Showing posts with label Bucharest. Show all posts
Showing posts with label Bucharest. Show all posts

Thursday, 28 March 2019

Improving Myelination through Social Interaction and more on Clemastine

Since anecdotal evidence is beginning to support this blog’s suggestion that pro-myelinating therapy might be beneficial in autism, particularly improving human adaptive behaviour, I will continue to highlight further supporting research.

Improving Jerry’s Brain Myelination - Hard without Tom

Today’s main paper shows how social intervention can also be used as a pro-myelinating therapy (in mice, like Jerry). I found the research interesting, but I think most parents would opt for a pill as a short cut.

The study looked at the effect of rearing an autistic mouse with social mice.  The autistic mouse shares the myelin defects of autistic humans. The research interestingly shows that it is the social interaction only after weening that has an impact on myelination. So in the human equivalent of this research, it is not interactions with Mum/Mom that matter most, it is interactions with toddler peers. So make sure your toddler with autism hangs out with bubbly neuro-typical toddlers, or has bubbly neuro-typical assistants/ therapists/kindergarten teachers.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction, poor communication skills, and repetitive/restrictive behaviours. Recent studies have indicated that early rehabilitative intervention can alleviate the symptoms of individuals with ASD. However, it remains unknown whether rehabilitative intervention can restore brain structures such as myelin, which generally shows abnormalities in individuals with ASD. Therefore, in the present study, we used a mouse model of ASD (BTBR mice) that demonstrated asocial behaviours and hypomyelination in the medial prefrontal cortex (mPFC) to investigate whether interaction with social peers (C57BL/6J mice) has an effect on myelination. We found that housing with C57BL/6J mice after weaning through adulthood increased the myelin thickness in mPFC, but not in the motor cortex, of BTBR mice. There was no effect of cross-rearing with C57BL/6J mice on axon diameter in mPFC of BTBR mice. This finding suggests that early rehabilitative intervention may alleviate myelin abnormalities in mPFC as well as clinical symptoms in individuals with ASD.
In the present study, we found that interaction with social peers, which has been shown to improve sociability (Yang et al., 2011), considerably influences myelination in the BTBR mouse model of ASD. This finding supports the theory that rehabilitative interventions can affect brain structures as well as brain functions in individuals with ASD.
Individuals with ASD who have received intensive early intervention demonstrate improved long-term outcomes, and the effectiveness depends on the age at intervention. Earlier interventions such as ABA lead to more substantial resolution of ASD symptoms (Harris and Handleman, 2000). Although the biological mechanisms underlying the effects of early intervention remain unclear, recent findings propose that myelination in the relevant brain regions is a potential factor.

First, we found that BTBR mice exhibit thinner myelin in mPFC, but not in the motor cortex, compared with C57BL/6J mice (Fig. 1a). This finding was similar to those in postmortem brain studies of individuals with ASD (Zikopoulos and Barbas, 2010). Because BTBR mice are generally considered genetic models of ASD (McFarlane et al., 2008), hypomyelination in mPFC could occur due to genetic mechanisms. The elevated expression of proinflammatory cytokines such as interleukin-6 in the brains of BTBR mice (Wei et al., 2016) may cause hypomyelination, as shown in our previous study (Makinodan et al., 2016). If so, myelin in the motor cortex of BTBR mice should also be thinner than that in the motor cortex of C57BL/6J mice.

