Showing posts with label Critical Periods. Show all posts
Showing posts with label Critical Periods. Show all posts

Thursday 29 November 2018

What, When and Where of Autism – Critical Periods and Sensitive Periods

When time is of the essence

All kinds of dysfunctions may appear in autistic brains, which in itself make it a highly complex condition. There is also the when and where aspects of these dysfunctions, which often gets overlooked, or lost in oversimplification.
This then has to fit into the concept of critical periods, that I introduced in an earlier post. 

Critical periods are times during the brain’s development when it is particularly vulnerable to any disturbance, for example an excitatory/inhibitory imbalance.
This then leads to another related concept which is that of sensitive periods; these are periods when the person should be responsive to particular therapy.
Sensitive periods are very important to be understood by those planning clinical trials, because a therapy may indeed be effective only when given within a specific time window. During this time the person is sensitive to the therapy, but they will not be a responder after the time window has passed.
I am pleased to say that more research is beginning to consider the when aspect and not just the what aspect of biological dysfunction in autism.
The where aspect reflects the fact that in one part of the brain there might be, say, NMDA hypofunction, while in another part the opposite is present, NMDA hyperfunction.  Since most therapies come as pills you swallow, you cannot treat one part of the brain for one problem and another part of the brain for the opposite problem. There is currently no way around this issue, you just have to do what is best for the brain overall. In practical terms it means you may make one problem better, but create a new one. 

New research in a mouse model suggests that the drug rapamycin can reverse autism-like social deficits -- but only if given early. The study is the first to shed light on the crucial timing of therapy to improve social impairments in a condition associated with autism spectrum disorder. Its findings could help inform future clinical trials in children with tuberous sclerosis complex. 

Full Paper:


Mefenamic Acid
I have mentioned mefenamic acid (Ponstan) in several posts. It is the only human autism therapy currently in development that has a treatment window.  It is suggested that the sensitive period to take this drug is the second year of life, to avoid severe non-verbal autism. 

The good news is that we have seen time and again that it is never too late to treat autism. Clearly the earlier you do start, the more extensive the long term benefit should be. So once you realize that intervention is possible, best not to delay.
When autism  is of a single gene origin, there really should eventually be scope to make some kind of permanent fix, if you can intervene very early and so still during that intervention’s sensitive period.  This might involve something very clever like gene editing, which you cannot do at home, or it might be just some drug therapy, like Rapamycin in TSC1 as in the above study.

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