Friday, 1 June 2018

Autism, Power Outages and the Starving Brain?

There are certain Critical Periods in the development of the human brain and these are the most vulnerable times to any genetic or environmental insult.  Critical Periods (CPs) will be the subject of post appearing shortly.

Another power outage waiting to happen

 Have you wondered why autism secondary to mitochondrial disease (regressive autism) almost always seem to occur before five years of age, and usually much earlier?  Why does it not happen later? Why is it's onset often preceded by a viral infection?
I think you can consider much of this in terms of the brain running out of energy. Humans have evolved to require a huge amount of energy to power their developing brains, a massive 40% of the body’s energy is required by the brain in early childhood.  If your overload a power grid it will end in a blackout.
We know many people with autism have a tendency towards mitochondrial dysfunction, they lack some key enzyme complexes. This means that the process of OXPHOS (Oxidative phosphorylation), by which the body converts glucose to usable energy (ATP), is partially disabled. 

We saw in earlier posts how the supply of glucose and oxygen to the brain can be impaired in autism because there is unstable blood flow.

It is just like in your house, all your electrical appliances might mean you need a 25KW supply, because you do not use them all at the same time. Just to be on the safe side you might have a 40KW limit. What if the power company will only give you a 20 KW connection? If you turn on the clothes drier, the oven, the air conditioning and some other things all of a sudden you blow the main fuse and perhaps damage the hard drive of your old computer.
So, in the power-hungry brain of a three-year-old, you add a viral infection and all of a sudden you exceed the available power supply from the mitochondria, that have soldered on for 3years with impaired supply of complex 1 and imperfect cerebral blood flow. By the sixth year of life, the peak power requirement from the brain would have fallen to within the safe limit of the mitochondria and its impaired supply of complex 1.  Instead of blowing the fuse, which is easy to reset, you have blown some neuronal circuitry, which is not so easy to repair.    

Too Many Synapses?
We know that it is the synapses in the brain that are the big energy users and we also know that in most autism there are too many synapses. So, in that group of autism there is an even bigger potential energy demand.

Note that in Alzheimer’s type dementia (AD in the above chart) you see a severe loss of synapses/spines as atrophy takes place. This occurs at the same time as a loss of insulin sensitivity occurs (type 3 diabetes). Perhaps the AD brain is also starved of energy, it does seem to respond to ketosis (ketones replacing glucose as the fuel) and it responds to Agmatine (increasing blood flow via eNOS).
We also know that adolescent synaptic pruning is dysfunctional in autism and we even know why. Interestingly by modifying GABAA function with bumetanide we may indeed allow the brain to eliminate more synapses (a good thing), so possibly an unexpected benefit from Ben Ari’s original idea.

"Working with a mouse model we have shown that, at puberty, there is an increase in inhibitory GABA receptors, which are targets for brain chemicals that quiet down nerve cells. We now report that these GABA receptors trigger synaptic pruning at puberty in the mouse hippocampus, a brain area involved in learning and memory." The report, published by eLife, "Synaptic pruning in the female hippocampus is triggered at puberty by extrasynaptic GABAA receptors on dendritic spines."            
These findings may suggest new treatments targeting GABA receptors for "normalizing" synaptic pruning in diseases such as autism and schizophrenia, where synaptic pruning is abnormal. Research has suggested that children with autism may have an over-abundance of synapses in some parts of the brain.

Synaptic pruning in the female hippocampus is triggered at puberty by extrasynaptic GABAA receptors on dendritic spines

Adolescent synaptic pruning is thought to enable optimal cognition because it is disrupted in certain neuropathologies, yet the initiator of this process is unknown. One factor not yet considered is the α4βδ GABAA receptor (GABAR), an extrasynaptic inhibitory receptor which first emerges on dendritic spines at puberty in female mice. Here we show that α4βδ GABARs trigger adolescent pruning. Spine density of CA1 hippocampal pyramidal cells decreased by half post-pubertally in female wild-type but not α4 KO mice. This effect was associated with decreased expression of kalirin-7 (Kal7), a spine protein which controls actin cytoskeleton remodeling. Kal7 decreased at puberty as a result of reduced NMDAR activation due to α4βδ-mediated inhibition. In the absence of this inhibition, Kal7 expression was unchanged at puberty. In the unpruned condition, spatial re-learning was impaired. These data suggest that pubertal pruning requires α4βδ GABARs. In their absence, pruning is prevented and cognition is not optimal.