Second, we found that social interaction with C57BL6/J mice increased the myelin thickness in mPFC of BTBR mice. Given an increase in the social interaction of BTBR mice after cross-rearing with C57BL6/J mice (Yang et al., 2011), the restoration of myelination could be attributed to mPFC neuronal activities in relation to social interaction (Yamamuro et al., 2017), on the basis of findings that myelination is axonal activity-dependent (Wake et al., 2011). On the other hand, the alteration of social experience in the present study did not change myelination in the motor cortex, indicating that myelination in the motor cortex is independent of social experience. Interestingly, cross-fostering of BTBR mice with C57BL/6J mice during the neonatal period produced no significant effects on ASD-like behaviors such as altered ultrasonic vocalization and repetitive behaviors (Yang et al., 2007), implying that social interaction with peers influences the symptoms of ASD more than the mother’s care. These findings are consistent with the denial of the “refrigerator mother” theory and higher contribution of nonshared environmental factors compared with that of shared environmental factors with regard to the development of ASD

 (d) The cumulative probability curve of g-ratio; At P65, the mPFC myelin is thinner in the BTBR-only group than in the B6-only group (P  0.05). After housing with C57BL/6J mice from P21 through P65, the mPFC myelin thickness has increased in the BTBR-mixed group compared with that in the BTBR-only group (P  0.05). After housing with BTBR mice from P21 through P65, there is no change in mPFC myelination in the B6-only group (P > 0.05).

I should remind readers of the Bucharest Early Intervention Project (BEIP); it was highlighted in the post below.  It was a long running study that included measurable brain damage/difference cause by childhood neglect.

The study showed that orphans placed in high quality foster care not only do better than peers left in the State orphanage, but you can actually measure difference using MRI imaging.

The study showed that poor treatment in the orphanage could produce autistic children.  This would not have surprised Kanner. It highlights a little publicized risk in adopting children from orphanages in poor countries.

Early Intervention for young children with severe autism

There are numerous different models proposed as therapy for kids with autism. One of the outliers is the Son Rise program. I remember going on a course in London 12 years ago to learn PECS (Picture Exchange Communication System) and the trainer clearly thought Son Rise was completely mad. I did employ a very broad interpretation of ABA in Monty’s early therapy, we also included a large element of getting down on the floor (à la Floortime method) and be as “crazy” as him, which is really what Son Rise is all about; “enter his world” and draw him out of it. I still do this and if Monty has some new script he keeps repeating, I join in and soon he is asking me to stop scripting. I am not reinforcing his script, I am hijacking it and then he no longer uses it.

Doing the unexpected I found very beneficial as a means to diminish aggressive behaviour. I find the idea of social rehabilitation leading to biological rehabilitation very appealing.  It is also quite therapeutic for the adult. I think many parents just do not know what to do when faced with aggressive behaviours from their small offspring; one way or another, best to figure it out before he is bigger and stronger than you.

What dose of Clemastine?

There is research that you can use to get an idea of how much clemastine you might need to promote myelination. I was forwarded some calculations based on the paper below.

Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis

I did skip to this chart below in the supplemental data to the paper, which shows what you want to know. One you get to 10nM concentration of clemastine things really start happening. Increasing the concentration by a factor of 100 only doubles the effect.  

Recall that  MBP = Myelin Basic Protein  (more is good)

Then you have to convert 10nM into a human dosage in your blood.

From high school chemistry nM means nanomolar.

In practical terms, 1 to 2 mg once a day in the evening seems a pretty sensible dosage and well within the standard allergy dose.

“Cross rearing with social peers” from today’s first study does have implications. I always thought it was a bit odd to combine multiple kids with severe autism in play activity, or social gatherings. I know lots of families with special needs kids hang out together. This might be better for the parents than the kids.

Hanging out with typical kids who are not in the slightest interested in a special needs kid does not work.

In kindergarten and primary school there usually is a constant supply of nice little girls who genuinely want to get involved with kids with severe autism. It repeats all around the world. It gets rarer after puberty, but even at 13 years old some girls are genuinely interested in social interactions with special people. Teenage boys really are not interested in including people with disabilities, unless they themselves are outsiders, like the gay ones (yes, I know that will upset somebody).  Girls are a safer bet.

The best way to “cross rear with social peers” is to have fun assistants at school. This works directly in the child being exposed to a fun bubbly person, but it also makes it much more likely that typical kids will want to join in.

In theory being a 1:1 assistant might be a good job for an Aspie, but having tried that for a year I can strongly suggest a lively enthusiastic young-at-heart NT assistant is the ideal. He/she also needs to be good at maths and science.
Happy myelinating!

