Thoughts on Autism Research
July 2, 2007 by Kristina Chew, PhD
Filed under Health
There’s been some (heated) (impassioned) discussion in the autism community of late (go here for one exchange) about research that focuses on possible environmental factors connected to autism “versus” research that focuses on genetics (and perhaps the publicity surrounding the vaccine court hearings has contributed to this). Now that Autism Speaks has announced (on June 29th) that it will fund 52 projects in autism research, for a total of $15.2 million, these exchanges will surely continue. Descriptions of the projects can be found here. Ten of the grants are specifically devoted to treatment students. Regarding the rest, Autism Speaks notes:
Along with the ten grants devoted to treatment studies, there are: 11 grants pertaining to determining the etiology, or causes, of autism — i.e., studies of genetic factors, environmental factors and epidemiology; 26 grants pertaining to gaining an understanding of the underlying pathobiology of autism — i.e., studies utilizing cell biology, molecular genetics, immunology, brain imaging, and basic neuroscience, including post mortem brain studies and animal models of autism features; and 6 grants pertaining to methods of better diagnosis of autism or associated dysfunction.
I think it useful to recall what Professor Matthew Belmonte of Cornell University wrote in a recent letter to the New York Times. Belmonte emphasizes that we need not see research on genetics and research on the environment as in opposition to each other:
“[G]enes can affect responses to the environment, and the environment can influence gene expression, making the genetic-environmental dichotomy a false one.”
Autism research, he noted, can be open to consider “multiple interacting causes.” Too, the 10th edition of Gene Genie on Genomicron notes that “the very definition of ‘gene’ is open to revision” and provides links to a number of blogs (including, I am grateful to note, this blog on Fragile X and mice.) And on the subject of “false dichotomies,” Genomicron notes that “nature versus nurture,” just like genetics and the environment, is a “false [dichotomy].”
Autism Speaks notes that it is hoped that findings from these research projects might find ways by which autism might be “more effectively treated and prevented”; one study will consider the effectiveness of melatonin and sleep problems in children. We have given Charlie melatonin for several months now and his sleep habits have become regular (with the occasional 3am wake-up). I prefer not to talk about “preventing autism” but rather about providing my son and autistic children and persons, and their families, with education, services, and understanding. I hope that Autism Speaks can start to think of ways to allocate funds to help families with things like daycare and after-school care. To offer a personal example, there are three people on this planet besides Jim and me who can take care of Charlie full-time (my parents who live in California and Charlie’s long-time babysitter/speech therapist); just finding someone reliable to meet him at the bus and stay with him for an hour or so would make my home commute less harried: How many parents of autistic children do not work because of not being able to find someone to watch their child?
I am not a researcher, but perhaps this would be a topic to pursue.
Lots of comments…no time to read but count me. I’m a parent who is now working but struggled to find care for our autistic son. Now, with the move in just two to three weeks it is again an issue. I must work, financially it is necessary but I am limited to part-time (during school hours) or late nights (when husband is home) until we can find trustworthy care, IF we find it.
Sure we can scientifically determine if there is an epidemic. Subtract out all PDDNOS, Aspergers and all other diagnosis that would not meet DSM-III criteria from the population headcount and see if they exceed the 1:10,000 that was globally stated during the time prior to DSM-IV. Any professional psychologist child seeing a ASD child should be able to simply check a box that says “Meets DSM-III criteria” and be done with this criteria change issue.
pD: “This would tend to cast considerable doubt on the notion that the inflammation is protective in any sense.”
If by inflammation you are refering to microglial activation, it is both protective and essential to neural development/function.
Hi notmercury –
“If by inflammation you are referring to microglial activation, it is both protective and essential to neural development/function.”
Curious statement in the context of this conversation.
In the Terbutaline study I mentioned, none of the rats developed the microglial activation if the agent in question was administered past post natal day 5. Given that, why should we assume that the activation is protective or essential? Would you suggest that the rats that did not develop microglial activation are at a disadvantage in either neuronal protection or essentials compared to the rats that did?