Strange Patterns of Growth
Longitudinal studies are when researchers collect the same data over long period of years. Most autism research is just based on a single snapshot in time.
One observation of mine is that some people with strictly defined autism (SDA) are born at the 90+ percentile for height, but then fall back to something like the 20 percentile. Body growth has dramatically slowed. Was this because energy has been diverted to the overgrowing brain? 
A five-year old’s brain is an energy monster. It uses twice as much glucose (the energy that fuels the brain) as that of a full-grown adult, a new study led by Northwestern University anthropologists has found.
It was previously believed that the brain’s resource burden on the body was largest at birth, when the size of the brain relative to the body is greatest. The researchers found instead that the brain maxes out its glucose use at age 5. At age 4 the brain consumes glucose at a rate comparable to 66 percent of the body’s resting metabolic rate (or more than 40 percent of the body’s total energy expenditure). 

“The mid-childhood peak in brain costs has to do with the fact that synapses, connections in the brain, max out at this age, when we learn so many of the things we need to know to be successful humans,” Kuzawa said.

“At its peak in childhood, the brain burns through two-thirds of the calories the entire body uses at rest, much more than other primate species,” said William Leonard, co-author of the study. “To compensate for these heavy energy demands of our big brains, children grow more slowly and are less physically active during this age range. Our findings strongly suggest that humans evolved to grow slowly during this time in order to free up fuel for our expensive, busy childhood brains.” 

Full paper: -

The high energetic costs of human brain development have been hypothesized to explain distinctive human traits, including exceptionally slow and protracted preadult growth. Although widely assumed to constrain life-history evolution, the metabolic requirements of the growing human brain are unknown. We combined previously collected PET and MRI data to calculate the human brain’s glucose use from birth to adulthood, which we compare with body growth rate. We evaluate the strength of brain–body metabolic trade-offs using the ratios of brain glucose uptake to the body’s resting metabolic rate (RMR) and daily energy requirements (DER) expressed in glucose-gram equivalents (glucosermr% and glucoseder%). We find that glucosermr% and glucoseder% do not peak at birth (52.5% and 59.8% of RMR, or 35.4% and 38.7% of DER, for males and females, respectively), when relative brain size is largest, but rather in childhood (66.3% and 65.0% of RMR and 43.3% and 43.8% of DER). Body-weight growth (dw/dt) and both glucosermr% and glucoseder% are strongly, inversely related: soon after birth, increases in brain glucose demand are accompanied by proportionate decreases in dw/dt. Ages of peak brain glucose demand and lowest dw/dt co-occur and subsequent developmental declines in brain metabolism are matched by proportionate increases in dw/dt until puberty. The finding that human brain glucose demands peak during childhood, and evidence that brain metabolism and body growth rate covary inversely across development, support the hypothesis that the high costs of human brain development require compensatory slowing of body growth rate. 

To quantify the metabolic costs of the human brain, in this study we used a unique, previously collected age series of PET measures of brain glucose uptake spanning birth to adulthood (32), along with existing MRI volumetric data (36), to calculate the brain’s total glucose use from birth to adulthood, which we compare with body growth rate. We estimate total brain glucose uptake by age (inclusive of all oxidative and nonoxidative functions), which we compare with two measures of whole-body energy expenditure: RMR, reflecting maintenance functions only, and daily energy requirements (DER), reflecting the combination of maintenance, activity, and growth. We hypothesized that ages of peak substrate competition (i.e., competition for glucose) between brain and body would be aligned developmentally with the age of slowest childhood body growth, and more generally that growth rate and brain glucose use would covary inversely during development, as is predicted by the concept of a trade-off between brain metabolism and body growth in human life-history evolution. 

