Friday, 15 June 2018

Raising Expectations?

Monty, aged 14 with ASD, has finished his year-end assessments in his first year at high school.  Monty has classic autism, which we can also call a type of Strictly Defined Autism (SDA), or what autism used to be under DSM3, before the diagnosis was extended in 1994 to include Asperger’s at the clever end and PDD-NOS in the middle.  From that point onwards, autism means entirely different things to different people.
For the last 6 years Monty has moved up each year with his neurotypical peers, who are two years his junior.  During those years I used to go to the parent teacher meetings at school and explain that if Monty could not keep up, it would be just fine to hold him back another year, for example if he came at the bottom of the class in most subjects. We held him back two academic years, 6 years ago, in the “big reset” and I assumed this would likely need to be repeated, since people with SDA cannot acquire skills as fast as typical people.
This blog is really all about using biology to try and have someone with SDA keep up with typical peers, or switch from SDA to something more Asperger’s-like.  This did look like an impossible task at the age of 9.
Can people aged 9 with SDA “catch up” academically with NT peers?  Remarkably, it does seem to be possible.
This year’s report card is nearly all As.
Big brother has just graduated from the same school and he is as amazed as me that Monty, the one with autism, now gets better grades than so many of the others. “What is the matter with the rest of them?”, he asks, “why can’t they beat him, he has autism”. 
The big difference is that Monty pays attention in class, has two great part-time assistants, does his homework and does academic work in the school holidays and he has his personalized PolyPill.
One teacher commented that if the others worked as hard as Monty, they would also be getting As.
Monty now comes home with another A* and his Assistant asks why we are surprised. Monty’s original school assistant from 3 to 8 years old, and so pre-PolyPill, never had such moments.

It is getting rather repetitive writing about Monty’s success in mainstream school – but what happens in the long run is what most parents really want to know. 
Since we all like a good story and a happy ending, most popular accounts of autism are not representative.
“The Reason I Jump” was written by the non-verbal Japanese, 13-year-old, Naoki Higashida, with help from his mother and then translated into English and other languages.  Most people loved this uplifting book, but some parents of non-verbal kids with autism clearly hate it, either because they do not believe he actually wrote much of it, or because it suggests that inside the head of the non-verbal child with severe autism is a literary genius.
The very detailed personal autism story is the one about Noah Greenfeld, now in his 50s. This man with severe regressive autism was the subject of 3 books written by his father in Noah’s youth and one by his brother decades later, so you can learn how things ended up, if you were left in any doubt.
Josh Greenfeld, Noah’s father, once described to the TV news show, 60 Minutes, the process he went through in his thinking about Noah.
“At first, you just hoped he’d be normal,” he said. “Then you just hoped he could talk. And then you just hoped he could communicate a little more or understand. And then, finally, you reached the point where you just hope he can be well fed, well taken care of — be happy, not feel pain. You become very, very basic.”

So, while it is very thorough story, going from failed use of ABA, to all kinds of institutions and numerous doctors, in essence nothing helped.
In his brother’s book there is a whole section about Noah recovering and adopting a “normal” life, but this turns out to be a trick the author is playing. This clearly upset many parents who bought the book, but not the literary reviewer at the New York Times.  
Even Noah’s Japanese mother, Fumiko Kometani, wrote a book, Passover, that includes him, for which she won a Japanese literary award, but the New York Times regarded it as anti-Semitic. Noah’s father was Jewish and the book is a Japanese perspective of living in the United States. 

A Place for Noah (1978)
''A Place for Noah'' (1978) picked up the account in August 1971, and focused on the family's six-year quest to find a school or day-care center where Noah could be educated or trained. On a deeper level, it is also about the family's struggle to keep a place for Noah in their hearts as well as their home. ''I can never kill the dream that is my son,'' Mr. Greenfeld wrote in January 1977.

The sweetest recent moment for the Greenfelds came in February 1986, in Tokyo, where Foumiko was presented with the Akutagawa Award, Japan's most important literary prize. As Mr. Greenfeld described it, ''It's as if there were a single Pulitzer Prize, and it came with a black belt.''
Is this a happy ending? ''With Noah, there is no ending,'' said Mr. Greenfeld, noting that Noah could not understand, or share in, his mother's triumph. ''With Noah, you think of the old Pearl Buck line - a continuing sadness that never ends.''

This is the book that won the Akutagawa Award in Japan but appears to have been loathed in the United States. 

This is the sibling's view of growing up in the upturned world of severe autism.

Noah Greenfeld, the subject of several well-received books by his father, Josh, was “probably the most famous autistic child in America.” Or so claims the journalist Karl Taro Greenfeld, Noah’s older brother. His new memoir supplies plenty of anecdotes to prove his point — a “60 Minutes” crew moves into the Greenfeld house; Karl’s juvenilia about Noah “ends up” in The New York Times and Esquire. Yet for Karl, living in a family that was “one of the public accounts of autism” was shaming. He became “locally famous,” as he puts it, “for nothing more than having a retard brother.”

One interesting point highlighted in the above short video is that Noah's brother wanted people to know what an autistic adult looks like, since he believes there will soon be many more. He is right, but his "autism" is not the one that most people will encounter. The SDA type of autism affects about 0.3% of the population, but Noah is at the severe end of SDA, so maybe 0.1% of the population. Soon in the US, the very flaky CDC figures will inevitably tell us that 2% of the population have "autism". Of those people with "autism", only 1 in 20 will look like Noah. One reason the CDC figures are misleading is that they apparently include "educational autism" (school diagnosed) as well as medical autism (diagnosed by some kind of doctor/psychiatrist). 

An Asperger blogger’s review of the books: -

Raising Expectations?
Coming back to the tittle of this blog post, for parents of children with Strictly Defined Autism (SDA), DSM3 type autism, or just call it severe autism, I think the experience of Josh Greenfeld, Noah’s dad, is pretty typical, albeit that Noah is at the severe end of DSM3 autism. This kind of autism is not something nice and does not end well. Noah's Dad gave up calling it autism in the end, he preferred to call it brain damage.
The fact that Josh lived to 90 years old and his son is still alive is remarkable and I see that as a success; but Noah never defeated autism.  It was not however what Josh wanted. In his words:-  "A fellow parent who had a developmentally disabled - I don't know what word to use anymore - child (told me) that we're the only parents in the world who somehow wish and pray fervently for our offspring to pre-decease us. And there's truth in that. Because if he's gone, then it's easier for us to go psychologically."
ABA did not work for Noah, at all. As his big brother summed it up “Noah flunked Lovaas” and Noah was treated by the man himself.
From reading this blog, you might imagine that Noah likely has severe regressive autism, caused by mitochondrial disease. What he likely needed was the mito cocktail developed by Dr Kelly, at Johns Hopkins, and quite possibly C7 (Triheptanoin), BHB (beta-hydroxybutyrate) and C8 (caprylic acid).  Even that might not have helped, but it is always better to at least try.  
I suppose I started my autism experience with realistic expectations a decade ago and so I get to keep raising them. ABA did help, we can say that “Monty graduated Lovaas”, but it was nowhere near enough.  If you want more, you have to treat the underlying biology.

I have not read any books like those in today's post, just reviews of them this week for this post. They are not my cup of tea.

I did read a lot of books on ABA  (not my cup of tea either, but necessary) and a little about neuropsychology (actually a good read). The neuroscience books (heavy going) are out of date by the time they are published and everything you could want to know is there in journals on the internet, for free, one way or another.

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.


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.


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

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 ( 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.

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

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.

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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.