Tuesday, October 21, 2008

Theory of Mind vs. Theory of Reality: The tradeoff along the Autism Spectrum

In any great organization it is far, far safer to be wrong with the majority than to be right alone. -- John Kenneth Galbraith

If the only tool you have is a hammer, you tend to see every problem as a nail.
-- Abraham Maslow

In the land of the blind, the one-eyed man is king.

How autism provides resistance to the delusional thinking of groupthink (aka drinking the Kool-Aid).

When your primary competition is with other people, life is a zero sum game. When your primary competition is with reality, there are no limits.

The cause(s) of Autism Spectrum Disorders (ASDs) remain unknown. The complex genetic disorder hypothesis posits ASDs are an emergent disorder of multiple genes, perhaps dozens or more. How a common disorder of so many genes could evolve has not been suggested. One hypothesis is that genes associated with ASDs did confer some advantage resulting in their selection in the past, but are now detrimental. I suggest ASDs are not disorders at all, but normal (even human defining) developmental responses, particularly to stress in utero and early childhood. This fundamental human neurodevelopmental paradigm programs the brain and behaviors mediated by that brain so as to optimize survival and reproduction depending on maternal and infant stress; invoking abilities to understand, interact with and manipulate other humans when times are good, and abilities to understand, interact with and manipulate the environment via tool production when times are hard. It is hypothesized that this trade-off between Theory of Mind (ToM) and Theory of Reality (ToR) is the quintessential trade-off along the Autism Spectrum. Implications for interaction difficulties between individuals with ASDs and Neurologically Typical individuals (NTs) are discussed. Prevention and treatment are also discussed.

Background ASDs

The Autism Spectrum Disorders (ASDs) are defined and diagnosed by difficulties in communication, social interaction and by repetitive behaviors. In ASDs, there is a high (but not absolute) concordance between monozygous twins, [1] moderate concordance between dizygous twins, [2], [3] and lesser concordance between siblings. With no generally accepted environmental cause, ASDs are thought to be primarily genetic in origin with associations of perhaps 135 genes.[4] No doubt the complex effects on brain structure and behavior observed in ASDs are not mediated via a single pathway, but calls to abandon a search for a single explanation are premature. [5]

A number of single mutations have been associated with multiple cases of autism-like symptoms. I call these "autism-like" because it is not clear if the cause and sequelae of these autism-like syndromes are identical to or even similar to the common cases of autism and ASDs (which remain unknown). A good example is Rett Syndrome which is known to be caused by a loss in the MeCP2 gene which is on the X chromosome. Females have 2 copies of the X chromosome, one of which is silenced. Active MeCP2 in some cells rescues the organisms from the fatal loss of MeCP2 which afflicts males (who have only one X chromosome). RS females develop seemingly normally until 6-18 months when they develop the characteristic RS phenotype which includes autism-like symptoms, but is also characterized by non-autistic symptoms of small head size, breathing abnormalities, vascular abnormalities, scoliosis, growth retardation and others. Because the effects of MeCP2 deletion are mediated through aberrant transcription of methylated DNA, then aberrant transcription of methylated DNA is sufficient to lead to autism-like symptoms. Perhaps the symptoms of common ASDs are also caused by DNA methylation, or perhaps via a shared final common pathway triggered by aberrant DNA methylation.

Nitric oxide is a pleiotropic signaling molecule used in thousands of metabolic pathways where it regulates, ATP supply, O2 consumption, steroid physiology, transcription, axon targeting, the cell cycle, epigenetic programming and many other aspects of physiology, development and neurodevelopment. Many of the pathways observed to be abnormal in ASDs are mediated through NO signaling.

I suggest that the final common pathway mediating autism and autism-like symptoms is low NO in utero, during neurodevelopment and as an adult. Low NO is the archetypal stress response. Virtually any type of stress ultimately results in low NO which physiology uses to trigger compensatory responses. For example, oxidative stress occurs when superoxide levels are increased. Superoxide consumes NO at near diffusion limited kinetics so a high superoxide state is necessarily a low NO state. NO inhibits cytochrome c oxidase. To release that inhibition and increase O2 consumption to maximize aerobic ATP production, the NO level must be lowered. Psychosocial stress increases oxidative stress through catecholamine oxidation, ATP stress increases oxidative stress through increased mitochondrial potential necessary to increase ATP flux, xenobiotic stress increases superoxide through the cytochrome P450 pathway, immune system stress increases superoxide through the respiratory burst. Just about any type of metabolic stress would decrease NO levels and according to the present hypothesis would tend to produce a more autistic-like phenotype. This may be the mechanism for the association of copy number variations with autism. This may also be the mechanism behind the ASD-like symptoms produced by MeCP2 deletion. Females with MeCP2 deletion are mosaic. Some of their cells do have appropriate methylation readout and some do not. Presumably this differential regulation of DNA expression causes metabolic inefficiencies and metabolic "stress" due to cells being out of "sync". In a mosaic organ with non-synchronous regulation, some cells would be working harder than others, perhaps even working at cross purposes. The final common pathway of essentially every kind of metabolic stress is decreased NO.