Daily glucose use by the brain peaks at 5.2 y of age at 167.0 g/d and 146.1 g/d in males and females, respectively. These values represent 1.88- and 1.82-times the daily glucose use of the brain in adulthood (Fig. 1 A and B and SI Appendix, Fig. S2), despite the fact that body size is more than three-times as large in the adult.

Glucose use of the human brain by age. (A) Grams per day in males. (B) Grams per day in females; dashed horizontal line is adult value (A and B). (C) Glucosermr% (solid line) and glucoseder% (dashed line) in males. (D) Glucosermr% (solid line) and glucoseder% (dashed line) in females.

The most relevant data is the line highlighted in yellow below, showing brain consumption of glucose peaks at 40% (of total body consumption) around 5 years old and drops to 20% in adulthood.

Our findings agree with past estimates indicating that the brain dominates the body’s metabolism during early life (31). However, our PET-based calculations reveal that the magnitude of brain glucose uptake, both in absolute terms and relative to the body’s metabolic budget, does not peak at birth but rather in childhood, when the glucose used by the brain comprises the equivalent of 66% of the body’s RMR, and roughly 43% of total expenditure. These findings are in broad agreement with past clinical work showing that the body’s mass-specific glucose production rates are highest in childhood, and tightly linked with the brain’s metabolic needs (40). Whereas past attempts to quantify the contribution of the brain to the body’s metabolic expenditure suggested that the brain accounted for a continuously decreasing fraction of RMR as the brain-to-body weight ratio declined with age (25, 31), we find a more complex pattern of substrate trade-off. Both glucosermr% and glucoseder% decline in the first half-year as a fast but decelerating pace of body growth established in utero initially outpaces postnatal increases in brain metabolism. Beginning around 6 mo, increases in relative glucose use are matched by proportionate decreases in weight growth, whereas ages of declining brain glucose uptake in late childhood and early adolescence are accompanied by proportionate increases in weight growth. The relationships that we document between age changes in brain glucose demands and body-weight growth rate are particularly striking in males, who maintain these inverse linear trends despite experiencing threefold changes in brain glucose demand and body growth rate between 6 mo and 13 y of age. In females, an earlier onset of pubertal weight gain leads to earlier deviations from similar linear inverse relationships.

What the researchers then did was to see how the growth rate of the brain is correlated to the growth rate of the body. In effect that what they found was that the growth of the body has to slow down to allow the energy hungry brain to develop.  One the brain has passed its peak energy requirement at about 5 years old, body growth can then gradually accelerate. 
The brain is the red line, the body is blue. The chart on the left is males and the one on the right is females. 
So, we might suspect that in 2 to 4-year olds who seem not to be growing as fast as we might expect, the reason is that their brain is over-growing, a key feature of classic autism.

Glucoseder% and body-weight growth rate. Glucoseder% and weight velocities plotted as SD scores to allow unitless comparison. (A) Glucoseder% (red dots) and dw/dt (blue dots) by age in males. (B) Glucoseder% (red dots) and dw/dt (blue dots) by age in females

Brain Overgrowth in Autism
As has been previous commented on in this blog, Eric Courchesne has pretty much figured out what goes wrong in the growth trajectory of the autistic brain; that was almost 15 years ago.

Brain development in autism: early overgrowth followed by premature arrest of growth.

