Apr 30 2009

The Genetics of Autism

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Comments: 71

A new genome-wide analysis of families with autism has found significant gene associations, adding to the growing evidence for strong genetic contribution to autism.  While this is still a long way away from explaining autism, it represents a significant advance in a very fruitful area of research.

But to put this into context, we need some background. Autism spectrum disorder (ASD) is not a single discrete pathophysiological disease. In fact, the term “disease” is probably not appropriate at all, which is why it is termed a “disorder.” Like many neurological conditions with primarily cognitive and behavior effects, ASD likely correlates with the organization and function of neurons in the brain – not a pathological disease process.

What this means is that there is likely to be a complex set of many factors that contribute to ASD – not one single cause. ASD is defined by the clinical symptoms that are evident – decreased social and verbal skills with a tendency to display repetitive behaviors or a narrow focus of interest. Brain function itself is highly complex, and these higher-order behaviors may just be the final common pathway of many potential underlying changes.

The same exact situation is true for other entities, like schizophrenia and attention deficit disorder (ADD). These syndromes are defined by clinical features, they represent a varied set of disorders with complex underlying causes. One difference, however, is that schizophrenia and ADD likely represent changes to particular parts of the brain, while autism is likely due to changes in the global architecture of the brain.

What all this means is that the genetics of autism is likely to be a complex puzzle, and so far that is what researchers are finding. ASD is not a genetic disease in the sense that, say, hemophilia is a genetic disease. Over the years, geneticists have identified a long list of simple genetic diseases – where a single mutation in a single gene causes disruption in the function of a single protein.  This class of genetic disorders is directly inherited, with various known patterns (autosomal vs X or Y linked or mitochondrial, and dominant vs recessive).

A separate class of genetic disorders is not directly inherited but for which there is a genetic predisposition. In these entities, certain genetic variants convey an increased risk of developing a disease or disorder, but it does not directly cause them.  ASD falls into this broad category.

How does a particular gene variant predispose to a disorder without “causing” it? There are two primary hypotheses to answer this question. The first is that one gene variant is not sufficient to cause a disease, but must be combined with other gene variants. Therefore, a person can have any of the gene variants that predispose to the disorder without having the disorder. No single implicated gene variant will correlate 100% with the disorder in question.

In these disorders predisposing gene variants are like a giant puzzle, but one that has many potential solutions. Perhaps there is a critical threshold – an individual will need to have a certain critical number of the predisposing variants, but in any combination, in order to manifest the disorder. This situation likely results from each variant decrease some physiological function by a small amount, but the cumulative effect of many variants impairs the function significantly enough to cause clinical manifestations.

The second way in which a genetic variant predisposes to without directly causing a disease or disorder is if there needs to be an environmental trigger. Perhaps the genetic variant only manifests if there is a particular environment in the womb. Some diseases, like multiple sclerosis, are now thought to be triggered, for example, by certain kinds of viral infections. Or a genetic variant may leave an individual more susceptible to a specific toxin or other environment stressor.

In fact, the interplay of environment and genetics is likely critical to the understanding of most genetic conditions, even the more direct genetic diseases. Genetics is only one factor in determining development. The environment of the womb (exposures to varying levels of maternal hormones, for example) is also critical.

Getting back to the genetics of autism, current models are therefore consistent with what is being found when the genetics of autism is researched – researchers are finding many genes that predispose to autism in a subset of cases but no single or simple universal cause. At present, 133 different gene variants have been linked to autism.

This new research, conducted by Dr. Hakon Hakonarson of the Children’s Hospital of Philadelphia, is a genome wide analysis involving about 10,000 individuals. This is a relatively new technique made possible by advances in computer technology and rapid DNA sequencing. They can compare genes across the entire genome among thousands of individuals and look for statistical patterns.

While this is a powerful technique, it is primarily a process of data mining for correlations. By itself this type of data cannot answer questions – but it can point us in the direction of the answers.

From the press release:

The new study has found a robust link between autism and six such variants. These do not invariably cause the condition, but they are about 20 per cent more common in children with autism than they are in those who are unaffected.

The results are especially significant because the variants lie between two genes, called CDH9 and CDH10, which are known to play an important role in forming nerve connections in the brain.

It is the last bit that makes these findings so interesting – more than a statistical fluke.  The gene variants that correlated with ASD are for proteins that are involved in the process of neurons forming connections with each other. There is already other lines of evidence that suggest what is different in ASD brains is a decrease in the amount of interconnectedness and communication among neurons. It is therefore likely no coincidence that this study found genetic correlations for proteins involved with neuronal connections.

This also is compatible with the finding that many separate genes are potentially involved with ASD – for there are many separate genes and processes involved with forming and maintaining neuronal connections. Perhaps each variant associated with ASD, by itself, does not result in any significant difference in the ability of neurons to connect to each other. But when a sufficient number of variants are present, with the proper environmental factors, neuronal connections are decreased resulting in ASD.

Researchers in this area are being properly cautious about the interpretation of this latest research. This is a significant finding, which strengthens the evidence for an important genetic role in ASD and advances our understanding of the ultimate causes of ASD. This, of course, creates the potential for biological interventions, although it is always difficult to predict the outcomes of translational research (developing clinical applications from basic science).

Autism researcher, Professor Simon Baron-Cohen, summed up the current situation:

The challenge for future research will be to establish which of these findings can be well-replicated in independent samples and by independent labs; what the functions of these genes are and where they are expressed; which aspects of the phenotype of autism they can explain; whether they relate to one sub-group or the whole autism spectrum; how many of these genes are necessary and sufficient to cause autism; and how they may interact with environmental factors. The puzzle is slowly being pieced together, and the science of autism is accelerating in promising ways.

The best research not only leads to answers, but more questions.  There are many questions to be researched in follow up to these current findings. But a picture of what is likely going on in ASD is emerging.

Further – this study shows how the technology of genetic research is accelerating. This is one avenue of research that is very information intensive and is yielding to the law of accelerating returns. As computer and sequencing technology continues to improve, our ability to rapidly gather data about the genome and its relationship to clinical entities is improving and accelerating.

71 responses so far

71 Responses to “The Genetics of Autism”

  1. lurkeron 30 Apr 2009 at 12:14 pm

    There is already other lines of evidence that suggest what is different in ASD brains is a decrease in the amount of interconnectedness and communication among neurons

    Hello Dr. Novella,
    regarding that statement, do you have some citation to refer to?

    I ask because I suspect the picture may be different and I refer to that publication:

    Casanova MF, van Kooten IA, Switala AE, van Engeland H, Heinsen H, Steinbusch HW, Hof PR, Trippe J, Stone J, Schmitz C. Minicolumnar abnormalities in autism.
    Acta Neuropathol. 2006 Sep;112(3):287-303. Epub 2006 Jul 4. PubMed PMID: 16819561.

    The author found that the brain tissue from autistic people had smaller minicolumn cross-section (“27.2 microm in controls and 25.7 microm in autistic patients”) but a similar number of cells relative to control which result in autistic brain having on average 23% more cells in total.

    The question I have in mind is that isn’t it possible that physiological difference rather than under connection account for the bigger picture?

    Thanks you

  2. HHCon 30 Apr 2009 at 12:29 pm

    I enjoy reading about the medical perspective on autism. When I began in the field, there was a focus on behavioral intervention. I had one little boy on my state case load with multiple behavioral interventions which staff ran daily as programs. House staff were so focused on making this handsome boy normal that the same staff missed the medical problems when they presented themselves. The young autistic boy had developed a gastrointestinal problem which rapidly manifested itself and killed him. They thought his symptoms were a new variety of autistic behavior.

  3. Magnuson 30 Apr 2009 at 12:41 pm

    AoA predictably tries to downplay the significance of this study.

  4. daedalus2uon 30 Apr 2009 at 1:46 pm

    There are two types of connection, the actual physical connections between neurons (each neuron has ~10,000 or so connections) and then the functional connection between neurons mediated by propagation of action potentials.

    When a neuron fires (on average) only one down stream neuron fires. If the average was greater than one, then the firing would exponentially avalanche into every neuron in the brain being activated; if the average was less than one, the avalanche would extinguish. Neither of those happens over the long term, so (on average) one down stream neuron fires for every upstream neuron that fires.

    Exactly how the single downstream neuron “decides” to fire is an excellent question, and one that is very challenging experimentally. I suspect that the answer relates to NO (bet everyone saw that coming ;). The usual method for measuring functional connectivity is the BOLD fMRI technique (Blood Oxygen Level Dependent functional Magnetic Resonance Imaging). Oxyhemoglobin and deoxyhemoglobin have different magnetic susceptibilities and changes in the magnetic susceptibility of a volume element in the brain can be measured real-time by the appropriate fMRI technique. When that is done, it is found that the oxyhemoglobin level increases slightly just before and during electrical activity in a particular brain region (usually but not always I will discuss why later). That increase in oxyhemoglobin is due to acute vasodilatation which acutely increases blood flow local to the vasodilatation and close enough to where there is neural activation that the vasodilatation is used as a surrogate for neural activation.

    What regulates acute vasodilatation is NO. NO activates sGC (at ~nM/L levels) sGC then makes cGMP which relaxes smooth muscle and causes vessels to dilate. What one is actually measuring in BOLD fMRI is where the NO level is acutely high enough to acutely activate sGC and cause vasodilatation (this physiology is not appreciated by many researchers who use the BOLD fMRI technique).

    It turns out that NO at nM/L concentrations does other things in the brain, such as inducing long term potentiation and long term depression. NO regulates the activity of a lot of voltage gated channels too, the channels that are responsible for the propagation of an action potential. I suspect that what the little puff of NO is doing is changing the probability of activation of a downstream neuron, probably increasing it. To meta-program the brain, the brain sends a puff of NO to the region that is needed to be activated and then action potentials propagate into that region and cause activation (or not) depending on the actual connections.