Saturday, 3 December 2016

Quantifying the Benefits of Stimulation over Neglect in Early Childhood

Today’s post is about the Bucharest Early Intervention Project (BEIP), which really deserves a mention somewhere in any autism blog.  It has been going for many years but they recently added some very tangible MRI data.

BEIP is a long term study lead by Charles Nelson, a professor of neuroscience and psychiatry at Harvard Medical School.  It compares the effect of neglect versus stimulation in early childhood.

You may be wondering the relevance of this to autism, in particular since Kanner’s old theory about refrigerator mothers was debunked long ago.

The study shows how physical development of the brain can be altered by the living environment of a young child.  It reinforces the fact that institutionalized of young children, with or without developmental disorders, is precisely the wrong strategy.

Bucharest Early Intervention Project (BEIP)

The Bucharest Early Intervention Project was a randomized controlled trial of foster care as an intervention for children abandoned at or around the time of birth and placed in one of six institutions for young children in Bucharest, Romania.

The BEIP began in 2000 with a comprehensive baseline assessment of 136 children and their caregiving environments. Following this assessment, half the children were randomly assigned to high-quality foster care (designed specifically for this study) and the other half to remain in institutional care. The average age at entry into foster care was 22 months (range=6-31 months). All children were seen for follow-up assessments at 30, 42 and 54 months, 8 years, and 12 years, and the development of children in foster care was compared to the development of children randomized to remain in institutional care and to a group of never institutionalized children (community controls). 