Author information


Due to the relatively late age of clinical diagnosis of autism, the early brain pathology of children with autism has remained largely unstudied. The increased use of retrospective measures such as head circumference, along with a surge of MRI studies of toddlers with autism, have opened a whole new area of research and discovery. Recent studies have now shown that abnormal brain overgrowth occurs during the first 2 years of life in children with autism. By 2-4 years of age, the most deviant overgrowth is in cerebral, cerebellar, and limbic structures that underlie higher-order cognitive, social, emotional, and language functions. Excessive growth is followed by abnormally slow or arrested growth. Deviant brain growth in autism occurs at the very time when the formation of cerebral circuitry is at its most exuberant and vulnerable stage, and it may signal disruption of this process of circuit formation. The resulting aberrant connectivity and dysfunction may lead to the development of autistic behaviors. To discover the causes, neural substrates, early-warning signs and effective treatments of autism, future research should focus on elucidating the neurobiological defects that underlie brain growth abnormalities in autism that appear during these critical first years of life.

Research from 2017: -

A record of children’s height and weight and even head circumference is usually collected by their doctor. In an earlier post I did ask why they bother if nobody is checking this data. If a child falls from the 90th percentile in height to the 20th, something clearly is going on.
When I discussed this with a pediatric endocrinologist a few years ago, we then measured bone-age and IGF-1. If you have low IGF-1 and retarded bone age you might opt for some kind of growth hormone therapy.
In what is broadly defined as autism, I think we have some distinctly different things possibly happening: -

Group AMD
Energy conversion in the brain is less efficient than it should be due to a combination of impaired vascular function and impaired mitochondrial enzyme complex production. No symptoms are apparent and developmental milestones are achieved.  As the brain creates more synapses it energy requirement grows until the day when the body has some external insult like a viral infection, and the required power is not available, triggering a “power outage” which appears as the regression into autism. In biological terms there has been death of neurons and demyelination.

Group Sliding Down the Percentiles 
This group looks like a sub-set of classic autism. The brain grows too rapidly in the first two years after birth and this causes the expected slowing of body growth to occur much earlier than in typical children. This manifests itself in the child tumbling down the percentiles for height and weight.
The brain then stops growing prematurely, reducing energy consumption and allowing body growth to accelerate and the child slowly rises back up the height/weight percentiles.

Perhaps all those excessive synapses that were not pruned correctly are wasting glucose and so delay the growth of the rest of the body?   
In the sliding down the growth percentiles group, does this overgrowing brain ever exceed maximum available power? Maybe it just grows too fast and so mal-develops, as suggested by Courchesne, or maybe it grows too fast and cannot fuel correct development?  What happens if you increase maximum available power in this group, in the way some athletes use to enhance their performance/cheat?
All I know for sure is that in Monty, aged 14 with autism, increasing eNOS (endothelial nitric oxide synthase) using agmatine seems to make him achieve much more, with the same daily glucose consumption. I wonder what would happen if Agmatine was given to very young children as soon as it was noted that they were tumbling down the height percentiles?  This is perhaps what the pediatric endocrinologists should be thinking about, rather than just whether or not to administer growth hormones/IGF-1.
If you could identify Group AMD before the “power outage” you might be able to boost maximum power production or reduce body growth slightly and hence avoid the brain ever being starved of energy. That way you would not have most regressive autism.


  1. Peter, If child is past puberty, do you think you could still prune the synapses? Would it be through bumetanide? Also what other rx and supplements do the same thing for pruning synapses? Thanks

    1. It looks like synaptic pruning continues throughout adolescence. It looks like GABAa receptors have to function for pruning to occur correctly, but it is a highly complex process involving many other things. So there is no single solution, but if you have excess neuronal chloride this will affect many things, one of which looks likely to be synaptic pruning.

      It does look like bumetanide is a wise choice for people with autism and the younger you start the more profound the results may be. Not all autism has excess chloride inside neurons, it should be noted.

    2. Great post Peter,

      Concerning my (yes again) talk about acute alcohol withdrawal and the effect being making me 100% human. alpha4 gaba receptors are involved in that along with LTP/LTD modulation, do you reckon it could explain the observed benefit it has on me or atleast partially, social communication and empathy comes 100% naturally in that state and is effortless.