    As I mentioned earlier, the BOLD fMRI technique does not always reflect neuron activation. Even in a highly activated volume element, most neurons are not activated. The brain doesn’t have the metabolic capacity to activate every neuron simultaneously. That is a seizure and seizures often result in metabolic stress and the “pruning” of the most metabolically challenged neurons. I see that as a “feature” to reduce metabolic demand and reduce the likelihood of future seizures and metabolic overload.

    There is recent data on monkeys where repeated visual stimuli elicited a BOLD fMRI response when a stimuli was expected but not provided. I think the puff of NO is simply enabling the action potential to propagate into that volume element where it can achieve a computation. If the action potential doesn’t propagate into the volume then there is no activation.

    I have a somewhat different perspective of autism (which I discuss at length on my blog), but one which is consistent with all the good data that there is. ASDs are not a “disease” any more than being short is a “disease”. ASDs are a property of a phenotype, not a genotype, exactly the same way that being short is a property of a phenotype not a genotype. There are genes that will tend to make one taller or shorter, but if you are sufficiently nutritionally deprived you will be short irrespective of what genes you have.

    Just as there are two types of neuronal connectivity that are important in brain function, those two types of connectivity are important in ASDs (and all other neurological properties). It is the connectivity that determines all properties of a neural network.

    NO is a major determinant of actual and functional connectivity. NO can exert signals between neurons even in the absence of a synapse. Many growth factors have effects mediated through NO. Low NO does cause neuronal hyperplasia in experimental animals. Social deprivation does cause low NO. Many of the social pathways are necessarily coupled to NO status.

    My hypothesis is that low NO in utero causes the characteristic neuroanatomy of ASDs, smaller and more numerous minicolumns (minicolumn number is set ~6 weeks gestation). This also epigenetically programs the brain to have a lower basal NO setpoint (by reduced expression of NOS containing neurons). If the NO level is too low, then the brain can’t achieve a sufficient level of functional connectivity to work properly. All natural neural networks self-regulate in the near percolation threshold, where the properties of the network change exponentially with changes in connectivity. That is there is an exponential increase as the percolation threshold is approached. There is also an exponential decrease as the percolation threshold is moved away from.

    This explains the characteristic observations of people on the autism spectrum. Stress causes NO levels to drop, and when the brain falls below the percolation threshold, the functionality collapses exponentially. In people with ASDs this is called having a melt-down. Because the social and communication pathway require more NO for appropriate functionality, they are the functions of the network that get disrupted first. People with ASDs are already closer to the percolation threshold (that is responsible for some of the savant abilities) than are NTs, so they are more sensitive to stress induced disruption. Stress can even make NTs more capable, provided that they don’t fall below the percolation threshold (in which case they get hit very hard with delusions and psychosis (as in PCP and stimulant drug of abuse-type psychosis), they don’t have the experience or the neuroanatomy to deal with it the way ASDs can (i.e. via stimming)). This also explains the difference between ASDs and NTs in their reaction to acute fevers. There is a paper by Zimmerman in Pediatrics (2007) where he showed that during acute fevers people with autism have improved behaviors, and that these improved behaviors go away when the fever resolves. I have a very long discussion of this on my blog. If you are below the percolation threshold, more NO moves you closer to it and improves the functionality of your neural network. If you are above the percolation threshold, more NO moves you away from it and degrades your functionality.

    I see the multiple genetic “causes” as affecting ASDs through the final common pathway of lower NO. A very good example is Rett Syndrome. This is caused by deletion of the MeCP2 gene which is on the X chromosome. Males only have one X chromosome so it is virtually always fatal in utero for them. Females have 2 X chromosomes and one of them is randomly inactivated during differentiation. MeCP2 codes for a protein that is important in reading out the DNA methylation that is important in the epigenetic programming of cells. The physical symptoms of Rett Syndrome are consistent with low NO. I suspect this occurs via metabolic stress, that because RS females are mosaic, with organs composed of cells with different epigenetic programming and readout of that programming, the cells in those organs cannot work “in sync”, that is they are not epigenetically programmed to function “the same” and so they may at times work less efficiently or even at cross purposes. A final common pathway of any kind of stress is low NO. I think that is how some of the various single gene disruptions that are associated with ASDs exert their effects.

    There are two types of connectivity that are important. The neuroanatomy is only slightly plastic in adults. The functional connectivity is highly changeable. My hypothesis is that raising the basal NO level will improve the functional connectivity of people on the autism spectrum and will have positive effects similar to what Zimmerman observed in fever. It can’t change the neuroanatomy, that is essentially immutable, so it isn’t a “cure”. It should improve the functionality of people on the spectrum.

  5. superdaveon 30 Apr 2009 at 2:51 pm

    If AoA really knew what they were doing, they would be all over this..but not a word from

  6. superdaveon 30 Apr 2009 at 3:06 pm

    Ah I spoke too soon. They essentially completely refute these findings. I don’t understand why. Shouldn’t any new information about autism be a good thing. It’s so clear that they have let their anti vaccine bias cloud their objective to help kids with autism.

  7. Karl Withakayon 30 Apr 2009 at 4:08 pm

    “The challenge for future research will be to establish which of these findings can be well-replicated in independent samples and by independent labs;”

    How refreshing to see such a reasonable, guarded statement. I’m too used to seeing alternative medicine studies that make huge leaps of logic/faith in their conclusions, or try to explain away any negative findings because they don’t match their preconceived beliefs.

  8. daedalus2uon 30 Apr 2009 at 4:36 pm

    Just to respond a little more to lurker’s question, there are multiple lines of research that implicate reduced functional connectivity in autism. Cassanova’s work does support that finding pretty well. ASD brains do have more cells, but they are smaller and with fewer long range connections and more short range connections.

    fMRI connectivity studies also implicate reduced long range connectivity in ASDs (they have smaller “volumes of interest” (that is volumes that show up as activated by fMRI).
    What is considered “long range” and what is “short range” makes a big difference. Connections inside a minicolumn are short range and are much smaller than what can be picked up by fMRI (and so far, every other in vivo measurement technique). Actual connections can be measured post mortem, but that tells you nothing about what the functional connectivity was (which is likely even more important).

    Research on sensory stuff in ASDs (in general) shows higher sensitivity and greater discrimination ability implying higher levels of sensory computation power. Sensory stuff requires pretty simple short-range connections, not complex long range connections required for very complex behaviors (such as language and communication which require emulating another human’s mental processes).

  9. Steven Novellaon 30 Apr 2009 at 4:36 pm

    Karl – you are right. This is typical of real scientists, and it is glaring when cranks and quacks wildly overstate their claims or have no self-skepticism.

  10. lurkeron 30 Apr 2009 at 5:23 pm

    Thanks you for your explanations; while I’m not familiar enough with the autism neuroimaging literature with the only paper I’m very familiar being this one:

    Koshino H, Carpenter PA, Minshew NJ, Cherkassky VL, Keller TA, Just MA.
    Functional connectivity in an fMRI working memory task in high-functioning autism.
    Neuroimage. 2005 Feb 1;24(3):810-21. Epub 2004 Nov 24. PubMed PMID: 15652316.

    It support a long range functional connection but I remember there being other papers supporting short range functional connections (which isn’t necessarily a deficit if the task reaction time is shorter…)

  11. daedalus2uon 30 Apr 2009 at 6:18 pm

    That paper does support to some degree the idea of underconnectivity in autism. But in that paper the stimulus was thinking about a letter, which is a pretty simple stimulus and may not be that different between the HFA group that they studied and the controls.

    In a later paper by the same group


    They looked at functional connectivity while looking at faces and pretty clearly showed reduced connectivity in autism. Impaired face recognition is a classic symptom of autism and is something that requires pretty complex computation, particularly when communication information is trying to be extracted from it. The brain volumes activated in the ASDs and controls were very different both quantitatively and qualitatively.

    What is quite interesting about this paper is that it shows that people on the spectrum process faces more as objects than as devices for communication. The differences in autism go beyond a simple problem of reduced connectivity, it also relates to what parts of the brain are being connected. In other words, the types of computation the brain is trying to do on the visual data stream is different for people with autism (process it as an object) vs. people who are NT (process it as a communication medium).

    Deciding whether to process a visual data stream as an object or as communication is a very high level and very complex computation process. A complex and specific effect most likely has a complex and specific cause. I think this points away from ASDs being due to a purely “pathological” genotype and more to them being a particular developmental outcome, a phenotype that is supported by multiple genotypes.

    My hypothesis is that being on the autism spectrum is a fundamental aspect of being human, and that every human genotype will support multiple phenotypes that are more or less autistic depending on the developmental pathway that genotype develops on. I try to expand on this in my theory of mind vs. theory of reality blog. Perceiving faces as objects (prosopagnosia or face blindness) is due to having too “strong” a theory of reality. Processing objects as faces (pareidolia) is due to having too “strong” a theory of mind.

    Being able to perceive things that others cannot might be an excellent survival feature. There is the saying that in the land of the blind; the one-eyed man is king. I would add the caveat provided the blind people don’t kill him first.

  12. Khym Chanuron 30 Apr 2009 at 7:40 pm

    Yeah, AoA insisting on no genetic component to autism doesn’t make much sense, since if autism was 100% environmental and 0% genetic, then wouldn’t their theory for autism-caused-by-vaccines call for a lot more than 1 in 150 children being autistic? Why not say “Aha, these must be the genes that are triggered by vaccination”?

  13. rc_mooreon 30 Apr 2009 at 10:16 pm

    Why not say “Aha, these must be the genes that are triggered by vaccination”?

    You need to look for the underlying premises of people who turn to psuedo-science to find the answer to this question.

    Anti-vax parents of autistic children do not really care whether vaccines cause autism or not. What they care about is that they are not the cause of there child’s disability.