Also considering that the original Pardo study showed that controls did not show microglial activation (or at least, significantly reduced rates of it), would you suggest that people without autism are somehow at risk of not getting enough microglial activation? Maybe we should start mandatory terbutaline injections for infants, just be to be sure everyone is getting adequate microglial activation. (?)
The authors say:
“Our findings indicate that beta2-adrenoceptor overstimulation during an early critical period results in microglial activation associated with innate neuroinflammatory pathways and behavioral abnormalities, similar to those described in autism.”
Where is the spin that this can be taken as anything but poor news?
Take care
-pD
Spin? I was merely disagreeing with your statement that inflammation is not protective in any sense. Clearly it can be and much depends on level and context.
You are free to draw any conclusions you would like from Pardo et al. but you may want to consider the authors’ own caveat: “At present, whether neuroglial activation is destructive, reparative, or reflects a retained fetal pattern, is unknown. It is also unclear whether neuroinflammation in autism correlates with behaviors seen in
this disorder.”
Note the mention of a retained fetal pattern. Microglial activation is a normal part of early neurodevelopment. I am perfectly willing to acknowledge that neuroinflammation might contribute to or even cause autism but I’d first like to see replication beyond a single study where the results and conclusions are far from ironclad.
Hi not mercury –
“I was merely disagreeing with your statement that inflammation is not protective in any sense. Clearly it can be and much depends on level and context. ”
My statement was that this type and amount of inflammation is not protective in any sense. If someone were having a discussion about people with 105 degree fevers, inserting the fact that fevers can be protective, while technically true, adds little to the conversation.
“Note the mention of a retained fetal pattern. Microglial activation is a normal part of early neurodevelopment”
Ack! If it were normal, why were the only rats that developed the activation those that got dosed during a specific post natal period? If the severity of activation was ‘normal’, shouldn’t we see no difference between rats dosed at pn day 2 and pn day 14, or for that matter, rats that didn’t get dosed at all? The whole point of the study is the there were two very different observations made, thus, one set of observations was outside normal.
The website you quote is considerably older than the terbutaline study, where they say quite clearly:
“Our findings indicate that beta2-adrenoceptor overstimulation during an early critical period results in microglial activation associated with innate neuroinflammatory pathways and behavioral abnormalities, similar to those described in autism. ” [my emphasis]
As far as protective or disruptive, given the fact that the agent in use has been shown to increase autism; I’m truly curious how or why you could possibly speculate a protective mechanism is in effect.
Here is what has been shown:
Have autism? You have more microglial activation. Get more terbutaline ? Get more autism. Get more terbutaline early in development? Get more microglial activation. Don’t have autism? You have less microglial activation. Don’t get terbutaline? Get less autism. Don’t get an terbutaline early in development? Get less microglial activation.
Argument: The activation might be protective.
Argument: The activation might not have anything to do with autism.
I may be depending on logic here, but in this case the logical twists necessary for your argument(s) are far more acrobatic.
Take care
-pD
We won’t get very far arguing so hard: as far as the nearest pub?
Perhaps inflammation is protective short term? More damaging long term?
Why not find ways of reducing long term inflammation and trying them out in practice to see the benefits and difficulties?
“I may be depending on logic here, but in this case the logical twists necessary for your argument(s) are far more acrobatic.”
Perhaps, though your “Have autism?” argument felt like a cephalopod Cirque Du Soleil in a centrifuge. Just a suggestion; Less passion, more Drone.
pD: “The website you quote is considerably older than the terbutaline study, where they say quite clearly”
Actually, my quote was from the terbutaline study though I may have an earlier version in my documents folder.
Another interesting quote from my copy:
“We found a delayed onset between terbutaline administration and the appearance of neuroinflammation, as microglial activation was not apparent on PN 6 but was robust by PN 30. This delay is in keeping with the later emergence of a neurobehavioral disorder that nevertheless originates from an insult during pregnancy.