      By the way I have a meeting with my psych coming tuesday about bumetanide, im pretty sure ill get it :D. Concerning my bodyweight, im 95kg and 6ft3, what dose would you recommend with in your back of the mind that I do seem to have urea problems (allthough they are still dropping in every bloodtest, from 10.4 down now to 7 whooahhaa).

    3. Aspie1983, I continue to be surprised just how important GABAa receptors are and how their sub-unit expression changes so many things.

      Ethanol does affect GABAa subunits so it could well explain what is happening to you.

      I would suggest 2mg of bumetanide taken before breakfast and at least an hour before leaving home. How much potassium is lost is highly variable. I give 500mg of potassium citrate in 200 ml of water at the same time as the bumetanide and have one large banana eaten mid morning.

      About 20% of people seem to lose a lot of potassium. You should measure K+ before starting and after a week or so.

      Don't forget to drink a lot more water so that you fully replace what is lost in diuresis. You should be drinking 3 liters of fluid a day. If you get dehydrated you will get symptoms and your blood pressure will reduce.

      If you do not control K+ you will get symptoms like muscle spasms.

      My son has never has any side effects, but some people do, so you have to be careful. I expect the doctor will know all this.

    4. Thanks Peter,

      I will talk to the psych and make sure he gives me them. Potassium citrate I still have at home (like 300grams or something). I eat allready very healthy, usually 3 main meals and a very small protein like snack 3hours before bed, every meal has vedgies and atleast 50grams worth of food, no gluten, only dairy I take is eco-yoghurt and goatcheese (for its butyrate content). I suspect I allready get lots of potassium in my diet, I eat around 350-500gram of vedgies per day on average. That being said Im sure bumetanide is powerfull at depleting sodium/potassium, so no doubt ill need some. Im thinking of starting the bumetanide first and after I start getting some minor spasms add some potassium in increments of 200mg per meal on top till the spasms end. And trust me I do know I will get spasms lol, I used to drink lots of coffee years ago and at around 4pm (like 3hours after my last coffee), Id get eye lid spasms.

      One thing else I used to always get which I noticed throughout the years and sometimes also recently, is that when I feel mentally good I often noticed I get head jerks, like if im sitting at the pc, my head would all of a sudden quick get a spastic response and quickly flexes to left shoulder.

      Now as you might remember Asperger is associated with decreased 5ht2a binding in the cortex and this is one of abnormalities that correspond to social functioning deficits. Now every study I read where they test drugs on 5ht2a ligand binding capacity with DOI (yes the 5ht2a agonist), they use the head-twitch response and wet dog shake as a marker for increased 5ht2a binding.

      I got 2 empty bloodwork papers laying around (my doc is very open, she allows me to use a pen to choose what I want to get checked lol, love her for that and has helped me so much), Id assume it be best I get my sodium/potassium levels checked before treatment and what would you say another I get drawn like 2 weeks or 2months after starting? Im new to bumetanide.

    5. By the way I also have oleamide coming my way (somewhat similar to PEA), which is shown (at least in studies) to amplify 5ht2a and 5ht2c activity by over 250% on top of that it increase CB1 binding (alot of autism/asd models also point to downregulated CB1 receptors and upregulated CB2 receptors).

      Im expecting pronounced results from that (and for all that it matters 23andme and stated that I have a poor response to the placebo effect lol)

  2. A very important bit of research just recently came out which explains how the gene PTEN controls the number of inhibitory neurons in the cortex:

    Press Release:


    The main findings in this paper are very interesting because it is suggested that PTEN dysfunction prevents the reduction of inhibitory interneurons that naturally occurs, once the number of excitatory pyrimidal cells have been set.

    Now, many studies I have seen have shown a reduction of inhibitory interneurons in the cortex in both animals and humans, in particular a class of inhibitory interneurons called parvalbumin interneurons, so this research is surprising even though PTEN is just one of many, many genes implicated in autism so resolving these discrepancies with this new research will probably take some time before anything is resolved.