    Many of us (including myself) have children we have passed genetic problems onto. Why do the anti-vax parents fight this fact so much?

    It could be an obsession with perfection, my favorite theory is that it relates to the religious Problem of Evil. Genetic disorders defy any appeal to free will or resource allocation when attempting to answer why a benevolent God would allow evil in the world.

    If those stymied by this problem can move the issue from genetics to humans making bad decisions, they can resolve the conflict.

  14. Doctor Evidenceon 01 May 2009 at 12:59 am

    “To meta-program the brain, the brain sends a puff of NO to the region that is needed to be activated and then action potentials propagate into that region and cause activation (or not) depending on the actual connections.”

    man that’s wild. I wonder if this is a simplistic
    mechanism (just looking ahead with a flashlight)
    or if there’s a more sophisticated ‘heuristic’ to
    powering things up. Also curious what a typical
    neuron activity rate is for a region (like 10% or

    (all other entries here have also been fascinating)

  15. eiskrystalon 01 May 2009 at 3:42 am

    One thing i don’t understand about this line of research is why the autism spectrum was not differentiated more in the lab.

    I can see it being a useful tag for basic diagnosis, but I would have predicted that finding a group of 10,000 with similar dysfunction would have yielded a higher gene influence and less genes being involved (ie less science work and more obvious effect). Thus avoiding the dreaded statistical noise.

    or is it simply that we are still very much in the infancy of autism analysis techniques and generating leads instead of answers is more important at this point in time?

  16. Steven Novellaon 01 May 2009 at 7:57 am

    eiskrystal – I tried to answer that above. The human brain is complex, especially when you are talking about higher cortical functions. Subtle changes in neuronal function or organization can have significant effects. There are thousands of subtle changes that can combine in complex ways to create an array of cognitive effects.

    Clinically the best we can do is define broad categories of types of problems. But all such categories have overlap, are very heterogeneous, and are fuzzy at the edges.

    Also, further remember that the single gene disorders have largely been defined. We have already picked the low-hanging fruit (although new variants and mutations are being discovered all the time, we have at least defined the clinical entities).

    Now we are working on the more complex disorders, where dozens of genes are interacting with environmental variables to create a spectrum of effects. That this kind of genetic analysis can find any solid correlations – and these correlations make sense physiologically, is a very powerful indicator that researchers are on the right track.

  17. daedalus2uon 01 May 2009 at 9:44 am

    Doctor E, there is nothing simple about nitric oxide physiology. No system comprising thousands of coupled non-linear parameters can be thought of as simple or simplistic. I don’t know what proportion of neurons normally fire when a volume element is activated. It is variable. I suspect it is around 0.01% at any given moment, but which ones are firing will change as the signals propagate around.

    Autism and ASDs are extremely heterogeneous. The only defining characteristics are behavioral, they can only be diagnosed behaviorally which requires observation and interpretation by a human clinician and so is inherently subject to bias.

    There is some relatively recent research with the objective of trying to better differentiate individuals with autism and autism-like conditions.


    What I find very interesting is that the identifiable syndromic cases of autism (where a genetic or teratogenic cause is known) are essentially all of the complex type, they exhibit dysmorphic features. I think this reflects a fundamental difference between the (at least two) types.

    I think that what they consider to be “essential” autism is (mostly) autism without an underlying genetic or developmental “abnormality”. I am using abnormal in the sense of the developmental pathways working “properly”, as when thalidomide or other teratogen causes autism (although thalidomide does cause dysmorphic features). This level of diagnostic sensitivity and differential diagnosis hasn’t made it into the genetic studies yet. The people doing the gene studies on autism are gene experts with access to equipment and procedures to do massive amounts of sequencing and DNA analysis. I think there is considerable (and naive) hubris among such researchers as to how easy physiology will be to understand once the genes have been identified. Things like the weather are known to be inherently chaotic and inherently unpredictable. Physiology is many orders of magnitude more complicated than is the weather.

    The concept of normal vs. abnormal development I am trying to express is difficult to articulate because the underlying normal physiology can support both good and bad outcomes (depending on the setpoint). The setpoint can be skewed by environmental influences. The sensitivity of the setpoint to being skewed is going to have a genetic influence, but there are many hundreds of thousands of different setpoints in physiology. Once a developmental pathway has been gone down, there may be no way to go back and change the outcome (or there may be back-up pathways that can correct previous errors).

    In any feedback regulated system that is not working right you can have good regulation around a bad setpoint or bad regulation around a good setpoint. I think essential autism is good regulation around a bad setpoint and complex autism is bad regulation around a good setpoint (although this is a very simplistic analogy). Nitric oxide is a major signaling molecule, and every pathway that is regulated by NO has the basal NO level as part of that signaling pathway. Changing the basal NO level will change the “setpoint” of every NO mediated feedback loop. There are many thousands of feedback loops regulated by NO, many of them important during development, many of them important in neurodevelopment, many of them are known to be skewed in a characteristic direction (in the low NO direction) in autism and autism-like disorders.

    An example of good regulation around a bad setpoint is anaphylaxis. Anaphylaxis is bad because it can easily kill you. But in the “wild”, if you had bacteria in your blood stream the only chance you would have to survive would be with a massive immune system activation that could easily kill you, i.e. anaphylaxis. Anaphylaxis isn’t a “bug”, it is a “feature”. Evolution has configured the immune system to minimize the sum of deaths due to insufficient activation (infection) and from too much (anaphylaxis). Every evolved feature is going to reflect this trade-off. If a feature is important enough and complex enough it will exhibit complex trade-offs. The immune system is complex enough, and there are many disorders of the immune system, for example allergies. The recent increase in allergies and asthma is not due to genetic effects, it is due to environmental effects. The immune system developmental and regulatory pathways are working properly; they are just working to a bad setpoint. It isn’t the regulation of the immune system that is bad; it is the setpoint that the regulatory pathways are trying to achieve. Anaphylaxis is good regulation around a bad setpoint.

    If you looked at anaphylaxis only as a disorder, and tried to understand it genetically, it would look a lot like the genetics of autism (my hypothesis). There would be many genes involved. There would be some clustering in families. You would never be able to isolate a single genetic “cause” of anaphylaxis because anaphylaxis is a normal property of an evolved immune system. If you weakened the immune system such that it couldn’t support anaphylaxis, then you would have a weak and crappy immune system that couldn’t protect against many infections. You would find associations with genes for the major histocompatibility complex, genes involved in antigen processing, genes that turn the immune system on and genes that turn it off. You would find genes that influence the myriad “setpoints” involved in immune system activation and suppression. You might think that you were making progress because you were finding associations with genes involved in the immune system, but (my hypothesis) that would be a mirage. The ability to support anaphylaxis is an inherent and immutable and emergent property of an evolved immune system that is good enough to protect against infection. Similarly (my hypothesis) the ability to support multiple phenotypes along the autism spectrum, the trade-off of theory of mind vs. theory of reality is an inherent and immutable and emergent property of the neurodevelopment of a human brain.

  18. Doctor Evidenceon 01 May 2009 at 11:20 am

    Neat! and somewhat “Hofstadter-ian”

  19. HHCon 01 May 2009 at 12:53 pm

    daedalus2u, I’m following your discussion. Would you say that an autistic individual goes into a type of anaphylactic shock when mentally processing sensory information for which a mental category has not been formed yet? Hence, the individual will scream and exhibit other overt behaviors when exposure to new stimuli occurs?

  20. artfulDon 01 May 2009 at 3:10 pm

    How about when the mental category is already there and waiting for the required sensory information to activate its function, except that the inferential system that translates the sensory data is out of order?

  21. lurkeron 01 May 2009 at 5:34 pm

    HHC and artfulD, I don’t think there’s any explicit processing or categorization done on noisy stimuli having the potential to upset me (closest example I can think off is the heavy street repair machinery…) and I also doubt that autistic of any kind have very different auditory cortex compared to mine.

    This is just my opinion and I don’t have much background to support it but that’s because I’m behind a paywall and can’t any longer access good article regarding the auditory cortex of autistic (I was working in a lab before and doing research on auditory cortex).

  22. lurkeron 01 May 2009 at 5:55 pm

    to add to my previous comments, autistic’s perception is fine

    The level and nature of autistic intelligence.
    doi: 10.1111/j.1467-9280.2007.01954.x (free download: http://psych.wisc.edu/lang/pdf/Dawson_AutisticIntelligence_PS_2007.pdf)

    Enhanced perceptual functioning in autism: an update, and eight principles of autistic perception.
    doi: 10.1007/s10803-005-0040-7

    Can spectro-temporal complexity explain the autistic pattern of performance on auditory tasks?
    doi: 10.1007/s10803-005-0043-4

  23. artfulDon 01 May 2009 at 6:03 pm

    The autistic brain retains the predictive apparatus that depends on signals that should allow it to make such predictions, and frustration results when certain of these signals are unitelligable or their pathways obstructed.

    Example: The mechanism is in place to react to perceived intentionality of any natural force, especially those whose intentions have been most controlling. But the system that discerns intentions in facial expressions can be out of whack. Which seems to be why some autistics will not look at faces – it interferes with their concentration on other more meaningful signals – accessible through their better understanding of more overt body language.

  24. lurkeron 01 May 2009 at 6:37 pm

    you’re operating at the level of cognition and I do admit that we have a fair share of difficulty there. Now for your example, I am not able to look at face (to be specific, the eyes) because they give too much information which result in a slight fear and that impede other process (like actually hearing what the person say). Keep in mind the order at which cognitive process happen:

    sensation –> perception –> cognition.

    With enhanced perceptual functioning (please do read the papers I mentioned in my previous post), we’re bound to pick up a lot more signal and noise from the environment and this will have an impact on our cognition (the effects which are well discussed here in this thread).

