Learning about Autism from the 3 Steps to Childhood Leukaemia

Special baby yoghurt to prevent childhood leukaemia, would quite likely also reduce the severity/incidence of some autism by permanently modulating the immune system.

Today’s post is about Leukaemia/Leukemia, another condition like autism, that is usually caused by "multiple hits".  It makes for surprisingly interesting reading for those interested in understanding autism.  

Leukaemia is a group of cancers that begin in the bone marrow and result in high numbers of abnormal white blood cells. Symptoms may include bleeding and bruising problems, feeling tired, fever, and an increased risk of infections. These symptoms occur due to a lack of normal blood cells.

Cancer research is making some great strides and, being English myself, I am pleased that some of the cleverest research is being carried out in England; the epicentre is the Royal Marsden Hospital/Institute of Cancer Research. Sadly, there is no such centre of excellence for autism research in England, or anywhere in Europe.  The best autism research usually comes from the US, Canada and increasingly China; the exception being bumetanide/NKCC1 research in France.  

Now straight to leukaemia and yoghurt.

              https://www.sciencedaily.com/releases/2018/05/180521131746.htm

Professor Mel Greaves from The Institute of Cancer Research, London, assessed the most comprehensive body of evidence ever collected on acute lymphoblastic leukemia (ALL) -- the most common type of childhood cancer.

His research concludes that the disease is caused through a two-step process of genetic mutation and exposure to infection that means it may be preventable with treatments to stimulate or 'prime' the immune system in infancy

The first step involves a genetic mutation that occurs before birth in the fetus and predisposes children to leukemia -- but only 1 per cent of children born with this genetic change go on to develop the disease.

The second step is also crucial. The disease is triggered later, in childhood, by exposure to one or more common infections, but primarily in children who experienced 'clean' childhoods in the first year of life, without much interaction with other infants or older children.

Acute lymphoblastic leukemia is particularly prevalent in advanced, affluent societies and is increasing in incidence at around 1 per cent per year.

Professor Greaves suggests childhood ALL is a paradox of progress in modern societies -- with lack of microbial exposure early in life resulting in immune system malfunction 

The same paradox applies to autism and is likely a big part of why medical autism is increasing in prevalence, once you adjust for some foolish doctors moving the goalposts of what is autism.

Here is another easy to read summary of what Professor Grieves is saying.

Missing microbes 'cause' childhood cancer

Our modern germ-free life is the cause of the most common type of cancer in children, according to one of Britain's most eminent scientists. 

Acute lymphoblastic leukaemia affects one in 2,000 children.

Prof Mel Greaves, from the Institute of Cancer Research, has amassed 30 years of evidence to show the immune system can become cancerous if it does not "see" enough bugs early in life. 

It means it may be possible to prevent the disease. 

Combined events

The type of blood cancer is more common in advanced, affluent societies, suggesting something about our modern lives might be causing the disease. 

There have been wild claims linking power cables, electromagnetic waves and chemicals to the cancer.  That has been dismissed in this work published in Nature Reviews Cancer. 

Instead, Prof Greaves - who has collaborated with researchers around the world - says there are three stages to the disease. 

§  The first is a seemingly unstoppable genetic mutation that happens inside the womb

§  Then a lack of exposure to microbes in the first year of life fails to teach the immune system to deal with threats correctly

§  This sets the stage for an infection to come along in childhood, cause an immune malfunction and leukaemia

This "unified theory" of leukaemia was not the result of a single study, rather a jigsaw puzzle of evidence that established the cause of the disease. 

Prof Greaves said: "The research strongly suggests that acute lymphoblastic leukaemia has a clear biological cause and is triggered by a variety of infections in predisposed children whose immune systems have not been properly primed."

Evidence that helped build the case included:

§  An outbreak of swine flu in Milan that led to seven children getting leukaemia

§  Studies showing children who went to nursery or had older siblings, which expose them to bacteria, had lower rates of leukaemia

§  Breastfeeding - which promotes good bacteria in the gut - protects against leukaemia

§  Lower rates in children born vaginally than by caesarean section, which transfers fewer microbes

§  Animals bred completely free of microbes developed leukaemia when exposed to an infection

This study is absolutely not about blaming parents for being too hygienic. 

Rather it shows there is a price being paid for the progress we are making in society and medicine. 