    Inhibitory interneurons of course can inhibit other interneurons in a process known as disinhibition, so this could be why you may have some of the cognitive slowing you might find in other intellectual disability syndromes like Down Syndrome where there is an excess of inhibitory interneurons in the prefrontal cortex, while at the same time having sensory networks that are hyperactive. Looking at imaging data and trying to figure out the "root cause" of hyperactive brain networks is a bit like trying to unscramble an egg, but researchers seem to be making steady progress nevertheless from everything I have read in the last 6-7 years alone.

    Now, I don't know exactly when in development this supposed inhibitory interneuron pruning is supposed to occur after the pyramidal cell growth has been arrested, but this paper claims it happens postnatally which of course with respect to autism etiology brings up more questions than answers. It does give some hope in the not too distant future that if you could detect PTEN dysfunction prenatally, you might be able to intervene postnatally to guide the baby's brain to a more normal path of neurodevelopment.

    1. Hi Tyler,
      Great find. Funny that you mention this because I was reading up the same subject a few days ago:

      The parvalbumin/somatostatin ratio is increased in Pten mutant mice and by human PTEN ASD alleles.

      This could also perfectly explain my bloodvalues!, Could the high TSH and thyroid problems be a link and a marker for low somatostatin!???

      My features:

      * very large build, very very broad shoulders, long arms, never broken a bone despite falling a billion times, I got all the features of high GH.
      * bloodtests ALLWAYS had shown high prolactin untill my doctor put me on levothyroxine to treat the high TSH (my TSH was at around 4.5-5, and no matter what diet changes or what I did it never came down naturally it is hardwired in my genes)

      Now look at wikipedias article on Somatostatin, its function also is:

      Inhibit the release of growth hormone (GH)[14] (thus opposing the effects of growth hormone–releasing hormone (GHRH))
      Inhibit the release of thyroid-stimulating hormone (TSH)[15]
      Inhibit adenylyl cyclase in parietal cells
      Inhibits the release of prolactin (PRL)

      What does everyone think? I mean after all prolactin and tsh can be measured in bloodtests.

    2. This could also mean that biogaia gastrus is actually helping as I noticed I flinch more often when lets say a loud noise appears all a sudden in the street. I used to never respond to that. Not to mention Ive actually signed up and went to 2 new meeting with new people, which the last time I have done is like ehmmmm years n years ago.

    3. The parvalbumin/somatostatin ratio is not a ratio of the amount of those proteins in the blood but the ratio of parvalbumin expressing GABAergic interneurons to somatostatin expressing GABAergic interneurons. Parvalbumin interneurons tend to synapse close to the soma of the postsynaptic neuron for strong all or nothing inhibition, while somatostatin neurons tend to synapse farther from the soma which makes them more modulatory and also more local to the dendrites it synapses with. They can also affect the presynaptic receptors of pyramidal cells to selectively act as wall between individual connections between pyramidal cells.

      Somatostatin interneurons also can disinhibit the function of parvalbumin interneurons by synapsing onto them which in some part of the brain will mean a decrease in overall inhibition.

      Somatostatin has many, many other functions in the body besides its prevalence in many GABAergic interneurons. Here is a good review which might help:

    4. Aspie, also probiotics as you well know can have very complex effects that go way beyond what they seem to demonstrate in vitro.

      Here is a study showing how a particular metabolite of tryptophan can exert a potent anti-inflammatory effect on microglia in the brain:

      Press Release:


      This study is specifically for MS and the metabolite I3S has been studied for a while and here is a brief description of it:

    5. Thanks tyler,

      I was aware of that metabolite and I think the way it shifts tryptophan metabolism + alters immune function + regulates my gut histamine levels has to do with the noticable effects it has on me.

      Looking at one of the links you mentioned, they once again mention the aryl hydrocarbon receptor.
      As I have said before the AHr activation is one step BEFORE HSF1/HSP70/NRF2 induction, it is literally the sensor that tells to induce nrf2, without AHr activation you can forget about nrf2 induction.

