passionless Droning about autism

Posts Tagged ‘BDNF

Hello friends –

I’ve been planning to write something about the idea of environmental enrichment for a while now but other stuff kept on popping up.  At a broad level, researchers are finding that the type of external stimulation an animal is raised or housed in can have dizzyingly unpredictable effects on a range of physiological and behavioral endpoints, many of which are of great interest to the autism community. This is a tough area to dance through in the autism world; the available literature has shades of refrigerator mothers, and TV based causation; yet, the underlying idea of environmental enrichment, that the external environment can affect a person in a very physical way, is something known to the autism community in concrete ways.  What’s more, much of our data in the environmental enrichment realm is nothing less than compelling.  It is exciting to know that we are beginning to have insight into the molecular mechanisms by which the environment can affect the body and brain, and with that insight, just maybe the wisdom to help our children and help ourselves.

From the biomarker side, a couple of neat studies would include Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice,  wherein striking reductions in amyloid proteins were found in knockout mice housed in a stimulating environment compared to those in standard housing.   Or the very recently published,  Complex environment experience rescues impaired neurogenesis, enhances synaptic plasticity, and attenuates neuropathology in familial Alzheimer’s disease-linked APPswe/PS1DeltaE9 mice which hits a lot of keywords with parallels to the autism research world.  There are many, many others including hits like Altered plasticity in hippocampal CA1, but not dentate gyrus, following long-term environmental enrichment, or hilariously named, soundbyte laden,  Hippocampal epigenetic modification at the brain-derived neurotrophic factor gene induced by an enriched environment. The lower level details of these studies and their many ancestors are beyond the scope of what I have time for now, but clearly anything that can be affecting synaptic plasticity, BDNF expression, and neurogenesis should be of interest to the autism community.

If we turn to measurements that go beyond frozen slices of tissue (but do not necessary exclude them), our data regarding behavioral differences in EE housed animals is also robust.  For example, we could look at Environmental enrichment delays the onset of memory deficits and reduces neuropathological hallmarks in a mouse model of Alzheimer-like neurodegeneration, which found that EE housed mice performed significantly better at memory tasks that other mice housed in non stimulatory environments.  Environmental-enrichment-related variations in behavioral, biochemical, and physiologic responses of sprague-dawley and long evans rats concludes by saying, The data support the claim that environmental enrichment may render animals more resilient to challenges.   Ouch.  Forgetting chronic diseases such as Alzheimer’s or Parkinson’s, which get a lot of attention in the EE world, even things like traumatic brain injury or lack of oxygen to the brain seem to show benefits from a stimulating environment, as we can see from studies like Environmental Enrichment Influences BDNF and NR1 Levels in the Hippocampus and Restores Cognitive Impairment in Chronic Cerebral Hypoperfused Rats or Empirical comparison of typical and atypical environmental enrichment paradigms on functional and histological outcome after experimental traumatic brain injury.  The flip side, a ‘de-enriched’ environment has findings along the lines of what you might expect; i.e., Environmental impoverishment and aging alter object recognition, spatial learning, and dentate gyrus astrocytes.  Ouch.

So what is, exactly, an enriched environment?  The methods section from Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice says this:

Animal experiments were conducted in accordance with institutional and NIH guidelines. Male offspring of transgenic breeding pairs APPswe × PS1 were separated from their mother at 3 weeks of age (after weaning), genotyped, and housed four males to a cage. Enriched environment was composed of large cages running wheels, colored tunnels, toys, and chewable material. For 1 month, mice were exposed to enriched environment every day for 3 hr and were returned to their original cages for the remaining 21 hr. After 1 month of daily enrichment, mice were introduced to the enriched environment three times a week for an additional 4 months. Mice were sacrificed at age of 6months. Following weaning, a control group of animals was maintained for 5 months in standard housing conditions.