Virtually all ASD physical symptoms are consistent with pathways regulated by NO being skewed in a low basal NO direction. I suggest that the ASD phenotype is a stress compensatory pathway mediated by low NO.

NO/ROS Balance Programs adult physiology in utero

The physiology of virtually all adult organs is known to be programmed in utero in response to a number of fetal stressors including nutrition[6] stress and hormonal factors. [7] NO/ROS balance in utero does lead to epigenetic programming of adult blood pressure in rats. [8] Stress is a low NO state. [9] The most characteristic physical feature of ASD children is a larger brain[10], with smaller and more numerous minicolumns. [11] Low NO is suggested to cause the characteristic minicolumn structure associated with autism[12] and the timing of stressors may be crucial to the development of the autism phenotype. [13] In guinea pigs, brief prenatal stress increases brain/body mass ratio, and changes adult behavior. [14] Prenatal stress increases learning ability in rats. [15] Prenatal stress does program hypothalamo-pituitary-adrenal function. [16] Low NO does cause neuronal hyperplasia. [17] The patterning of many neural structures is determined in part by gradients in NO mediating proliferation, differentiation, or apoptosis. [18] There are increased asymmetries in the brains of ASD individuals[19], suggesting differential regulation of neuronal growth when the sizes of those structures are formed in utero. Stress in utero causes adaptive changes in the adult physiology of multiple organs; it would be beyond surprising if it did not exert adaptive influences on the most important organ, the brain.

I suggest that low NO in utero, brought about by maternal stress leads to the ASD phenotype in affected individuals, and the genotype that leads to the ASD phenotype was adaptive under conditions where humans evolved, in the “wild”, but is perhaps now less adaptive due to environmental change(s). What possible advantages could the ASD phenotype hold?

The Brain is fundamentally the most Human organ

Humans evolved large and complex brains only because such brains conferred survival and reproductive benefits. Human evolution was shaped mostly by events 100k or more years ago. Humans are social animals, as are all primates. Humans are unique in their use of language with syntax and grammar to convey complex ideas. Humans are the only extant hominin that manufactures and uses tools. The first instances of manufactured stone tools date to about 2.5 to 2.7 MYA (million years ago), and was near universal by 2 MYA[20]. Manufactured tools of perishable materials perhaps were earlier. Modern humans are good at tool manufacture and tool use. Tool use has profoundly shaped human evolution and those parts of the human genome that affect brain structures important for tool creation and use. Similarly, communication and language has profoundly shaped human evolution and those parts of the genome that affect brain structures important for language acquisition and use. The major structures of the brain are formed in utero and early childhood, and are then largely fixed throughout adult life. It is only in utero and early childhood that neurons can be epigenetically programmed to form the major structures in the brain with the characteristic neuroanatomy observed in ASDs such as increased asymmetries, larger numbers of neurons[21] and larger brains.

Brain size at birth limited by female pelvis: Brain optimization requires tradeoffs

The size of the newborn brain is limited by the size of the mother's pelvis through which it can be successfully born. In the absence of medical C-section, cephalopelvic disproportion results in significant infant and maternal mortality. What ever advantages a large brain at birth provides it comes to naught if the infant or mother dies. The structure and size of the brain at birth must be an evolved trade-off between the multiple tasks that brain will be called upon to perform at birth and over the life of the individual and the substantial risk during a natural birth. The only time the most fundamental aspects of brain structure can be modified is while those structures are being formed. Much of the formation of those brain structures occurs in utero, much of it in the first trimester following closure of the neural tube (which is when teratogens such as thalidomide can cause autism). Epigenetic programming of cells occurs when those cells are dividing and undergoing differentiation. Much of the differentiation in early human development occurs in the first trimester. Patterns of methylation modify DNA expression and modify the phenotype of that differentiated cell for the lifetime of that cell. Many neurons do not divide over the lifetime of the individual. NO does modify methylation through the folate pathway and so modifies DNA methylation in ways that are quite complex (for at least this one gene system). Presumably multiple genes are epigenetically modified in complex ways by this same mechanism.

Oxidative stress and low NO cause changes in DNA methylation. Presumably this is part of the normal mechanism by which stress (which results in oxidative stress and low NO) causes global epigenetic reprogramming of diverse genes in diverse tissue compartments under diverse circumstances. Psychological stress causes long lasting changes in neurological functioning as for example PTSD. The details of how psychological stresses of what types cause the characteristic neurological changes that manifest as PTSD are mostly unknown. We know it happens, so there must be physiology that supports those characteristic changes.