  25. artfulDon 01 May 2009 at 7:15 pm

    The perception is where the inferential process gives meaning to the sensation which then becomes part of the data from which the predictive apparatus gives direction to the organism involved, human or otherwise.
    “Too much information” as you put it translates into more information than the type you can ascribe meaning or purpose to, with the rest at the same time having less meaning or purpose than you instinctively expect from that source.
    But I do appreciate the references and will follow up as time permits.

  26. HHCon 01 May 2009 at 8:26 pm

    lurker, I am not quite sure whether your heavy street machinery repair example deals only with the primary auditory cortex, and/or the “sensory cortex,” or the “psychic cortex”.

  27. artfulDon 01 May 2009 at 10:28 pm

    Perception \Per*cep”tion\, n. [L. perceptio: cf. F. perception. See Perceive.]

    1. The act of perceiving; cognizance by the senses or intellect; apperhension by the bodily organs, or by the mind, of what is presented to them; discernment; apperhension; cognition.

    2. (Metaph.) The faculty of perceiving; the faculty, or peculiar part, of man’s constitution by which he has knowledge through the medium or instrumentality of the bodily organs; the act of apperhending material objects or qualities through the senses; — distinguished from conception. –Sir W. Hamilton.

    Matter hath no life nor perception, and is not conscious of its own existence. –Bentley.

    3. The quality, state, or capability, of being affected by something external; sensation; sensibility. [Obs.]

    This experiment discovereth perception in plants. –Bacon.

    4. An idea; a notion. [Obs.]

    –Sir M. Hale.

    Note: “The word perception is, in the language of philosophers previous to Reid, used in a very extensive signification. By Descartes, Malebranche, Locke, Leibnitz, and others, it is employed in a sense almost as unexclusive as consciousness, in its widest signification. By Reid this word was limited to our faculty acquisitive of knowledge, and to that branch of this faculty whereby, through the senses, we obtain a knowledge of the external world. But his limitation did not stop here. In the act of external perception he distinguished two elements, to which he gave the names of perception and sensation. He ought perhaps to have called these perception proper and sensation proper, when employed in his special meaning.” –Sir W. Hamilton.

    Source: Webster’s Revised Unabridged Dictionary (1913)

  28. maliathon 02 May 2009 at 1:45 am


    How would you respond to the following published studies which show higher basal plasma NO levels in autistic patients:


    Those are the unique identifiers. All studies were accessed from Medline via Ovid.


  29. daedalus2uon 02 May 2009 at 8:01 am

    Grant, None of those studies measured NO levels, they all measured the terminal metabolites of NO, nitrite and nitrate. Measuring the terminal metabolite of NO tells you something about NO/NOx physiology, it tells you nothing about what the NO level is in any particular tissue compartment. Trying to infer NO levels from nitrite and nitrate levels would be like trying to infer oxygen levels from its terminal metabolite CO2 or H2O. It is simply an approach that is not appropriate.

    NO levels in blood specimens measured in vitro are not a useful measure of anything. Hemoglobin is the normal sink for NO, and takes up NO so rapidly that the half life of NO in whole blood is much less than a second (but that half life is concentration dependant). Unless you took extremely elaborate steps to measure the NO level before the NO was taken up by hemoglobin, any measurement of NO would not reflect what the NO level was in vivo.

    Quite a good paper on NO is


    It touches on some of the richness and complexity of NO physiology so far as it is currently known. It is pretty clear that there is a lot that is not well understood about NO physiology and so the picture can only get more complicated. I think at least a few orders of magnitude more complicated, but I am one of the few NO researchers who embrace the complexity of NO physiology even though there are no techniques yet to measure them. The levels of NO that are important in autism are in the nM/L range. There are no techniques to measure these in vivo at the length (sub cellular) and time (sub second) scales that are known to be important.

    You can infer NO levels in the endothelium by the state of vascular tone, and how vascular tone is affected by the infusion of NO donors. People with hypertension, obesity, and all the other low NO disorders have what is called “reduced vascular reactivity”, that is when NO is infused, their vessels do not respond as much as individuals with a normal vascular reactivity. My inference is that their basal NO level in the endothelium is lower, so it takes more exogenous NO to raise the NO level to the point where it activates sGC and causes vasodilatation. I think this is what is being observed in the BOLD fMRI results.

    Autism is a state of oxidative stress. A state of oxidative stress is a low NO state because the primary compound of oxidative stress, superoxide, destroys NO at diffusion limited kinetics. It is not possible to have high levels of superoxide and NO simultaneously. One can have high levels of one or the other, and which ever one is more abundant will destroy the one that is less abundant. Switching between a state dominated by NO to one dominated by superoxide is a generic stress response. Essentially every kind of stress will do that, and the low NO state then primes physiology to respond to the stress, for example low NO makes mast cells more sensitive to degranulation, low NO in effect increases the “gain” on the immune system by also disinhibiting NFkB.

    Essentially all the physical symptoms of autism are consistent with a lower level of NO, but it takes a sophisticated understanding of NO physiology to appreciate that.

  30. Esattezzaon 02 May 2009 at 9:40 am

    Daedalus, first of all, I’ll admit I’m out of my league here (*raises hand* lowly grad student, party of one) but your NO theory, while incredibly interesting (and more incredibly something I haven’t heard of before) seems a bit premature to call. Obviously, you’re the expert.

    In fact, you say:
    “Essentially all the physical symptoms of autism are consistent with a lower level of NO, but it takes a sophisticated understanding of NO physiology to appreciate that.”

    But, come on, don’t play THAT trump card. Throughout your posts, your reasoning is sound and you provide support, but I’m just saying, that last statement sounds a bit too much like the line the anti-vaxers use about thimerosal: “the characteristics of autism are essentially mercury-poisoning”.

    All I’m saying is be careful before you start thinking this is a magic bullet for improving autism symptoms. I’m only warning you because I have admired the logic and information that you’ve presented in other posts and I’ve found that everyone could use a bit of a reality check about the awesomeness of their own area of research. (though yours does seem to be pretty awesome — I’ll be sure to read up on it)

    And now I will go off and hope that your sceenname is not hiding the identity of one of the researchers working at my school, because that would be terribly awkward.


  31. HHCon 02 May 2009 at 4:24 pm

    Read the Quebec, Canada & Wisconsin study. Having tested a zillion persons myself, I prefer the work of A.B. Silverstein, full scale IQ equivalents of sums of scaled scores.

  32. daedalus2uon 02 May 2009 at 5:48 pm

    lurker, the “conventional wisdom” (which happens to be wrong) of autism research is that any difference in ability is a sign of a defect or deficit; even when that difference is ability is superior functionality.

    AD, the “perception” of intentionality when it is not there is a type 1 error, a false positive. NTs are very prone to type 1 errors when they misperceive intentionality by attributing anthropomorphic motivation to inanimate and non-human things.

    That is what pareidolia is, the misperception of a naturally formed object as a deliberate representation of something. It is a type 1 error.

    The classic example is Uta Frith’s work with animated triangles where people with ASDs had a reduced ability to impute emotional states and emotional motivations to the animated triangles. This was called a “deficit” in mentalizing, a deficit in the ASD theory of mind.

    Was this a type 1 error, a false positive, or a type 2 error a false negative? It was neither. It was not an error; triangles don’t have a mental state. There is no “mental state of the triangles” for the ASD individuals to correctly impute. The imputation of mental states to triangles is a type 1 error, a false positive committed on the part of the NTs who imputed emotional motivation to inanimate objects. Applying anthropomorphic thinking to non-human things is extremely common. I think this happens when people inappropriately use their theory of mind to try to think about things for which it doesn’t work, trying to think about non-human things. A theory of mind is only useful for thinking about other sentient entities that share the same theory of mind. It is completely useless for every thing else.

    People who only have a theory of mind to think with are incapable of appreciating this.

    Logical thought, the kind that Dr Novella is trying to promote is not done with a theory of mind. It is done via emulation using a theory of reality.

  33. daedalus2uon 02 May 2009 at 5:52 pm

    HHC, no, I would not characterize a meltdown as any kind of anaphylaxis. Anaphylaxis is actually extremely well controlled. It has to be to turn on and off so many things in just a few seconds. Under the right circumstances, anaphylaxis is a life-saving paradigm to evoke. A seizure might be somewhat analogous, but not really. The only life-saving aspects of a seizure is the ablation of some of the firing neurons to reduce the likelihood of a future seizure. I can’t really think of any circumstances where you would want a seizure, there are plenty where you would want anaphylaxis. In any physiological pathway that is controlled (that would be every pathway) there are circumstances where the control breaks down. Control has not broken down during anaphylaxis. That is can cause death is not because there is anything “broken”. It can cause death because invoking the immune system hard enough and strong enough to be sufficiently responsive can cause death.

    If the neural pathways are incapable of supporting a mental concept, then the idea cannot be thought about. I think this is more of a problem for NTs, who have very large and very elaborate but very specific neural pathways to think their complex but specific NT thoughts. ASDs have neural pathways that cannot support the complexity of the NT thoughts but the pathways are more general and can support more ideas but to a lower degree of specificity.

    When an idea or data stream cannot be identified or mapped into neural structures, there is nothing that the neural structures can do with it. A data stream must be recognizable as something for a computation to be done on it and for an output to be produced.

    Stress, anxiety or distress can’t come from a data stream being unrecognizable; it can only come from the data stream being recognized as something dangerous. I think that can easily happen if ASD individuals are taken advantage of or abused during a period of weakness or confusion. It isn’t the weakness or confusion that causes the distress, the distress is a pre-emptive and conditioned response to the abuse that often follows being weak or confused.

  34. artfulDon 02 May 2009 at 7:51 pm

    “Stress, anxiety or distress can’t come from a data stream being unrecognizable; it can only come from the data stream being recognized as something dangerous.”