So, assuming that microglial activation is pathological in autism but also a normal and essential part of early neurodevelopment, that leaves the simple task of deciding how and when to intervene. Try to suppress microglial activation by too much or too soon you risk induction of developmental delays.
I guess what I am trying to say is something similar to anon_please’s statement: “Neuroinflammation is a very complex issue and we do not quite have enough information yet (as is clearly stated on Pardo’s lab site) to determine if it’s something negative or whether it’s actually something positive (reparative). “
By the way, if you read up on microglia and what constitutes “activation” and how that is quantified in post mortem brain tissue, it becomes clear that it isn’t and on/off type of mechanism. Like so many other biological processes there are multiple shades of gray. Fuzzy logic, if you will.
This out today in the WSJ:
Not only is every new brain different from any other, but the variations within each one as it adapts, swells and contracts _confound analysis_.
“A developing brain looks weird,” said pediatric neurologist Katrina Gwinn at the National Institute of Neurological Disorders and Stroke, who directs the NIH project. “Something that might be normal in an adult might look abnormal in a child.”
… more soon …
Hi not mercury –
George is right. I owe you a beer.
Anyways,
“We found a delayed onset between terbutaline administration and the appearance of neuroinflammation, as microglial activation was not apparent on PN 6 but was robust by PN 30. This delay is in keeping with the later emergence of a neurobehavioral disorder that nevertheless originates from an insult during pregnancy.”
I’ll admit to being a bit confused. I was under the impression that the agent was administered after birth. (?) From the abstract:
“Newborn rats were given terbutaline (10 mg/kg) daily on postnatal days (PN) 2 to 5 or PN 11 to 14 and examined 24 h after the last dose and at PN 30″ [my emphasis]
I may try to get a complete copy of the paper.
“So, assuming that microglial activation is pathological in autism but also a normal and essential part of early neurodevelopment, that leaves the simple task of deciding how and when to intervene.”
As far as intervention, why not stop administering
beta2-adrenoceptors as a start? They didn’t see any activation in animals that didn’t get dosed.
“Try to suppress microglial activation by too much or too soon you risk induction of developmental delays”
How interesting. Do you have any studies on this you would be willing to share?
“Neuroinflammation is a very complex issue and we do not quite have enough information yet (as is clearly stated on Pardo’s lab site) to determine if it’s something negative or whether it’s actually something positive (reparative). “
I thought about this for a while. I suppose, it is possible that the terbutaline caused an as of yet undetected reaction, which the activation is attempting to rectify. I guess I was arguing against the premise that the levels of activation seen were not indicative of any problems, which was not explicity made.
If the inflammation is protective, it is protecting against something that was initiated via terbutaline administration.
No more blogging for me until Monday!
Take care.
-pD
pD, have a good weekend and good luck sending the virtual beer, not sure of its effect on neural functioning……
Wow.
Well, regarding the comment many posts ago:
“As the kids get older such words as: cure; recovery; toxicity; poisoning can have a heavy impact on how they affect a child’s sense of self. This has been an over-riding concern of mine of late because of significant first-hand experience in this regard.”
So, what words should be used then to explain prescription medication?
Just curious….
I think as parents, we are all “creative” enough to find the right words our children can understand to explain improving their health and well being.
Regarding the prescription medications that Charlie takes, they are for “improving …. health and well being”; for helping him to do better in the classroom. Not a cure etc.; yet another tool. Best regards—
afterthought:
Personally, ALL brains look weird!!!
LOL!!!!!
Bottom-line: Before you (the generic you) tell a child that they are “poisoned” you had better be d*mn certain beyond all doubt and be prepared to stand by that ascertation for the rest of your life.
Hi Dr. C:
Yeah, that’s my point. Many kids take medication, could be for helping asthma,… some kids have diabetes and need insulin. How is that explained? Don’t we talk about a “cure” for juvenile diabetes and or obesity? Those kids aren’t put out or messed up because of it.
I understand the point that Anon_please is trying to make…. but playing the role of “devil’s advocate”, I am just asking the question:
“whats the difference?” Why is using the words “recovery” or “cure” so bad when it comes to “treating symptoms” in autism?
