cortisol awakening response is the case, while in depression/anxiety there is often an increased CAR's, which is the opposite!!!

      Those predisposed to malfunction of the circadian rythm, obviously high attention should be payed to optimizing sleep (magnesium oil is a winner for me with no tollerance at all).

      I dont think theres much you can do about it, other than you said, minimize the sound exposure for your kid by investing in some wireless headphone.
      Does your kid sleep in a completely dark room? I have invest in curtains a few years ago that completely make the room black, not a single light beam can get through.

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    2. Tyler, yes very interesting and it fits in to the discussion of Nitric Oxide, this time it is both nNOS and eNOS that are reduced by noise during sleep. We saw that in late middle age oxidative stress causes a loss of eNOS which is why older people often develop high blood pressure. That you can mitigate with NAC and some Agmatine.

      Agmatine also reduces neuronal nitric oxide, which is the opposite of what the study might suggest you want. But, it looks much more complex. The problem is NOS "uncoupling", which appears to mean that the NOS enzyme which should produce NO does not do so due to oxidative stress and/or too little of the cofactor BH4.

      So we have noise during the night causing both eNOS and nNOS uncoupling.

      This might suggest taking NAC before going to bed if you live near an airport or even someone who snores loudly.

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    3. nNOS is extremely important and overlooked, it is critical for learning and has a strong connection with NMDA function, NMDA agonists increase nNOS, where NMDA antagonist seem to decrease them.

      I can only speak for myself but D-aspartic acid, l-glycine, ZMA absolutely WRECK my sleep quality, I believe this is due to them affecting REM sleep. Some studies claim that in some forms of autism/asd there is less REM sleep, but im afraid its far more complex than that, its not just a matter of how much REM sleep someone gets, but the actual structural changes in the brain that happen during REM sleep seems to be disrupted in autism.
      Id wake up literally 20 times per night, every 10mins or less.

      Recently tried oleamide by the way Peter, which can potentiate REM sleep too, it wrecks my sleep too, tried small doses during day time, all did was make me drowsey.

      Then theres alcohol and acute sleep deprivation (which has been shown to have fast acting antidepressant effects in multiple studies) which cause REM sleep deprivation and this completely normalizes my brain for the next day.

      It turns out that curcumin (yes from tumeric), increases nNOS:

      Curcumin ameliorates memory deficits via neuronal nitric oxide synthase in aged mice.
      https://www.ncbi.nlm.nih.gov/pubmed/23665290

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    4. Interesting ideas Peter, I have only ever given NAC during the morning or afternoon.

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  7. Agnieska, thanks for the information on Diamox. We will look into it further. -Mira

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  8. Hello, I just wanted to ask whether you ever checked Montys cytokines and whether you think its a useful tool for checking up whether some therapies work? Also, how would one go about introducing bumetanide in a hot country in the summer? How often would one need to check minerals in blood to make sure there is no disbalance? We are gearing up for this, so any practical advice would be great. What I would think is that we should do 2 blood tests for minerals in 10 days to get a baseline and perhaps fix an existing disbalance and also find and get quality supplements in case they are needed. Then start the pills, and follow up with blood testa every 7 days for 6 weeks to see how it goes. Any suggestions to this plan?

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    1. Tatjana, it all depends how easy it is to draw blood. For some kids this is a big problem.

      I think you probably only need to measure electrolytes once before starting. They should not vary unless your child is sick or taking other drugs. The result is most likely that everything is normal. Potassium is the most important one.

      Based on the starting point of potassium, you adjust diet and add a small supplement when you start the bumetanide. For most people this is enough, but for about 20% they seem to lose more potassium and so closer monitoring is required.

      The mistake some people have made is to start bumetanide and do nothing to increase potassium levels. I think this is irresponsible. An extra banana a day has zero potential to do any harm.

      After a week measure potassium again and see if it is in higher part of the normal range. If it is lower then you have to add more potassium.

      You have to make sure the child drinks more water. My son did this all by himself. When he asks for water make sure you have it available, or just keep offering it. My son drinks 2.5 to 3 litres a day of fluids.

      Read up about signs of low potassium and dehydration, these are clearly issues that can occur, but are entirely manageable/preventable.

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