    That’s complete nonsense. The unrecognizable is extremely stressful in circumstances when other signaling does not offer the prospect of safety. A very important purpose of signaling is to assess the danger/safety conditions in the surroundings. Absence of signaling sufficient to allow the making of such a distinction can be extremely stressful.

  35. daedalus2uon 02 May 2009 at 8:18 pm

    AD, so when you close your eyes you become extremely frightened? When you are in silence you become extremely frightened? When you are in an odorless environment you become extremely frightened? My experience is that I default to an at rest state. My experience is that most people default to an at rest state unless they have been conditioned otherwise.

    I suppose if your default state was one of high stress and being extremely frightened, then silence might elicit that in you. That is quite an unfortunate circumstance, one that you should try to get treatment for. Defaulting to a low stress at rest state is a lot better.

  36. daedalus2uon 02 May 2009 at 8:22 pm

    Esa, I have a lot of stuff on my blog that relates to NO and autism. There is a lot more that I haven’t blogged about yet, and right now I don’t have access to an internet connection that allows me to post more there. If you change the “2” in my handle to a “4” and then add at yahoo dot com you will get my email address. I can send you some of the posters I have presented which go into more detail.

    My laptop hard drive died and a number of other things are in flux right now. I am not at a university and my institution is quite limited in its capabilities.

    It does take a sophisticated view of things to appreciate that NO is involved in autism. NO physiology is very complex and there are many misconceptions about it, even among senior researchers in NO.

    I completely understand that people are skeptical of what I have to say. So am I. I have a train of logic back to facts in the literature for everything. That is not something that the “mercury causes autism” crowd ever had.

    So far, no one has been able to show me where I am wrong, although many have said that what I am saying can’t be correct because it is “too simple”. There is nothing about NO physiology that is simple. No system of thousands of coupled non-linear parameters can be said to be simple.

    Many people have admonished me as you have to be more circumspect and speak with less certainty of how NO is involved in autism. If I didn’t have multiple chains of facts and logic all coming to the same conclusions I would be. There are “enough” independent pathways leading to the conclusion that low NO is involved in autism that I consider the result to be quite robust. I am not saying that I have a “cure”, simply that some of the symptoms will get better for some people if they increase their NO level (which is very difficult to do and there are no generally recognized ways of doing so). Zimmerman’s fever paper showed that behavioral symptoms can get better with fever. If that is through the mechanism of increased NO from iNOS, then more NO from another mechanism will help too. The hypothesis that low NO is not associated with autism is incompatible with what is in the literature. I am willing to consider that I am wrong, but if I am, then thousands of papers in the literature are wrong too, and will have to be discarded.

    Eventually, people will come to appreciate that I am correct. I appreciate that people are unable to appreciate that now because they haven’t read as much of the NO literature as I have. I know they won’t appreciate it until they understand the details of NO physiology and there are a lot of details. Getting up to speed in this particular field is not easy because there is a lot of wrong stuff in the literature about NO. Why there is wrong stuff in the NO literature is complex. A lot of it relates to how technically challenging the field is. NO species are quite reactive by multiple mechanisms and many of the active species are extremely labile and cannot be isolated. A lot of free radical reactions are important. Free radicals react with NO with essentially diffusion controlled kinetics. Some researchers with big egos jumped to some wrong conclusions and find themselves unable to consider that they are wrong. The idea that nitrated proteins is a sign of too much NO is a wrong idea. The papers claiming higher NO levels in autism based on measurements of nitrite and nitrate in plasma are not atypical. The conclusion that there is higher NO in autism is simply wrong based on a flawed test. Essentially all of the papers claiming that too much NO is bad are wrong and are based on flawed understandings of NO physiology. Too much NO can be bad, but the only time that happens is during sepsis (where too little NO is worse).

    It has been said that it takes about 10,000 hours of study to become expert in a field. I have about 20,000 hours in NO physiology. I read very fast, I am not quite hyperlexic and have access to a pretty good library. I am trying to get others in the autism field up to speed in NO physiology, but until they appreciate how important it is, they won’t spend the time to understand it. With wrong papers saying that NO is high in autism non-experts mistakenly think that NO physiology is not a fruitful avenue of research in autism. I am more than happy to try and bring people up to speed in NO physiology and how it relates to autism (and to everything else). That was why I started blogging and why I spend so much time putting comments on blogs.

    The “mercury causes autism” and the “vaccines cause autism” crowd has really poisoned research looking for environmental effects. The “curbies” have too. The reason that there are so many quack treatments for autism is precisely because it is caused by low NO. That makes it particularly sensitive to the placebo effect (which increases NO levels). The “genes cause autism” has sucked all the research funding away from other potentially fruitful avenues. That effort is not wasted, we do need to understand the genes associated with autism, but my own belief is that an understanding of autism (and treatments for it) will not come from genetic studies.

  37. artfulDon 02 May 2009 at 9:24 pm

    When anyone (you being a self-identified exception) closes their eyes, they do so when they have made an assessment that they can do so safely. Even then, and even in a sleep state, the sensory apparatus is still receptive to any signals that safety is in danger of being compromised.

    Perhaps if your default state is a complete lack of attention to the outside world, it’s because you exist in some form of cocoon.

    I am not autistic. I am confident my signaling apparatus works and therefor I am not distressed by the uncertainty that would arise if I found that it didn’t, or that I suddenly couldn’t read faces or draw other necessary inferences from sights and sounds around me.

    I’m not sure why you also alluded to experiencing a state of rest in an odorless environment. But perhaps that cocoon has a smoke alarm?
    For a guy that expressed a fear of looking into the “black box” of his emotional brain, you are certainly calm about what your “experience” tells you is in there.

  38. daedalus2uon 03 May 2009 at 7:15 am

    AD, you are using sloppy thinking.

    The absence of a signal is the absence of a signal. All that can be imputed from it is that there is no signal. Organisms may be conditioned to associate the presence or lack of any environmental stimuli with danger or pain, and be conditioned to respond accordingly to the loss of a signal. That is a conditioned response, not the default response of a normal organism.

    The sensory apparatus does remain receptive to signals during sleep, and if no signals arrive, the default state is to remain at rest and asleep. That is what I was saying.

    Many people have been conditioned to respond to ideas they do not understand with fear, anxiety and then attack those who have expressed the ideas they do not understand. This is an extremely common response. I do not think it is a default response, I think it is a conditioned response that is learned. When I come across a concept that I do not understand, I try to understand it. I don’t blame the concept and attack the person who expressed it.

    I agree with you that too many individuals do respond with fear and anxiety and attack those who express ideas that are not understood. That is why Dr Novella is attacked for his informed, reasoned and logical analysis of many subjects. I have great empathy for people such as Dr Novella who are attacked for inconvenient ideas, especially when those ideas are correct.

    People with ASDs are not distressed that they can’t read faces. They are distressed when they are attacked by NTs because they can’t read faces.

  39. artfulDon 03 May 2009 at 1:33 pm


    Absence of a signal in a functional signaling apparatus means one thing – but absence of an understandable signal when the brain cries out for one is an entirely different matter.

    You write: “Organisms may be conditioned to associate the presence or lack of any environmental stimuli with danger or pain-”

    That is as wrong as wrong can be. The essence of biological life is contained in its signaling apparatus, and no such forms would survive from day one without this most basic “instinctive” capacity to feel a form of pain and associate it with avoidance of the source.
    It’s in the “genes” just as autism now appears to be. Go read some Damasio and forget about the NO obsession for the nonce.

    The conditioning you refer to is part of a learning process that could not occur without the instinctive process being the foundation for that learning. Discernment is the nature of what is being learned.
    You’re going to tell me now that cellular life can’t learn except you’ve already claimed it can be conditioned. An inability to discern the “meaning” of signaling, which by the way never stops until life stops, can stop that life from functioning at all.

    Autistics function because they exist under the protection of social groups. The group dynamic supplies the discernment that allows them to grow and hopefully prosper. In a way the frustration that you deny exists is a signal crying for help with that discernment.

  40. maliathon 03 May 2009 at 5:13 pm


    You responded to the studies I posted by making an outright claim that measurement of nitrate/nitrite in plasma is not appropriate for measuring levels of NO. You followed that statement by reasoning that plasma nitrate/nitrite levels would not tell you specifically where the raised nitric oxide originated. So which is it, are they not reliable because they simply don’t tell you, or because they don’t tell you where it came from? Then, you made a false analogy to oxygen metabolism and using CO2 as a measurement tool. We’ll take each claim separately

    Just to be clear, nitrate/nitrite IS a reliable tool for measuring raised levels of NO:


    Your claim that elevated NO can arise from different parts of the body is absolutely true. However, the original studies I posted compared autistic children against controls. In order to refute the conclusion, you would have to say one of two things:

    1) The studies have selection bias. The autistic children that were chosen have other disease states that are leading to raised NO levels

    2) Autism leads to elevated NO, but it is being created outside of the brain and has nothing to do with the neurological states.

    The first option is a bit absurd. The second one is still possible. It may be the case that autism leads to greater NO accumulation for reasons totally outside of the brain.

    Where is it you conduct your research?

  41. maliathon 03 May 2009 at 5:24 pm

    Also, just to be clear, I am not claiming that raised NO is a cause of symptom of autism. Also, I am not claiming that therapy with NO would not help autism.

  42. weingon 03 May 2009 at 5:47 pm

    I wonder what role these genes play in face recognition.

  43. DevilsAdvocateon 03 May 2009 at 6:37 pm

    I can’t believe you all just keep on blogging and posting right in the middle of the NHL play-offs. Priorities, people, priorities.

  44. daedalus2uon 03 May 2009 at 8:27 pm

    None of the 3 papers you link to state that nitrite plus nitrate is a good measure of NO concentration. What they say is that it is a good indication of nitric oxide synthase activity which I agree with. Nitric oxide concentration and nitric oxide synthase activity are not identical. They do not say that nitrite plus nitrate is a good measure of NO level because it is not.