    6. On top of that reuteri acts to regulate TLR4 (yes the innate immune system). It works by antagonizing it.

      Now TLR4 and DARPP32 (this regulates anywhere from dopamine systems to amygdala volume) are closely intertwined. The drug Ibudilast that Peter has talked about before in the past with regards to cognition is also a TLR4 antagonist.

  3. Central Amygdala Somatostatin Neurons Gate Passive and Active Defensive Behaviors.

    The ability to develop adaptive behavioral responses to threat is fundamental for survival. Recent studies indicate that the central lateral amygdala (CeL), in particular its somatostatin-expressing neurons, is crucial for both learning and the expression of defensive response. However, how exactly these neurons participate in such processes remains unclear. Here we show for the first time in behaving mice that the somatostatin-expressing neurons in the CeL acquire learning-dependent responsiveness to sensory cues predicting a threat. Furthermore, our results indicate that these neurons gate the behavioral output of an animal: whereas high activity in these neurons biases toward passive defensive responses, low activity in these neurons allows the expression of active defensive responses."

    This could the impaired fear response and apathy like symptoms in me.

    Differential fear conditioning in Asperger's syndrome: implications for an amygdala theory of autism.

    At the neurobiological level, it is still debated to what extent abnormalities of the limbic system, in particular the amygdala, may be responsible for the emotional disturbances characterising ASD. ---->>> Here we show that a group of individuals with Asperger's syndrome exhibit a pattern of abnormality in differentially acquiring fear <<<----, which suggests that their fear responses are atypically modulated by conditioned and non-conditioned stimuli. On the basis of these results and the existing literature we suggest that ASD may be characterised by atypicalities in the integration of physiological and cognitive aspects of emotional experiences which we argue arise because of poor connectivity between the amygdala and functionally associated cortical areas.

  4. Which is very odd by the way, because I responded very bad to low dose clonazepam, extreme irritability, I hated everyone on it.

    "Interestingly, a very low dose (0.0625 mg/kg) of clonazepam---a PAM of GABAA receptors containing the α1, α2, α3, or α5 subunit---completely rescued abnormal social behaviors and deficits in fear memory (154). At this low dose, clonazepam is not anxiolytic or sedative (154). Dysfunction of GABAergic neurons may result in upregulation and/or sensitization of postsynaptic GABAA receptors, which would explain why such low doses of clonazepam are effective."

    Quoted from a study.


    Agmatine seems to effect somatostatin!

  6. Peter, What about CBD as immunomodulator and antiinflammatory?

    1. Valentina, a lot of money is going into CBD research, it seems to help some people, but I have not really looked at it.

  7. It is all very interesting.

    Two questions come to my mind: aren't the younger siblings of children with autism the group to target? With boosting maximum power production etc? The risk of autism in siblings is increased and the preventive measures are safe enough I guess.

    Also, what about treatments used in glucose transporter deficiency (GLUT1 deficiency), which leaves "the brain starved for energy" e.g. triheptanoin which seems to do more than just be a source of ketone bodies?

    1. Agnieszka, there are emerging tests (one uses EEG) to diagnose autism in babies just 3 months old. I think these tests are the way to select who might benefit from autism protection/minimization strategies.

      I would start by applying "brain power boosting" therapies on people with Alzheimer's. At least you know who has it.

    2. Peter, speaking about triheptanoin, someone thought about it for Alzheimer's. The study is on mice, not humans:

      Triheptanoin supplementation to ketogenic diet curbs cognitive impairment in APP/PS1 mice used as a model of familial Alzheimer's disease.

      "Some ketogenic diets have been tested as therapeutic strategies for treating metabolic disorders related to a deficiency in glucose-driven ATP generation. However, ketone bodies are not capable of providing extra tricarboxylic acid cycle intermediates, limiting the anabolic capacity of the cell."