Findings through the assessment at 12 years of age suggest that early institutionalization leads to profound deficits in many domains examined to date, including cognitive (i.e., IQ) and socio-emotional behaviors (i.e., attachment), brain activity and structure, alterations in reward sensitivity and processing, and a greatly elevated incidence of psychiatric disorders and impairment. 
The foster care intervention was broadly effective in enhancing children’s development, and for specific domains, including brain activity (EEG), attachment, language, and cognition, there appear to be sensitive periods regulating their recovery. That is, the earlier a child was placed in foster care, the better their recovery. Although the sensitive periods for recovery vary by domain, our results suggest that placement before the age of 2 years is key.
There are a few areas, such as executive functioning (i.e., memory and cognitive monitoring), in which placement into foster care does not significantly impact development/performance. 
In 2015 another paper was published.
BEIP initially enrolled 136 children in research. Only 69 were involved in the MRI study, of these, 23 were drawn from the group randomly assigned to foster care, 26 from a group assigned to remain in orphanages, and 20 from the local community, as controls. Lead author Johanna Bick, a clinical psychologist at the Boston Children’s Hospital, and colleagues in the BEIP group used an MRI technique called diffusion tensor imaging to look at the microstructure of 48 white matter tracts in each child, comparing results at 2 years and 8 years of age.
The analysis found that the children who stayed in orphanages were consistently worse off—with less mature development in four key sets of white matter. The most affected tracts included nerve circuits involved in general cognitive performance, emotion, maintaining attention and executive function, and sensory processing. Another analysis suggested that the foster care group was more like the community group in brain development, but this finding appears to be less robust.
Other nonrandomized studies have reported broad cognitive deficits or reduced white matter in adults and some children who suffered neglect or maltreatment in the past. They highlighted "the same regions that we find affected by early life neglect. These results and those from BEIP converge," Bick claims.
Four estimates of white matter integrity (Fractional Anisotropy, and Mean, Radial, and Axial Diffusivity) for 48 white matter tracts throughout the brain were obtained through Diffusion Tensor Imaging.
Significant associations emerged between early life neglect and microstructural integrity of the body of the corpus callosum and tracts involved in limbic circuitry (fornix crus, cingulum), fronto-striatal circuitry (anterior and superior corona radiata, external capsule) and sensory processing (medial lemniscus, retrolenticular internal capsule). Follow up analyses revealed that early intervention promoted more normative white matter development among previously neglected children who entered foster care.
Results suggest that removal from conditions of severe early life neglect and entry into a high quality family environment can support more normative trajectories of white matter growth. Findings have implications for public health and policy efforts designed to promote normative brain development among vulnerable children.
The BEIP study started ten years after the fall of communism in Romania, when the outside world became aware of life inside their orphanages.  As childless couples from the West started to adopt Romanian orphans it became clear that there was a very high prevalence of autism and other disorders.
Romania had been a country under extreme communism with a dictator, Nicolae Ceaușescu, but his official tittle he was General Secretary of the Romanian Communist Party, from 1965 to 1989.  He had some very particular ideas.  He wanted to encourage large families so both abortion and contraception were banned.  He did not like the idea of foreign debt and in his later years decided to pay down the nation’s debt as a matter of urgency.   In 1982, to be rid of foreign debt, Ceaușescu ordered the export of much of the country’s agricultural and industrial production. What followed was extreme poverty and people did not have enough food.  Excess children were deposited at the orphanage because there was no food to feed them at home.  So Romania developed a totally oversized orphanage system, that was itself extremely poorly funded.  Children were often totally neglected, left unclothed, some chained to their beds and given no stimulation.  Older children beat younger children.  All kinds of children ended up in orphanages and most had living parents.  Even after the Revolution of December 1989 which ended with Ceaușescu  and his wife being executed by firing squad, things did not improve very much, due to the dire state of the economy.  Foreigners later started to adopt children from Romania’s orphanages.
Nelson did not go to Bucharest to study autism, he went to study the consequences of neglect and to see if those consequences could be reversed.
The studies do show how a warm stimulating environment can reverse some physical brain malformations, but most effectively intervening before the age of two.
There are clear parallels with autism where some children effectively exclude themselves and when great efforts are made to engage with them using any one of a variety of therapies from Floortime, to Son Rise to ABA, great progress can sometimes be made.
When my own son was diagnosed aged 3.5 years, the developmental pediatrician told me that there was no way to predict his outcome, because up to the age of 5 years old the brain can develop remarkably.  She sees very many such children.
In the parts of the US autism diagnoses is possible before the age of 2 years old.  It would be useful if clinicians routinely carried out MRI scans of such children and the tracked their development keeping a note of what therapy the parents implemented.  Then we might see whether there were indeed defects in the microstructural integrity of the body of the corpus callosum and tracts involved in limbic circuitry and in which children these defects reduced in later years.
Monty’s new assistant was just telling me how she went to a Floortime seminar, but there was nothing much new in it and she will instead continue with he plans to study ABA.  There are so many of these therapies, the most ridiculed one is Son Rise.  My conclusion a long time ago was that it does not matter which of these “hands on” interventions you follow, you just need to be animated, energetic and engage with the child in an intensive fashion all day and every day.
A child with severe autism is trying to do the opposite, preferring to sit in a swing or watch videos all day.  This is hardly more stimulating than the Romanian “orphan” neglected in his dormitory with twenty other boys.
Just as Nelson has shown that normal babies can be made to develop brain abnormalities by their living environment and that these abnormalities can be reversed by changing their living environment, we need to know to what extent similar brain abnormalities exist in some autism and whether they are reversible, in some cases, by intense Mary Poppins-like intervention.  I suspect this is indeed the case.  If people with autism were routinely monitored this would be easy to prove one way or the other.
If the parents of the two year old, just diagnosed with autism, were told the child was in the 20% group that has some structural brain anomalies that are known to be partially reversible by some extreme Mary Poppins-like intervention, they probably would do something about it.
In fact all kids would benefit from a Mary Poppins, but perhaps some much more so than others.
Monty had his own Poppins, his full time assistant, for several years and she achieved what had seemed impossible.  I really do not believe many parents can achieve this themselves, unaided.  All day long, providing a stimulating, educative, one on one environment is a huge task. Doing it for one hour a day is not enough.