    There are 3 independent parameters that are needed to describe nitric oxide; nitric oxide concentration, nitric oxide production rate and nitric oxide destruction rate. If the concentration is not changing, then the production and destruction are equal. If the production rate and the destruction rate are equal, then the concentration that occurs is completely independent of the production rate.

    Look at the paper by David Wink.


    It is quite good. There are multiple different levels of NO that are important in different cellular compartments, from nM/L to microM/L. These occur simultaneously.

    I have no dispute with the data that those authors presented. My disagreement is with their interpretation. I have no reason to suspect selection bias. The research seems competently done. The major confounding factor in plasma NOx measurement is dietary nitrate and serious infection. If they avoided those, then their measurements are very likely accurate. What is not competent is how they confuse plasma nitrite and nitrate as being equivalent to NO. They say it enough times in what they write that it doesn’t seem like they are just being sloppy. This is a common confusion that many researchers have.

    There can be a high production rate of NO, but if there is a high destruction rate (by the superoxide produced as a consequence of a state of oxidative stress) then the concentration of NO can be low. If the destruction rate is high enough to cause a low concentration, then the production rate doesn’t matter.

    All the NO signaling pathways depend on the NO concentration, not the NO production rate. It is changes in the NO concentration that affect the NO pathways, not changes in the NO production rate that are matched by changes in the NO destruction rate.

  45. artfulDon 03 May 2009 at 8:54 pm

    daedalus2u wrote:
    “People with ASDs are not distressed that they can’t read faces. They are distressed when they are attacked by NTs because they can’t read faces.”

    But here’s someone that put the lie to that better than I ever could:


    ‘The renowned autism expert Tony Atwood is fond of putting it this way: “Autism is anxiety looking for a target.” Autism and anxiety go hand-in-hand. Autism affects a person’s ability to communicate with others or to understand the world around him, and that’s bound to cause anxiety and panic sometimes.’

  46. maliathon 03 May 2009 at 9:28 pm

    You’re right, I should not make the claim that NO metabolite concentration is identical to NO concentration, because it isn’t. Although, in most cases it works well in predicting NO concentration. The first three papers I posted showed that measurements of NO metabolites were elevated in autistic patients (among other things, including adrenomedullin). The second three papers I posted showed that NO metabolites are a reliable indication of NO synthase activity.

    The papers suggest that constitutive production of NO in patients with autism is high. So, what reason do we have to suspect that the rate of destruction of NO in these patients is also abnormally high? What reason do you have to believe that in actuality, the basal level of NO is low? Furthermore, if the increased concentration of metabolites is due to change in nNOS, then localized effects could be exerted very quickly. Here’s a weak, but relevant paper observing polymorphisms in nNOS in autistic patients:


    I understand what you’re saying – maybe we shouldn’t take the results at face value. But, why shouldn’t we?

    Also, when it comes to therapy. Couldn’t we do a simple double-blinded controlled clinical trial? Give half of the child patients a vasodilator nitrate, and the other half a placebo. Your theory would predict measurable results.

  47. maliathon 04 May 2009 at 1:41 am

    I apologize, this is the link I meant to paste:


  48. maliathon 04 May 2009 at 1:50 am

    Ugh. Once again, I apologize. THIS is the study I meant to paste (for real this time):


  49. daedalus2uon 04 May 2009 at 6:25 am

    AD, Tony Atwood would be more credible regarding autism if he actually listened to what people with autism had to say about themselves.


    Linking to an anti-vaccine pseudoscience site, one that advocates chelation for people with autism, doesn’t “prove” anything about autism, other than that you are not as careful as to your sources as you should be.

  50. daedalus2uon 04 May 2009 at 6:37 am

    NOx levels integrate NO production rates over variable time periods.

    We know that the rate of NO destruction in these autistic patients equals the rate of NO production. If the production rate exceeded the destruction rate then NO would accumulate. We know that NO has not accumulated to a few nM/L because these patients do not have systemic vasodilatation. They are not in hypotensive crisis due to systemic vasodilatation. Therefore, their NO level is below a few nM/L and their NO destruction rate equals their NO production rate.

    Nitrate vasodilators are not NO donors. Giving organic nitrates will not increase NO levels. There is some pretty good evidence that nitroglycerine actually reduces NO levels (via complex feedback inhibition), but the effects of GTN are quite complex and not well understood. Viagra lowers NO levels via feedback inhibition and reduces NO mediated pathways not involving sGC (Viagra inhibits the phosphodiesterase that cleaves cGMP which is the effector molecule produced by sGC when activated by NO).

    NO/NOx physiology is under intense regulation. Nitric oxide physiology is extremely difficult to perturb artificially. There are no generally recognized ways of increasing basal NO levels that work long term. Supplemental arginine (the substrate for NOS) doesn’t work long term, physiology compensates and produces arginine resistance. Inhaled NO doesn’t work, the NO is converted to NOx before it leaves the lung. Dietary nitrate can help in the short term. There is some thought that the health effects of green leafy vegetables is from the nitrate they contain (a few thousand ppm). The only way I know is with the bacteria I am working with. None of the other methods work long term.

    If you look at the actual signaling pathways that are perturbed in autism, those that involve NO are all perturbed in the direction you would expect if the basal NO level was lower. Because there are no barriers to NO diffusion, all NO sensors only sense the sum of NO from all sources. The basal NO level is important in all pathways that involve NO, and changes to the basal NO level affect those pathways with no threshold (there is no threshold because NO is already in the active range where any change affects the output). Low NO is consistent with neuroinflammation, sleep disorders, neuronal hyperplasia, oxidative stress, cardiac hypertrophy, the gender bias, increased anxiety, and a lot of other things.

  51. maliathon 04 May 2009 at 7:07 am


    “We know that the rate of NO destruction in these autistic patients equals the rate of NO production. If the production rate exceeded the destruction rate then NO would accumulate. We know that NO has not accumulated to a few nM/L because these patients do not have systemic vasodilatation. They are not in hypotensive crisis due to systemic vasodilatation. Therefore, their NO level is below a few nM/L and their NO destruction rate equals their NO production rate.”

    The metabolites of NO have accumulated. The fact that they are not in shock due to the NO does NOT mean they do not have a higher basal level of NO. In fact, I suggest you examine the quote from one of the studies I posted earlier (http://www.ncbi.nlm.nih.gov/pubmed/7796509):

    ” … because of the long half-life, nitrate will accumulate in plasma once it is produced. Because of the large volume of distribution (21% of body weight versus the 4% of body weight usually attributed to plasma volume, the compartment in which nitrate is measured), simple measures of plasma nitrate underestimate by a factor of 4 to 6 the actual production of nitrate or NO by the body.”

    Here is another claim you made:

    “Nitrate vasodilators are not NO donors. Giving organic nitrates will not increase NO levels.”

    Delivering nitroglycerine or nitroprusside does indeed increase NO. That’s the mechanism by which they work.

    “There are no generally recognized ways of increasing basal NO levels that work long term.”

    I never said those drugs work long term. But, according to your theory, short term doses would result in beneficial results. No?

    Again, why should we believe those studies are false in their assumption that the NO metabolites do no indicate an increased basal NO concentration? You still have not given a good reason for why this is the case.

    You claim that lower NO concentrations explain the effects of autism. However, we could also postulate other vasodilator mechanisms and the genetic analyses proposed in Novella’s post as possible mechanisms to explain the effects.

  52. daedalus2uon 04 May 2009 at 8:18 am

    Nitrate is not a vasodilator. NO is a vasodilator. Accumulation of nitrate does not cause vasodilatation; accumulation of NO does cause vasodilatation. Vasodilatation is not observed, therefore there is no accumulation of NO. If there is no accumulation of NO, then NO is destroyed at the same rate it is produced. When NO is destroyed it is converted from a species that causes vasodilatation (NO) to one that does not (nitrate).

    The fact that they are not in hypotensive shock does conclusively demonstrate that the level of NO in their endothelium is not elevated. Authentic NO always causes vasodilatation. There is no resistance or accommodation to the vasodilatation produced by authentic NO. The accommodation occurs in pathways outside the NO-sGC-cGMP-vasodilatation feedback loop (usually by generation of superoxide to destroy NO, or asymmetrical dimethyl arginine to inhibit NOS, or arginase to reduce arginine levels). There are other things that can cause vasodilatation too, but authentic NO always does. If you don’t have systemic vasodilatation then you don’t have systemic high NO.

    Sodium nitroprusside is an NO donor. If you could administer SNP you could increase NO levels where ever you injected it. The half life of SNP is only a few minutes. SNP can only be administered in an in-patient hospital setting where it can be administered continuously. Even then, it is not clear that SNP has NO mediated effects remote from the vasculature.

    Glycerol trinitrate causes endothelial dysfunction that is characterized by decreased vascular reactivity. This indicates decreased basal NO in the endothelium.


    The metabolism of GTN is quite complex and is not fully understood. GTN resistance is likely due (in part) to irreversible inhibition of mitochondrial aldehyde dehydrogenase.


    It is well known that GTN is not an NO-donor because it doesn’t behave as an NO donor. If it did, it would not exhibit tolerance. GTN does exhibit tolerance; GTN is not an NO donor. SNP does not exhibit tolerance. SNP is an NO donor.

    Tolerance comes from trying to manipulate a feedback controlled physiological pathway. You can’t regulate a feedback controlled system by trying to manipulate it from the outside without first disabling the feedback. The feedback mechanisms will try to restore the perturbed parameter to the setpoint and will drive themselves to physiological limits to try and do so.