DNA methylation mediated through NO does influence expression of genes that are involved in some autism-like syndromes, such as Fragile-X mental retardation gene (FMR1). Aberrant readout of DNA methylation is implicated in the autism-like symptoms of Rett Syndrome (RS). Many of the symptoms of RS are characterized by physiology being skewed in the direction of low basal NO.

Fundamental brain optimization tradeoff: Theory of Mind (ToM) for Theory of Reality (ToR)

Humans are unique among animals for their abilities at communication; language making and language using and tools; tool making and tool using. These abilities are highly dependent on a large brain with substantial plasticity for self modification via learning throughout life. The relative importance of these two extremely important human behavioral characteristics is dependant upon the environment the infant is born into. The major neuroanatomy of the brain originates from structures arising during early neuron proliferation and differentiation during and after neurulation in the first trimester. These structures are then elaborated on later in utero. It would be beyond surprising if the relative aptitude of the brain for communication and/or tool making/using (including manual dexterity for manipulating objects) were not to some extent programmed in utero.

That trade-off would show up as a trade-off between abilities to understand and manipulate other humans (Theory of Mind), and abilities to understand and manipulate reality (Theory of Reality). These are the differences that are seen in people along the autism spectrum. I will discuss how a less developed ToM interferes with ASDs communicating with neurologically typical individuals (NTs) and their very well developed ToM. For the most part ASDs don't pick up the nuances of communication, particularly how it relates to motivations, beliefs and other mental states. The NT ToM forces NTs to think in anthropomorphic terms, even when it is inappropriate because they lack a robust ToR.

I spend a lot of time trying to explain this in several different ways using several different analogies. What I am trying to describe is exceedingly complex, as complex as an entire human brain. Something that complex cannot be described simply except in simplistic terms. It would be like trying to describe a library in a single paragraph.

Good times --> Need Good ToM

One hypothesis of this paper is that when times are good, and a woman's first trimester of pregnancy is characterized by low stress, then the "optimum" infant brain will be one optimized for better communication. If times are good, there will be plenty of other humans around, and the infant's primary competition for food and mates will be with other humans. Because times are good, the cultural information the adults have is working well to produce those good times. Copying that good cultural information with high fidelity is important. Good communication, a good ToM with the ability to understand and manipulate other humans is the best strategy when times are good.

Hard times --> Need Good ToR

When times are hard, a woman's first trimester will be characterized by high stress. The optimum infant brain will be skewed away from communication because during evolutionary time, hard times meant fewer humans in the territory. With fewer other humans around the need for communication is reduced. The cultural practices of the adults are not working well to produce good times. If the cultural practices are not working well, they need to be modified until they are working well. When times are hard, there won't be many other humans around because they will die in infancy. Competition will be against reality for food, shelter, and to stay alive. The adults don't know how to make good times, so that is something the infant will have to figure out for him/herself.

Theory of mind, theory of reality and theory of cognition

I will make a distinction between being able to think about something (cognition) and being able to think about that thinking process (meta-cognition) and coin a term Theory of Cognition (ToC), to denote the ability to think about and emulate different types of cognition. The term is an attempt to be analogous to ToM and ToR, which are meta-abilities to think about and compare multiple models of other minds (necessary for communication by emulating other mental states), and multiple models of potential realities. I am making this distinction because the different types of computation that humans do are not necessarily mapable onto each other.

Analogy:
Word processing ToM Theory of Mind Emulating other minds
Spread sheet software ToR Theory of Reality Emulating Reality
Operating system ToC Theory of Cognition Choosing Emulations


Trying to understand human communication with a ToR might be like trying to write a document not with word processing software but with a spread sheet. A document could be written in a spread sheet. It would be slow, cumbersome and the document wouldn't have the right formatting and wouldn't be as polished as something done in a word processor. On the other hand, a large spread sheet calculation simply can not be done using word processing software. The word processing software doesn't support the primitive functions, addition, subtraction, multiplication, etc that a spread sheet calculation requires. Some of the complex word processing functions can be emulated on a spread sheet but spell checking and grammar correction would be very cumbersome and difficult.

This is the sense that I am trying to convey, that people with a robust ToM can do good and robust communication that is nuanced, and well understood by others with a matching and robust ToM. Their shared ToM is analogous to the word processing software, and a well formatted document is analogous to human communication between individuals with a shared ToM. The ToR is analogous to the spread sheet software and the large spread sheet analogous to a highly technical ToR. A theory of cognition (ToC) would be the selection of the proper software type to do the required computations (ToM(English), ToM(French), ToM(ASL), ToR). There are multiple ToMs, each language is different to some extent, although there are other communication modes, body language, cultural signals, gestures. There is only one ToR, the one which accurately describes reality as it actually is. Individuals may have a ToR that is highly specialized and individualistic, physics or medicine for example. But all of the different ToRs all mesh into one (or should) because they all describe a single reality.