Coming into contact with beneficial bacteria is complicated; it's not just about embracing dirt. 

But Prof Greaves adds: "The most important implication is that most cases of childhood leukaemia are likely to be preventable." 

His vision is giving children a safe cocktail of bacteria - such as in a yoghurt drink - that will help train their immune system. 

This idea will still take further research. 

In the meantime, Prof Greaves said parents could "be less fussy about common or trivial infections and encourage social contact with other and older children".

Good germs

This study is part of a massive shift taking place in medicine. 

To date we have treated microbes as the bad guys. Yet recognising their important role for our health and wellbeing is revolutionising the understanding of diseases from allergies to Parkinson's and depression and now leukaemia.

Childhood Leukaemia Incidence is Rising

The overall prevalence of all types of leukaemia is about 1.5%.

Today we are just looking at one sub-type, acute lymphoblastic leukemia (ALL). It usually occurs in children aged 2 to 5 and if not treated promptly is fatal within a matter of months.

ALL is the most common type of childhood cancer. Approximately 3 of 4 children and teenagers who are diagnosed with leukemia are diagnosed with ALL. It is most common in children younger than 5, with most cases occurring between the ages of 2 and 4.

The prevalence of ALL is increasing while that of adult leukaemia is static.

Age-Adjusted Incidence Rates of Childhood Acute Lymphocytic Leukemia by Race and Ethnicity, SEER 13, 1992–2013

While nobody ever talks much about it, ethnicity clearly is very relevant to autism incidence. It is not just about wealth and poverty; some ethnic groups are more prone to certain diseases than others. In the case of childhood leukaemia you have the most risk if you are a white Hispanic American.

In the case of autism, it looks to be parents who are Non-Hispanic White Americans who have the highest risk and if you are Jewish and high IQ the risk goes up further.

It is not all about genes

In about 10% of autism you can trace the cause back to a single miscreant gene, or entire chromosome, but for most autism it is much more complex.

For many genes, an error does not mean that a related dysfunction is guaranteed to occur it just makes you predisposed to that dysfunction. As we see with childhood leukaemia, most children with the miscreant gene never develop that cancer. Only 1% of all the children with the risk gene develop the cancer.  

This is one reason to be very careful opting to carry out Whole Exome Sequencing (WES), because you will likely discover genetic mutations that are associated with all kinds of possible conditions, but quite possibly none of the dysfunctions have, or will ever, occur in that person.

There are some genetic conditions that invariable do occur, but most often there are tell-tale physical signs. A short little finger (pinkie) is one I was discussing recently with someone, to help them narrow down a possible diagnosis.

Short 5th finger/Hypoplasia (congenital reduction in size) of the fifth finger

Dr Grieves' full paper 

A causal mechanism for childhood acute lymphoblastic leukaemia

In this Review, I present evidence supporting a multifactorial causation of childhood acute lymphoblastic leukaemia (ALL), a major subtype of paediatric cancer. ALL evolves in two discrete steps. First, in utero initiation by fusion gene formation or hyperdiploidy generates a covert, pre-leukaemic clone. Second, in a small fraction of these cases, the postnatal acquisition of secondary genetic changes (primarily V(D)J recombination-activating protein (RAG) and activation-induced cytidine deaminase (AID)-driven copy number alterations in the case of ETS translocation variant 6 (ETV6)–runt-related transcription factor 1 (RUNX1)⁺ ALL) drives conversion to overt leukaemia. Epidemiological and modelling studies endorse a dual role for common infections. Microbial exposures earlier in life are protective but, in their absence, later infections trigger the critical secondary mutations. Risk is further modified by inherited genetics, chance and, probably, diet. Childhood ALL can be viewed as a paradoxical consequence of progress in modern societies, where behavioural changes have restrained early microbial exposure. This engenders an evolutionary mismatch between historical adaptations of the immune system and contemporary lifestyles. Childhood ALL may be a preventable cancer.  

Childhood acute leukaemia is the most common paediatric cancer in developed societies, accounting for  one- third of all cases, with a variable incidence rate of 10–45 per 106 children per year and a cumulative risk of ~1 in 2,000 up to the age of 15 years1. The most common paediatric leukaemia, acute lymphoblastic leukaemia (ALL), is an intrinsically lethal cancer, as evidenced by a universally adverse clinical outcome before effective therapy was developed. Currently, however, cure rates for ALL using combination chemotherapy are around 90%, making this one of the real success stories of oncology. While this is a cause for celebration, the current treatment remains toxic, traumatic for young patients and their families, and carries some long- term health consequences. It is unfortunate that we have remained ignorant as to the cause of ALL. The open question as to whether this cancer is potentially preventable is  therefore important.