  53. maliathon 04 May 2009 at 8:57 am

    “Nitrate is not a vasodilator. NO is a vasodilator. Accumulation of nitrate does not cause vasodilatation; accumulation of NO does cause vasodilatation. Vasodilatation is not observed, therefore there is no accumulation of NO. If there is no accumulation of NO, then NO is destroyed at the same rate it is produced. When NO is destroyed it is converted from a species that causes vasodilatation (NO) to one that does not (nitrate).”

    As you have repeatedly said, which is 100% true, the half-life of NO is very brief. The vasodilatory effects are short lasting. Increased metabolites of NO indicate increased NO creation. Local synthesis of NO (such as that from nNOS) will create very temporary (and very local) increases in NO, but long term increases in NO metabolites.

    “The fact that they are not in hypotensive shock does conclusively demonstrate that the level of NO in their endothelium is not elevated. Authentic NO always causes vasodilatation. There is no resistance or accommodation to the vasodilatation produced by authentic NO. The accommodation occurs in pathways outside the NO-sGC-cGMP-vasodilatation feedback loop (usually by generation of superoxide to destroy NO, or asymmetrical dimethyl arginine to inhibit NOS, or arginase to reduce arginine levels). There are other things that can cause vasodilatation too, but authentic NO always does. If you don’t have systemic vasodilatation then you don’t have systemic high NO.”

    Again, as you have previously claimed (which is true), the half-life of NO is extremely brief (3-10 seconds). The metabolites of NO, however, accumulate. And, the increased detection of NO metabolites does INDEED say that the basal level of NO is increased. Where the NO is being produced is of question. The studies I linked posit that nNOS might be the source.

    AGAIN, I ask you, where are the NO metabolites coming from in these autistic patients if it’s not from NOS?

    Also, you linked studies concerning the feedback control of NO inducing drugs. My claim was that according to your theory, even short term NO inducing drugs would induce positive, measurable effects.

    From the first study you linked:

    “A major therapeutic limitation inherent to organic nitrates is the development of tolerance, which occurs during chronic treatment with these agents.”

    Did I say chronic use?

    From the second article:

    “Again, we focus on ALDH2 and describe the current controversy on the role of ALDH2 inactivation in tolerance development.”

    Both of these studies address long term use. According to your theory, short term doses would have an effect. In fact, in your blog, you actually address increases in short-term iNOS activity during fever as a possible mechanism by which short term increases in NO can alleviate symptoms of autism.

    So, which is it? Do short-term increases in NO production alleviate symptoms of autism or not?

    And again, I’m not saying doses of NO won’t help. In fact … I really thought it was possible given your explanations. I thought I was throwing you a freakin’ bone by saying that trials involving small doses of nitroprusside and nitroglycerin might help.

  54. lurkeron 04 May 2009 at 9:37 am


    to answer your 01 May 2009 at 8:26 pm question, I cannot even do an educated guess because I used to have severe memory problems (on top of other health problems…) for a few month during this winter and I plan to get back working on this material during the summer.

  55. daedalus2uon 04 May 2009 at 10:32 am

    The NO metabolites are coming from NOS, but the NO metabolites can be increased without an increase in the NO concentration.

    During hypoxia there is increased production of superoxide. Superoxide is an O2 metabolite. Does increased superoxide indicate increased O2? It can, hyperbaric O2 will reliably induce seizures and death from increased oxidative stress. Hypoxia also causes oxidative stress. Oxidative stress is a controlled physiological state with multiple feedback mechanisms turning in on, turning it off and regulating it.

    If you have a thermostatically controlled water bath, set for 50 degrees C, and you put ice in it, the temperature will drop and the heater will turn on. So long as there is ice in the bath, the temperature will be at 0 degrees C, irrespective of how much heat the heater is dissipating. If the heater is gas fired, you will see a massive increase in combustion products with no increase in bath temperature.

    There is no increase in bath temperature (analogous to NO concentration) no matter what the increase in combustion products (analogous to NO metabolites such as nitrate) because the heat production (analogous to NO production by NOS) is matched by the heat consumption by melting ice (analogous to NO destruction).

    More NO will help, but simply stimulating NOS likely won’t. It could make it worse, just the way that putting ice in the water bath stimulates the action of the heater, but lowers the temperature of the bath.

    Using a mechanism that elicits a change in the feedback may provide a short term benefit and a longer term detriment. Depending on the time that the “therapeutic effect” is looked for, a short term benefit with a long term detriment could look like only a detriment. What is “long term” and what is “short term” is not known. It is known that there are multiple pathways with multiple time constants. It might be a few hours, it might be a few days. The compensatory pathways that restore the original setpoint may work faster than the pathways that would be affected positively.

    I would really like for this to be tested, but unless it is tested right, it is likely to not work. A half-assed test that sets the field back won’t help anyone.

  56. artfulDon 04 May 2009 at 1:37 pm

    Daedalus, are you saying that because Tony Atttwod was quoted on an ezine, which also reports on others with different views, that he must also share those views, when he has specifically written on his own site that he doesn’t? The site that you referenced referred to him as a “respected expert in the world of Autism.” Maybe it’s you who should be a bit more careful of your “citings.”

    Bottom line is that he says “Autism is anxiety looking for a target.”

    And also says: “Autism and anxiety go hand-in-hand. Autism affects a person’s ability to communicate with others or to understand the world around him, and that’s bound to cause anxiety and panic sometimes.”

    Where is he wrong, and where are any experts that support your rather odd position that autism and anxiety are NOT companions?

    It seems that on the one hand you claim to be on track with an NO project devoted to alleviating that anxiety, but which on the other hand you claim doesn’t exist. Sloppy thinking indeed.

  57. HHCon 04 May 2009 at 2:25 pm

    lurker, Sorry to hear about your extensive health problems. Hope your able to return to your interests soon 🙂

  58. daedalus2uon 04 May 2009 at 2:54 pm

    AD, I never said that anxiety is never associated with autism, what I said is that the anxiety associated with autism usually comes from people with autism anticipating being maltreated by people without autism.

    If you read the article on the petition that I linked to, you would know that there are many people with autism who disagree with Attwood’s characterization of them. Those people with autism sufficiently anticipate being maltreated as a consequence of what Attwood has said that they have taken action to get him to change it.

    My interpretation is not that those people with autism are anxious because they don’t understand what Attwood is saying; rather they are anxious because they do understand and anticipate being maltreated.

    When you link to a site with the preface “But here’s someone that put the lie to that better than I ever could” you are saying that the person who you are quoting is more expert than you are.

    The person you quoted, Rachel Evans, is not someone that I would consider an expert. She thinks that autism is caused by mercury poisoning and advocates chelation, homeopathy and cranial sacral therapy to treat it.

  59. artfulDon 04 May 2009 at 4:01 pm

    Daedalus, first of all I didn’t quote Rachel Evans, I quoted what Attwood was reported to have said and also confirmed for my own satisfaction that he said it. And yes, Attwood IS more expert than I am, and clearly more expert than you are. You can drag all the red herrings you want across the odd trail behind you, but you are studiously avoiding any mention that Attwood has specifically advised that chelation is dangerous to the point of causing some deaths, and is similarly cautious about the rest of the herrings stinking up your tracks.

    And are you now changing your tune by dancing around the question and saying autistics are anxious because they anticipate being maltreated? And mistreated by a man who has done more for the cause as a clinical psychologist than you will ever do through your self-absorbed quest for evidence that psychology has nothing to offer. Or through your compulsive fixation with proving that autism is somehow just another adaptive phenotype.

    Oh and there’s this from Wilipedia:
    “Dr. Tony Attwood (born Feb 9 1952) in Birmingham, England) is an English psychologist who lives in Queensland, Australia, and author of several books on Asperger’s Syndrome.
    He received an honours degree in psychology from the University of Hull, an M.A. in clinical psychology from the University of Surrey, and a Ph.D. from University of London under Uta Frith. His most famous book, Asperger’s Syndrome: A Guide for Parents and Professionals, provides information on diagnosis, problems of social relations, sensory issues, motor control and other typical issues which face people with Asperger’s and their support networks. The book has now been translated into 20 languages [1]
    Attwood also has a clinical practice at his diagnostic and treatment clinic for children and adults with Asperger’s Syndrome, in Brisbane, begun in 1992.”

    Are you perhaps a bit miffed because he also knows a lot more about Asperger’s Syndrome than you are personally comfortable with? And so to concede that he knows anything definitive about autism may be to concede to his overall expertise on a subject a bit too close to the home you pretend you actually live in?

    You can change the tune but the melody lingers on. As does the catchy lyric: “Autism is anxiety looking for a target.”

    Your target seems to be NO. Anything other than that being a nono.

  60. daedalus2uon 04 May 2009 at 5:23 pm

    AD, you did quote her. You even put quotation marks around the words you cut and pasted from her article; “The renowned autism expert Tony Atwood” (sic). You even copied her misspelling of Tony Attwood’s name.

    When looking for a description of the mental state of people with autism, I think it is better to listen to what people with autism actually have to say about their own mental state. When you do listen to what people with autism have to say, what you hear is them saying things like:

    “Autism It’s not like you think”

    “Many autistics say they are not unhappy because of their autism but because of the way they are treated by the outside world”


    I highly recommend looking at this site for people who are trying to get an understanding of what it is like to have autism or to have Asperger’s. When I first saw this site, the scales fell from my eyes and I realized I did have Asperger’s.

    My target isn’t NO. I don’t have a target, I am following a path.

    Where ever facts and logic lead me I will go. An awful lot of facts and logic are leading me straight to NO for an awful lot of conditions, including autism. Why no one else seems to want to follow me there is not something that I understand. I don’t think that they understand either, at least none of them have been able to articulate any facts or logic as to why the path I am on is wrong. If they are not using facts and logic to decide to not follow the path I am on, my facts and logic won’t be able to convince them otherwise.