      "Present findings support the concept that ketogenic diets supplemented with anaplerotic compounds can be considered potential therapeutic strategies at early stages of Alzheimer's disease."

      I am not sure if triheptanoin can be obtained outside clinical trials.

    3. Agnieszka,

      Anaplerotic Triheptanoin Diet Enhances Mitochondrial Substrate Use to Remodel the Metabolome and Improve Lifespan, Motor Function, and Sociability in MeCP2-Null Mice

      These results suggest that an approach using dietary supplementation with anaplerotic substrate is effective in improving symptoms and metabolic health in Rett syndrome.

  8. Interesting post indeed, and I look forward to the one on critical periods in development since we have at least some of them ahead!
    The theory on a starved brain eating up the energy meant for growth seems well backed up.
    I wonder if this correlates to, or is a different thing, from bone growth? With a low bone growth, you get osteoporosis but also a short stature. In my daughters condition, osteoporosis is common finding and there is at least a weak connection to RSK2, downstream of ERK1/2.


    1. Ling, I think one thing going on in SATB2 may overlap with MS. In both conditions Estrogen Receptor Beta is involved which results in problems with osteoporosis and myelin.

      Tyler recently highlighted some ER beta agonist research in MS.

      I think you need an ER beta agonist, as do people with MS.

    2. Thanks for reminding me of the ER beta path.
      Oh, and I have looked around for 45 minutes now, but can't find Tylers comment anywhere...

      I wish I knew what happened with AJ and that genetic result, this silence has got me totally worried.


    3. Ling,I was going to ask Peter the same thing

    4. Ling, here is the link to Tyler's comment:-

      also you can google "indazole chloride MS" to find more

    5. Thanks Peter!


  9. This is a random question about chloride levels. An increased level of blood chloride (called hyperchloremia) usually indicates dehydration, but can also occur with other problems that cause high blood sodium, such as Cushing syndrome or kidney disease. ... It seems dehydration would be v. unhealthy as chloride levels would rise?

    1. Dehydration will cause lots of problems and is a risk if you take bumetanide and do not drinks extra fluids. It does seem that some people with autism have odd levels of some electrolytes and this will then effect numerous ion channels. With chloride the problem is the level inside neurons and not the level in blood. There is no practical way to measure this.

  10. I just came across some new research that suggests a "stress" vaccine might be on the horizon that could treat neuroinflammatory disorders in the brain via injecting an inert (heat killed) species of bacteria into the blood that promotes an anti-inflammatory state:

    Press Release:


    Now autism is not really mentioned specifically in this research (they focused more on depression and PTSD), but anxiety issues and neuroinflammation are pretty much always a factor in autism in one way or another and this so-called "vaccine" sure does seem promising with respect to attenuating many symptoms of autism that are indirectly tied to neuroinflammation, and in particular microglial dysfunction, especially since anecdotal reports of just about every parent I have talked with, including myself, suggests that stress challenges can dramatically increase autistic symptoms and interventions that reduce stress (such as a good nights sleep) can dramatically decrease autism symptoms as well.

  11. Ughhhh!!! somewhat disappointing news:

    Probiotic supplementation and associated infant gut microbiome and health: a cautionary retrospective clinical comparison

  12. Here is another recent review on gut dysbiosis, and astaxanthin, which probably spurs someones interest here:

    "Dietary carotenoids (including pro-vitamin A carotenoids and non-pro-vitamin A carotenoids, e.g. xanthophylls) and their supplementation may increase the production of retinoic acid (RA).
    RA sequentially induces the maturation of gut immune system, e.g. B cell activation, and IgA production. Xanthophylls activate
    T cells and natural killer cells resulting in the production of IFN-gamma. IFN-gamma further stimulates the differentiation and maturation of B cells to produce IgA, and in turn promote the gut health."

    There is more information, including a figure showing the impact of astaxanthin on a wide range of bacteria strains in the gut.



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