Lets consider the implications of these findings.  Reducing amyloid buildup has been a holy grail of the pharmaceutical companies for a long time now, though it is possible that this plan of attack was based on bad assumptions.  Tens of millions of dollars (or hundreds of  millions) have been thrown at synthetic ways to reduce or eliminate the buildup of amyloid plaque in mice, rats, and recently, people with mixed to poor results.  Even if it turns out that amyloid isn’t causing Alzheimer’s, that doesn’t do anything to change the fact that these researchers were able to make very significant changes to biological systems by setting their rats up in a rat mansion with rat delivered food and a rat tennis court for a few hours a day.   Despite the mixed findings as of late on the effect of brain training in order to stave off dementia, I think most of us have known someone, or Kevin Baconed one degree out to know someone who has seemingly either degenerated with a stagnant environment, or kept on trucking through old age with a more active lifestyle.  Is their environment participating?

So what about autism?  The most extreme and tragic parallels can be seen in studies of children from orphanages, notably in Romania, where children were raised in absolutely destitute surroundings.  A recent study is entitled Stereotypies in children with a history of early institutional care with these findings:

RESULTS: At the baseline assessment prior to placement in foster care (average age of 22 months), more than 60% of children in institutional care exhibited stereotypies. Follow-up assessments at 30 months, 42 months, and 54 months indicated that being placed in families significantly reduced stereotypies, and with earlier and longer placements, reductions became larger. For children in the foster care group, but not in the care as usual group, stereotypies were significantly associated with lower outcomes on measures of language and cognition.

CONCLUSIONS: Stereotypies are prevalent in children with a history of institutional care. A foster care intervention appears to have a beneficial/moderating role on reducing stereotypies, underscoring the need for early placement in home-based care for abandoned children. Children who continue to exhibit stereotypies after foster care placement are significantly more impaired on outcomes of language and cognition than children without stereotypies and thus may be a target for further assessments or interventions.

Another study that looks specifically towards autistic like behaviors in children raised in orphanages is Early adolescent outcomes of institutionally deprived and non-deprived adoptees. III. Quasi-autism.

BACKGROUND: Some young children reared in profoundly depriving institutions have been found to show autistic-like patterns, but the developmental significance of these features is unknown.

METHODS: A randomly selected, age-stratified, sample of 144 children who had experienced an institutional upbringing in Romania and who were adopted by UK families was studied at 4, 6, and 11 years, and compared with a non-institutionalised sample of 52 domestic adoptees. Twenty-eight children, all from Romanian institutions, for whom the possibility of quasi-autism had been raised, were assessed using the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS) at the age of 12 years.

RESULTS: Sixteen children were found to have a quasi-autistic pattern; a rate of 9.2% in the Romanian institution-reared adoptees with an IQ of at least 50 as compared with 0% in the domestic adoptees. There were a further 12 children with some autistic-like features, but for whom the quasi-autism designation was not confirmed. The follow-up of the children showed that a quarter of the children lost their autistic-like features by 11. Disinhibited attachment and poor peer relationships were also present in over half of the children with quasi-autism.

CONCLUSIONS: The findings at age 11/12 years confirmed the reality and clinical significance of the quasi-autistic patterns seen in over 1 in 10 of the children who experienced profound institutional deprivation. Although there were important similarities with ‘ordinary’ autism, the dissimilarities suggest a different meaning.

Similarly depressing findings can be found in places like Institutional rearing and psychiatric disorders in Romanian preschool children, or Placement in foster care enhances quality of attachment among young institutionalized children.   There is a gripping This American Life about a child adopted from Romania.    Please be sure your head is in the right place before listening to part II, which describes a family trying to decide of their very severely autistic son should be placed in residential care.  I ran into this episode on accident one day in the car when I was already feeling bleak and walked out the other end pretty fucked up for a few days; those guys are really good and the narrative can hit very close to home for some.