    All I have are facts and logic. If they are not convincing to you, then I feel like Theodore Roosevelt must have felt when he said “Negotiating with those pirates is like trying to nail currant jelly to the wall.” My understanding is that he added “and the fault is not with the nail”, but have been unable to find verification on line. My analogy is that my facts and logic are like nails, and your artful dodging is like the currant jelly, an inference I am sure you will appreciate.

  61. artfulDon 04 May 2009 at 6:12 pm

    Daedalus, I quoted her reference to Tony being an expert, which you have yet to convincingly deny or refute. Unless she had to be wrong because she didn’t spell his last name right?
    But if the real Attwood would please stand up, he’d tell you the oddizm site you have referenced was devoted to self-delusional coping mechanisms. Autistic woo personified. As much a part of the cult of autism as are the anti-vaccinationists. Talk about irony. Oh, that’s right, you don’t do irony.

    And as you say, all you have are facts and logic. But if it’s a fact that experts on all sides disagree with you, then perhaps all you have left is logic. Which, in case you’d like to know, actually doesn’t exist without facts.

    (And Roosevelt actually was saying the fault lies with the hammer. So much the more for your understanding of inference or irony.)

  62. artfulDon 04 May 2009 at 6:50 pm

    And considering the kinship of Daedalus & Icarus, perhaps
    you’ll be interested in the Icarus project referenced here:

  63. daedalus2uon 04 May 2009 at 7:19 pm

    There are no facts that real experts disagree about. I have no disagreements with any real expert. I don’t disagree that many people with autism experience anxiety. You seem to think that I am disagreeing with that, I am not.

    I do disagree that the essence of autism is anxiety. I haven’t looked at Tony Attwood’s work in any kind of detail. He hasn’t published very much research. When you brought him up I did remember that there was some petition against him which I went and found reference to.

    The real “experts” on the internal experiences of people with autism are the people with autism themselves. That is such an obvious fact that for many is it completely self-evident. Why you and so many other NTs are unable to appreciate such an obvious and self-evident fact is one of the blind spots that NTs have and as a blind spot are unable to appreciate that they have a blind spot. My hypothesis as to why NTs have this particular blind spot is because whatever someone with autism says doesn’t feel authentic and “truthy” to NTs, so they discount it to zero or even negative (as you have done). Saying that Oddizim’s site ”was devoted to self-delusional coping mechanisms. Autistic woo personified. As much a part of the cult of autism as are the anti-vaccinationists.” is part and parcel of what people with autism go through every day.

    If Tony Attwood is unable to listen to people with autism and understand their experience, then he cannot be an expert on what that experience is. No matter how many NTs proclaim him to be an expert on the experience of people with autism, if the people with the real experience of what autism is like disagree with him then he is no expert.

    If you were dismissed out of hand by people who didn’t understand you and who then called you delusional and cultish every time you opened your mouth, wouldn’t you get a little bit anxious? Every time a person with autism interacts with someone who is NT is an opportunity for that NT person to bully the person with autism.

    I think that is why no one is following my NO research. As someone with Asperger’s, my facts and logic don’t sound as truthy as the lies of the NT frauds and scam artists. So be it. In the fullness of time the role of NO in those physiological pathways will be better understood and a whole lot of people will let out a big D’oh.

    The statement you quoted by Attwood is sound bite, something so simplistic it cannot be correct. Something so simplistic it cannot be a correct way to describe millions of people. NTs like their simplistic sound bites. People with Asperger’s like to have a lot of detail that more accurately describes reality.

    I am not really sure what your point is, other than to try and dispute what I have to say and try and criticize my NO ideas even though you do not understand them. That is a typical NT behavior, trying to denigrate and even destroy that which they do not understand. I have an explanation for why NTs are like that too. Not all NTs are, some of them can learn to be different, but they have to open their minds and try to think outside their NT box. That is very difficult for some NTs to do, many of them simply can’t.

  64. artfulDon 04 May 2009 at 8:42 pm

    My point was to counter your objections to the following, which had not been addressed to you to begin with:

    “The autistic brain retains the predictive apparatus that depends on signals that should allow it to make such predictions, and frustration results when certain of these signals are unitelligable or their pathways obstructed.”

    No-one said the essence of autism is anxiety. Anxiety is a result, not a cause. Essence better describes function and causation. Symptomatic would better describe the effect (although I expect Attwood would have a better word).
    I don’t recall having attacked you on your NO ideas, but it’s clear by your own admissions that others have. I object to your rejection of anything that suggests there are psychological effects involved that may point to an additional basis for what is clearly a biological problem. And if you find it to be a phenotype, that tells us nothing about causation. Worse, the implication that it’s an adaptive phenotype tells us you feel the perceived problems are illusory.

    You say Tony Attwood hasn’t published very much research. Note he has authored or co-authored numerous books on the subject, 12 referenced on this page alone:

    In no way does he try to denigrate anything about the problem, unless you simply see designating this general syndrome as problematic as a denigration.

  65. daedalus2uon 05 May 2009 at 7:53 am

    I find the story you linked to very sad.

    I think that schizophrenia and psychosis are at the extreme opposite end of the autism spectrum with the neurologically typical in the middle. Not my idea, but that of Crispi and Badcock (doi:10.1017/S0140525X08004214 ).

    My hypothesis of schizophrenia (not as well formed as my hypothesis of autism) is that the neuroanatomy is caused by high NO during certain periods of neurodevelopment in utero, often due to an acute infection such as the flu. At a talk by a senior researcher on the effects of exposure to infections in utero, he repeated an epidemiological estimation that someone had made, that if flu during pregnancy were eliminated it would eliminate 20% of schizophrenia.

    High NO in utero causes the brain to develop at the extreme non-autism end of the autism spectrum (my hypothesis). The epigenetic programming of the brain that results leaves those individuals more susceptible to low NO effects later in life (they are less adapted to low NO). I think it is low NO that then triggers the psychotic breaks. Without the fine grained minicolumns and better short range connectivity of the ASD brain (and no doubt other things), the schizophrenic brain is more susceptible to low NO induced reductions of functional connectivity to below the percolation threshold. In people with autism this causes a meltdown; in people with schizophrenia it causes a psychotic break.

    That is what bipolar is, cycling around the percolation threshold. Very low functional connectivity can induce euphoria and mania. My hypothesis is that euphoria and mania is what physiology induces during a near death metabolic state where you have to be euphoric and manic to have even a small chance of survival, as when running from a bear.

    Every time the brain induces this euphoric manic state, there is some brain damage; a pruning of the brain to reduce the metabolic load to reduce the likelihood of a reoccurrence. This is the same end state that abusers of stimulants end up in. The same state the huffers of solvents end up in. It is my understanding that sufficient doses of stimulants such as amphetamine can induce psychosis in anyone and in everyone. The psychosis (usually) resolves afterward. I think this occurs due to acute changes in functional connectivity. In people with the schizophrenic neuroanatomy anatomy and epigenetic programming the reduced functional connectivity can become permanent and they remain psychotic.

    What these people need is more NO. What is so sad is that the systems that are put in place to deal with these people put them under such stress that it lowers their NO levels and makes them worse. That is the essence of bullying, putting people under stress to reduce their NO level and functional connectivity such that they can be taken advantage of; the NT approach to “competition”, not with ideas, facts and logic, but with social pressures and bullying. When people are in extremis, making them have to fight for anything will make them worse. I guess to bullies, that is the point.

    I recently heard a news item on NPR where they looked at homeless people who abused alcohol. The conventional approach is to have zero tolerance for alcohol consumption before supplying a homeless person with housing. The story talked about a different approach where they gave people a safe place to live, and didn’t take it away if they abused alcohol. The report was very interesting, over a year, the people with housing reduced their alcohol consumption more, had better nutrition, and used emergency medical services less. The savings in reduced emergency medical services exceeded the cost of the housing. It was cheaper to simply give them a safe place to live and they did better, then to hold it out as a carrot.

  66. daedalus2uon 05 May 2009 at 9:27 am

    Grant, I just came across a paper which shows a reduction in NO in the blood stream due to nitroglycerine


    They measured actual NO via electrochemical techniques, not the metabolites nitrite and nitrate. This technique is quite specific to NO, but is quite tricky. It is probably too invasive to be done in humans.

  67. Anti-Vax madness « Mal-Contenton 07 May 2009 at 12:16 pm

    […] is that no one knows for sure what causes autism. The evidence so far points to a combination of genetic factors and possible environmental factors in utero but, even that is still very new […]

  68. son 09 May 2009 at 2:10 pm

    “People with ASDs are not distressed that they can’t read faces. They are distressed when they are attacked by NTs because they can’t read faces.”

    I get distressed by not being able to correctly interpret the facial expression of someone I am speaking to. Intriguingly I am fairly good at reading faces of people not speaking to me. So, is it the anxiety of not being sure that I can interpret the facial expression that confounds my interpretation or is it an intrinsic inability to understand faces at close range or in emotinally charged situations (like speaking to another)?

  69. artfulDon 09 May 2009 at 2:33 pm

    The difference may be that you’re uncertain whether you can meet the higher expectaions of those speaking directly to you, since their expressons are part of the communication process.

    Those not expecting any response from you relative to an understanding of their expressions are thus not likely to foster
    a corresponding degree of anxiety.

  70. son 12 May 2009 at 7:26 am

    I am also thinking if distance may make a difference.

    At some distance both eyes and mouth are seen, while at (very)close range (say 0.5-1 meter) you have to focus on either. If ASDs and “shy” people have a propensity to focus on the mouth (as reported by some), and if the area around the eyes is more important to “decipher” emotional clues etc, then there is a possibility that greater distance may make interpretation easier for some.

    Anyhow, enough speculation and musings for now.

  71. […] about epidemics. But she’s wrong (which is pretty much the case with everything she says); there are strong genetic indicators of autism, but the underlying cause is still unknown. She makes claims about what triggers autism, when in […]

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