Most cases of childhood ALL are potentially preventable. But how? Lifestyle changes including day care attendance or protracted breastfeeding in the first year of life can be advocated but would be difficult to achieve. A more realistic prospect might be to design a prophylactic vaccine that mimics the protective impact of natural infections in infancy, correcting the deficit in modern societies. Reconstitution or manipulation of the natural microbiome or helminth injections are strategies under consideration for early- life immune disorders in modern societies, including autoimmune and allergic conditions. Oral administration of benign synbiotics (bacteria species such as Lactobacillus spp. and oligosaccharides) can have profound and beneficial modulating effects on the developing immune system. The results of those endeavours might inform approaches for preventing BCP- ALL. Cross collaboration of scientists working in disparate fields of early- life immune dysfunction — allergy, autoimmune disease and ALL — would be beneficial.

Other modulators of risk in childhood aLL 

In addition to patterns of infectious exposure and inherited genetics, other factors are likely to contribute to multifactorial risk, including diet and chance. For acute lymphoblastic leukaemia (aLL) as well as acute myeloid leukaemia (aML) and most other paediatric cancers, risk is significantly and consistently elevated in association with higher birthweights or, possibly, accelerated fetal growth. a plausible interpretation of this link is that higher weight, possibly orchestrated via insulin-like growth factor 1 (iGF1) levels, may provide a greater number of cells at risk. iGF1 potentiates expansion of B cell lineage progenitors. Recently, evidence has been presented, using mouse models of aLL, that a restricted diet can have a risk- reducing impact. intermittent fasting was shown to block expansion of leukaemic cell populations and progression of disease. the effect operated via attenuation of leptin receptor expression on leukaemic cells, possibly enforcing differentiation. Diet or calorie intake may, therefore, have a modulating impact on risk of aLL, reinforcing the likely multifunctional nature of causation of aLL, as in cancer in general. random events or chance get short shrift in cancer epidemiology, but it has long been recognized that contingency and chance pervades all of biology. Some posit that a substantial number of cancers are due to chance alone, but this has been contentious. Chance is likely to be an ingredient in each and every cancer, including childhood aLL. this is because inheritance of risk alleles is a lottery at conception, because exposures including infections, at particular times, may or may not happen and because mutational mechanisms alter genes independently of their function.

Conclusion

Professor Grieves looks like my kind of academic/researcher. We came across another such one, Dr Peter Barnes, also English, who is known for translational research in asthma and COPD. What matters is applying/translating research, not making a good living publishing inconsequential research, editing a journal and being on the board of some charities. In the real world, results are what count.  

In the academic world it seems to be quantity of publications that matter.  I vote for quality over quantity.

Intestinal bacteria are clearly a fundamental part of human health, but to fully understand the implications will take many decades of research. Even today, we can see the critical importance of exposure to a wide range of bacteria very early on life and indeed during pregnancy.

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.

Conclusion

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. 

Josh Greenfeld, Who Chronicled His Son’s Autism, Dies at 90

A Child Called Noah (1972)

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.

A Client Called Noah (1987)

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.''

Passover, Fumiko Kometani (Noah’s Mother)

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

Boy Alone, A Brother’s Memoir  (2009), Karl Greenfeld

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: -

http://autismgadfly.blogspot.com/2009/05/noah-greenfeld-flunked-lovaas.html

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.

PS  

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.

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.

EEG signals accurately predict autism as early as 3 months of age

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.

Autism: A “Critical Period” Disorder?

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

Is birth a critical period in the pathogenesis of autism spectrum disorders?

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.

The Cerebellum, Sensitive Periods, and Autism

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.

Sensitive and critical periods during neurotypical and aberrant neurodevelopment: A framework for neurodevelopmental disorders

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.

Critical period inhibition of NKCC1 rectifies synapse plasticity in the somatosensory cortex and restores adult tactile response maps in fragile X mice

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 GABA_A 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:-

Autism spectrum disorder: Critical treatment period 

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