Calling up images from the dark(er) days of autism and Bettleheim we have an array of studies on the effect of maternal separation and subsequent physiological and behavioral effects that have parallels in autism findings.  For example, here is an abstract from Behavioural and neurochemical consequences of early weaning in rodents

Among all mammalian species, pups are highly dependent on their mother not only for nutrition, but also for physical interaction. Therefore, disruption of the mother-pup interaction changes the physiology and behaviour of pups. We review how maternal separation in the early developmental period brings about changes in the behaviour and neuronal systems of the offspring of rats and mice. Early weaning in mice results in adulthood a persistent increase in anxiety-like and aggressive behaviour. The early-weaned mice also show higher hypothalamic-pituitary-adrenal activity in response to novelty stress. Neurochemically, the early-weaned male mice, but not female mice, show precocious myelination in the amygdala, decreased brain-derived neurotrophic factor protein levels in the hippocampus and prefrontal cortex, and reduced bromodeoxyuridine immunoreactivity in the dentate gyrus. Because higher corticosterone levels are persistently observed up to 48 h when the mice are weaned on postnatal day 14, the exposure of the developing brain to higher corticosterone levels may be one of the effects of early weaning. These results suggest that deprivation of the mother-infant interaction during the late lactating period results in behavioural and neurochemical changes in adulthood and that these stress responses are sexually dimorphic (i.e. the male is more vulnerable to early weaning stress).

The rapidfire analysis tells us that altered HPA-Axis activityBDNF levels, and anxiety all have parallels in autism, along with perhaps the most consistent finding in animal studies that have interest to autism, the problems of being born male and consequent risk factors from nearly everything.   This is a review paper, but there are a gazillion others with titles like Maternal separation disrupts dendritic morphology of neurons in prefrontal cortex, hippocampus, and nucleus accumbens in male rat offspring, Short- and long-term consequences of different early environmental conditions on central immunoreactive oxytocin and arginine vasopressin levels in male rats, or Prolonged maternal separation decreases granule cell number in the dentate gyrus of 3-week-old male rats.

Though I’m pretty sure that this should be clear to everyone, just to be sure, I’m not proposing a refrigerator mother theory of autism. But the data is the data and the logical opposite of an enriched environment is also born out.

So what?  Well, this reminded me of the “Rat Park” studies an Internet friend told me about, wherein researchers seemed to find that animals dosed with opiates for several weeks would voluntarily wean themselves from the drugs if moved to much larger enclosures where they had access to either drugged water or plain water.  The startling thing about the Rat Park studies isn’t so much what was learned about opiate addiction, so much as the broader implications that the existing studies on drug addiction might not be studying the right thing; that instead of testing the effects on opiate availability on rodents, they were testing the effects of opiate availability on chronically depressed rodents.   Following through, it occurs to me that in addition to the bazillion other problems we have moving from rodent to human with anything other than a hopeful educated guess, we must grudgingly admit that the condition the animals were housed in may be affecting a lot of findings.  As if we didn’t have enough confounders already!

But more importantly, these types of findings are beautiful portraits of complexity, the dispassionate hand of nature and the dangers of thinking you understand.

There are so many instances where we have found that as we gain the ability to make more detailed observations, we learn that our existing conclusions were crude facsimiles of reality, and oftentimes, conclusions that had been formed on dangerously unsound foundations.  By way of example, exposure to lead and consequent effects on neurodevelopment.  At one point, lead was used as a pesticide, eventually we figured out that wasn’t such a good idea, but it should be fine in paint and gasoline.  Then we removed it from paint.  Then gasoline.  And just a few years back, the ‘safe’ level of lead was deemed to be zero; and even the tiniest increases in lead were associated with developmental problems.  Of course, this was always the reality, but it was not until we applied filters of sufficient sophistication that our observations were adequately powered to understand the reality.   Are our studies of any number of factors clever enough to discern the changes we’d like to understand when we realize that subtle changes are still changes?