In the case of diabetes — medication/treatment might stabilize glucose, but the person may always be seen as one with diabetes.
In autism, I think, it’s not the “cure” part that is such the problem, but rather changing the “stigma” about what autism is and how it presents, or what it means to people involved etc.,,
maybe I am just naive….
I think the use of the “cure” in regard to autism is somewhat misapplied and has roots in a medicalized notion of disability. Certainly a parent wants to address any comorbid medical issues a child may have; the question is, to what extent are various medical issues comorbid with autism, or intrinsic to it?
I guess I would say that my son takes medications not for “autism” but for the effects that some medications have on him as regards anxiety, for instance. But—-and his neurologist emphasizes this—the medications are just to help him be in a better way (so to speak), so that he can be better prepared to pay attention, focus, be educated—–they are far, far from a “cure.” Indeed, we gave him them in the hopes that these might help him.
Always a guessing game, it sometimes seems…..
AJ, where do you live? I’m in the Austin area and have a sitter!
Just to add my two cents into the neuroinflammation discussion (or more correctly, to wordsmith someone else’s thoughts):
According to Dr Casanova’s minicolumns and autism hypothesis (see here for an overview), the autistic brain has a higher number of minicolumns of narrower than average width, with smaller than average neurons. (Note that this is within the normal distribution of minicolumnar widths – albeit at the tail end – and does not by itself automatically result in autism.) Estimates suggest that each minicolumn is connected to 10^3 similar modules, so therefore a higher number of columns means a higher number of overall connections. Each connection consists of axons and oligodendrocytes necessary to myelinate them.
From Casanova’s “Neuropathological and Genetic Findings in Autism: The Significance of a Putative Minicolumnopathy” Neuroscientist (2006) paper:
“During development, the number of oligodendrocytes is adjusted to ensure even spacing along the length of the axons. This results in the death of oligodendrocytes along regions of cellular crowding (Barres and others 1992). Dying cells provide chemotactic signals for monocytes and their differentiation to form macrophages and microglia (Perry and others 1985; Perry and Gordon 1988). Not surprisingly, microglia activation is prominent in the gray-white matter junction of autistic patients (Vargas and others 2005). It may be the case that the innate immune response observed in the neocortex and adjacent white matter of autistic patients is the result of tissue modeling, a fetal pattern of development that persists to the postnatal years.”
Other alternatives are also discussed, but from the above it should be clear that microglial activation in a brain with a higher number of narrower width minicolumns (again, whether autistic or not) could be beneficial.
Just testing…
Just to add my two cents into the neuroinflammation discussion (or more correctly, to wordsmith someone else’s thoughts):
According to Dr Casanova’s minicolumns and autism hypothesis (see http://a-shade-of-grey.blogspot.com/2006/09/autism-and-minicolumns.html for an overview), the autistic brain has a higher number of minicolumns of narrower than average width, with smaller than average neurons. (Note that this is within of the normal distribution of minicolumnar widths – albeit at the tail end – and does not automatically result in autism.) Estimates suggest that each minicolumn is connected to 10^3 similar modules, so therefore a higher number of columns means a higher number of overall connections. Connections consist of axons and oligodendrocytes necessary to myelinate them.
From Casanova’s “Neuropathological and Genetic Findings in Autism: The Significance of a Putative Minicolumnopathy” Neuroscientist (2006) paper:
“During development, the number of oligodendrocytes is adjusted to ensure even spacing along the length of the axons. This results in the death of oligodendrocytes along regions of cellular crowding (Barres and others 1992). Dying cells provide chemotactic signals for monocytes and their differentiation to form macrophages and microglia (Perry and others 1985; Perry and Gordon 1988). Not surprisingly, microglia activation is prominent in the gray-white matter junction of autistic patients (Vargas and others 2005). It may be the case that the innate immune response observed in the neocortex and adjacent white matter of autistic patients is the result of tissue modeling, a fetal pattern of development that persists to the postnatal years.”