It gets thornier for the autism community in particular.  One thing a lot of our kids aren’t very good at are “complex environmental interactions”, in fact, a lot of our kids are flat out terrible at them.  After a couple of weeks/months/years of soul crushing experiences trying new things out with kid autism, some parents might start to think to themselves that a trip to the zoo, or the museum, or the movie theater or even the super market just isn’t worth it.  The result, while not necessarily an abject environment can start to resemble a single square mile of ocean, indistinguishable from the sea for backwards or forwards; the real world equivalent of a DVD set on repeat play.  I speak from experience, a rule in our household when one of the parents had to leave the other home for a weekend with kid autism was ‘survive, don’t thrive’. If that meant a trip to the same lake, spinning the same DVD, and a meal of the same food, but a relatively meltdown free weekend, that was OK.

We survived, but did we spite ourselves in the process?  Were we reinforcing at a neurochemical level some of the causes of the very behaviors that were causing us to retreat to the middle of the ocean?  We are starting to learn that this might be somewhat of a self fulfilling prophecy; taking a child who already does very poorly in new environments and run him or her through the same things over and over could be exacerbating their ability to handle new environments in a physiological way.  The data is the data.

That being said, there is an upside, a big one; the flip side is that parents have a chance to make real and salient changes in their child by the least controversial methods possible; gentle but repeated exposure to new things.  For some of us, this means a lot of shitty days and late night drinks to get through to the other side.  That’s OK.  It’s worth it.  Steel yourself for a meltdown and turn off the goddamned TV, take kid autism to the zoo, or the bounce house playground, or art festival, or a ‘non-autism’ friends house.  A lot of our children might need a helping hand, a gentle push, or a well meaning shove into the world,  but someone has to do it, and the world isn’t going to get any less complicated while we wait.  When it works out, and you have even a single new experience your child enjoys, that is an enriched environment for you, and enriched environments aren’t just for rats and kids.

– pD

Hello friends –

I ran into a few abstracts,  read a few papers, and tried to get my way through one really dense paper in the past few weeks that got me thinking about this post.  It’s  all shook up, like pasta primavera in my head, but hopefully something cogent will come out the other end.  (?)

Of the metabolic conditions known to be associated with having a child with autism, hypothyroidism is one that I keep on running into by way of the pubmed alert grapevine.  By way of example, we have two studies that looked for autoimmune conditions in family members which found hypothyroidism to be one of many autoimmune diseases as a risk factor for autism, including,  Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism, and Increased prevalence of familial autoimmunity in probands with pervasive developmental disorders.   This shouldn’t be too surprising, we know that, for example, perinatal hypothyroidism is a leading cause of mental retardation, with similar findings for the condition during pregnancy.  It turns out, it appears that rates of hypothyroidism are slightly increasing, though at this time, the increases are of relatively small proportions, and as such, may be artifacts unrelated to an actual increase in classically recognized hypothyroidism.  In any case, I think it is safe to say that interference with thyroid metabolism is something to be avoided at all costs when possible.

So after having read about that, this paper showed up in my inbox a while ago:

Effects of perinatal hypothyroidism on regulation of reelin and brain-derived neurotrophic factor gene expression in rat hippocampus: Role of DNA methylation and histone acetylation

Thyroid hormones have long been known to play important roles in the development and functions of the central nervous system, however, the precise molecular mechanisms that regulate thyroid hormone-responsive gene expression are not well understood. The present study investigated the role of DNA methylaion and histone acetylation in the effects of perinatal hypothyroidism on regulation of reelin and brain-derived neurotrophic factor (BDNF) gene expression in rat hippocampus. The findings indicated that the activities of DNA methyltransferase (DNMT), methylated reelin and BDNF genes were up-regulated, whereas, the activities of histone acetylases (HAT), the levels of global acetylated histone 3 (H3) and global acetylated histone 4 (H4), and acetylated H3, acetylated H4 at reelin promoter and at BDNF gene promoter for exon II were down-regulated in the hippocampus at the developmental stage of the hypothyroid animals. These results suggest that epigenetic modification of chromatin might underlie the mechanisms of hypothyroidism-induced down-regulation of reelin and BDNF gene expression in developmental rat hippocampus

This gets interesting for autism because reelin, and bdnf levels have been found to be decreased in several studies in the autism population, with direct measurements, genetic expression, mouse knockout based models of autism , and genomic alterations all being implicated.  There have been some negative genetic studies, but considering that it isn’t always the genes you have, but the genes you use, our other available evidence certainly points to BDNF and reelin involvement with some percentage of children with autism, and the association is such that a reduction in reelin or BDNF is a risk factor for developing autism.  It would seem that the paper above might give some insight into the lower level details of the effects of hypothyroidism and subsequent developmental trajectories; modifications of reelin expression; through epigentic mechanisms, no less!.  That’s pretty cool!

Then, I got my hands on a review paper that tries to go into detail as to the functional mechanism by which reelin deficiency could contribute to ASD, Neuroendocrine pathways altered in autism. Special role of reelin.  It is a review that touches on a variety of ways that reelin contributes to neurodevelopment that have findings in the autism realm, including neuronal targeting and migration during brain formation, interactions with the serotonin and GABA systems, testosterone, and oxytocin.   In short, there are plenty of ways that decreased reelin expression can impact development in ways that mirror our some of our observations in autism.

Of the many things that convince me that we are doomed, the proliferation of chemical compounds whose interactions within our bodies we scarcely understand is among them.   In my readings on endocrine disruptors, one thing I found that seemed to be worrying lots of researchers was that some classes of these chemicals are capable of interfering with thyroid metabolism, and in some cases interfering with development of cells known to be associated with autism.    Terrifyingly enough, since I read those papers, several others have come out, including Polybrominated Diphenylether (PBDE) Flame Retardants and Thyroid Hormone during Pregnancy and Mini-review: polybrominated diphenyl ether (PBDE) flame retardants as potential autism risk factors.     At this point, it is important to point out that, as far as I know, there have not been any studies showing that non occupational exposure to PDBEs or other environmental pollutants can lead to classically defined hypothyroidism, at least none that I know of. (?)    Be that as it may, I think it is realistic to assume any interference in thyroid metabolism is a bad thing, and while finding people in the outlier regions of hypo (or hyper) thyroidism gives us information on extreme environments, it would take someone with a lot of misplaced faith to assume that we can safely disturb thyroid metabolism just a little bit, and everything will come out in the wash.

I’ve had the argument made to me in the past that environmental pollutant driven increases in autism lacked biological plausible mechanisms; this argument is almost always made within a context of trying to defend the concept of a static rate of autism.  While the papers I’ve linked to above do not provide conclusive proof that our changing environment is causing more children to be born with autism, they do provide increasing evidence of a pathway from pollutants to ASD, and indeed,  the lack of biological plausibility becomes an increasingly flacid foundation on which to assume that our observations of an increased rate of autism are illusory.   Unfortunately, in my opinion, the focus on vaccines has contributed to the mindset that a static rate of autism (or nowadays, maybe a tiny increase), must be protected at all costs, including some ideas on the application of a precautionary principle that seem outright insane to me (or at least, the exact opposite of what I would consider to be a precautionary path).

One thing is for certain, the number of child bearing women in developing countries with measurable concentrations of chemicals known to interferre with thyroid metabolism nears 100% in the industrialized nation as we eat , drink, breathe and bathe in the microscopic remnants of packaging materials, deteriorating carpet fibers, and baby clothes that are made to be fire resistant.  This is an environment unambiguously different than that encountered by any other generation of infants in the history of mankind.  To believe that we can modify our environment so drastically without having an impact seems incredibly naive to me, or on some days, just plain old stupid.

– pD

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