Other oligodendrocyte alternatives are also discussed, but from the above it should be clear that microglial activation in a brain with a higher number of narrower width minicolumns (again, whether autistic or not) could result in microglial activation that in this case would be beneficial.
Okay, I’m having no luck getting my full comment posted here (tomorrow it will probably show up 20 times), but in the meantime, according to Dr Casanova’s minicolumn hypothesis, autistic brains have a higher number of minicolumns of narrower widths. The result is a higher number of overall connections, which consist of axons and oligodendrocytes to myelinate them.
From Casanova (2006):
“During development, the number of oligodendrocytes is adjusted to ensure even spacing along the length of the axons. This results in the death of oligodendrocytes along regions of cellular crowding (Barres and others 1992). Dying cells provide chemotactic signals for monocytes and their differentiation to form macrophages and microglia (Perry and others 1985; Perry and Gordon 1988). Not surprisingly, microglia activation is prominent in the gray-white matter junction of autistic patients (Vargas and others 2005). It may be the case that the innate immune response observed in the neocortex and adjacent white matter of autistic patients is the result of tissue modeling, a fetal pattern of development that persists to the postnatal years.”
Other oligodendrocyte alternatives are also discussed in the paper, but from the above it should be clear that microglial activation in a brain with a higher number of narrower width minicolumns (again, whether autistic or not) could result in microglial activation that in this case would be beneficial.
My comment above makes a bit more sense if the following is included:
Just to add my two cents into the neuroinflammation discussion (or more correctly, to wordsmith someone else’s thoughts):
According to Dr Casanova’s minicolumns and autism hypothesis (see here for an overview), the autistic brain has a higher number of minicolumns of narrower than average width, with smaller than average neurons. (Note that this is within the normal distribution of minicolumnar widths – albeit at the tail end – and does not automatically result in autism.) Estimates suggest that each minicolumn is connected to 10^3 similar modules, so therefore a higher number of columns means a higher number of overall connections.
My comment above makes a bit more sense if the following is included.
Just to add my two cents into the neuroinflammation discussion (or more correctly, to wordsmith someone else’s thoughts):
According to Dr Casanova’s minicolumns and autism hypothesis (see http://a-shade-of-grey.blogspot.com/2006/09/autism-and-minicolumns.html for an overview), the autistic brain has a higher number of minicolumns of narrower than average width, with smaller than average neurons. (Note that this is within the normal distribution of minicolumnar widths – albeit at the tail end – and does not automatically result in autism.) Estimates suggest that each minicolumn is connected to 10^3 similar modules, so therefore a higher number of columns means a higher number of overall connections.
Maybe it’s all those multi-lettered words—-”oligodendrocyte”—-with Greekish roots— I just found your comments (sorry, they got marked as spam—I think because of the URLS). Let the discussion continue—-
I think ’spam’ is probably an appropriate label for most of my comments
My comment above would make more sense if I added the following:
Just to add my two cents into the neuroinflammation discussion (or more correctly, to wordsmith someone else’s thoughts):
According to Dr Casanova’s minicolumns and autism hypothesis (see a-shade-of-grey.blogspot.com/2006/09/autism-and-minicolumns.html for an overview (http omitted to get past the spam filter)), the autistic brain has a higher number of minicolumns of narrower than average width, with smaller than average neurons. (Note that this is part of the normal distribution of minicolumnar widths – albeit at the tail end – and does not automatically result in autism.) Estimates suggest that each minicolumn is connected to 10^3 similar modules, so therefore a higher number of columns means a higher number of overall connections.
Sorry to all for the repetition. I thought my comments had disappeared (and the word perseveration is coming to mind).
I promise I’ll stop now.
Not at all, really! What is blogging but perseveration…..I apologize for not despamming your comments till now!
I like it when blogs have a little message indicating that the comment is being held for moderation. That way, you know why it hasn’t just appeared as soon as you hit “post”. And if it’s not there the next day, e-mailing the blogger sometimes helps. (How useful that is depends on the blogger in question.)