In this analogy I am trying to illustrate that a specialized piece of computation machinery may work very well for one task (word processing) and not at all for another (spread sheet calculation). If you tried to input a spread sheet into a word processor, you would get many error codes, many misspelled words; the word processing software would reject it as badly formed. A very well formed spread sheet cannot be read on a word processor. This is analogous the problem that some NTs have with understanding people with ASDs.

Normal background "housekeeping" features can impede communication. Many types of different word-processing software have automatic spell checking. If a word is spelled wrong, the software will change the spelling to match the spelling to one of the words in its dictionary. If the word is not misspelled, but is simply not in the dictionary, the software can't recognize it and will change it anyway. This is a type 1 error, a false positive. The software falsely identifies a character string and modifies it to match its default identity. This is an inherent property of specialized pattern recognition systems. There is a trade off of type 1 errors (false positive) for type 2 errors (non detection). If you don't have access to modify the "error correction function", it may be impossible to type certain strings because the error correction keeps changing them. In certain word processing software this can be extremely annoying and make writing outside the scope of the software impossible. If the software won't let you have certain character strings in your document, you can't write about them. If your ToM won't let you have certain ideas, you can't think about them. Appreciating that your ToM doesn't have the capacity to think certain thoughts is extremely difficult.

Being unable to conceptualize ideas is not uncommon. There are people who believe in the literal truth of ancient texts and are unable to conceive that they do not accurately describe reality, irrespective of what data can be collected today. These beliefs are from a ToM, shared with others of their community. Such beliefs did not arise from observations of reality, they were told to individuals by other individuals who believed them. Those false beliefs are derived by those false beliefs being communicated to the individual and so shaping their ToM. Such beliefs are often extremely resistant to change.

Learning can be looked at as modification of the brain's neural network so the neuroanatomy can support what ever new idea it is that is being learned. Usually this takes a long time and is quite difficult. Learning physics or mathematics is difficult because the normally developing neural patterning doesn't support that type of thinking the way it supports language. I will discuss this more later.

A mother's necessity makes her child an inventor.

Maternal stress --> fetal development along autism spectrum --> Asperger phenotype

The hypothesis of this paper is that low NO in utero causes development along the autism spectrum so as to program the brain in utero to one that supports a better ToR. Precisely the phenotype that is needed when mothers are stressed and so times are hard. What ever technology and cultural practices are being used, they are not working well enough and so new ones need to be developed.

Which individuals are most adept at tool use today? It is people with Asperger’s, people with ASDs. Many scientists and engineers have Asperger’s, and it is suggested that Einstein, Newton, and many brilliant scientists had Asperger’s. [22] Asperger even said “It seems that for success in science or art a dash of autism is essential.” [23] The stereotypical nerd is someone with facility at math, science and with characteristically poor social skills[24]. The mirror neuron system[25] (responsible for understanding the actions of other individuals) exhibits dysfunction proportional to ASD severity. [26]

The major barrier to revolutionary scientific innovation is conventional thinking and existing paradigms. [27] What Kuhn calls “normal science”. Ideas transmitted culturally are difficult to displace even when wrong. It is nearly 150 years since Darwin’s “Origin of Species”, with overwhelming data supporting and no datum inconsistent with evolution, yet in the USA, 40% of the population believes evolution is false. [28] Some on the Nobel Committee were unable to accept relativity as valid and so Einstein received the Nobel Prize for the photoelectric effect, not relativity. [29]

Cultural notions of what is appropriate affect abilities (i.e. what people think they or anyone can do). Women exposed to a hypothesis wrongly attributing mathematical ability to genes on the Y chromosome have impaired mathematics performance. [30] A degree of social isolation from disrupted mirror neurons may insulate ASD individuals from incorrect paradigms of science, technology and the peer pressure associated with cultural practices which must be abandoned to overcome hard times. No doubt 2.8 MYA everyone “knew” stones didn’t make good tools. The first stone tools were not developed after committees of peers reviewed proposals and selected the highest scoring for implementation; they were developed by the “Einsteins” of the time working alone. Acquisition of nut cracking skill by capuchin monkeys (Cebus apella) using stones as hammer and anvil takes about 2 years and requires considerable repetitive nonproductive effort while watching proficient individuals. [31] No doubt repetitive trial and error was needed to acquire de novo skill(s) to manufacture stone tools 2 MYA, and such individuals had to ignore criticism that they were bizarre for “uselessly” banging stones together.

These culture notions are transmitted through the robust NT ToM. To avoid being adversely influenced by potentially incorrect ToMs, ASDs require a weaker ToM, a ToM that perhaps allows some communication, but one that can easily be ignored, resulting in the ability to ignore the "Kool-Aid" which is a stronger version of groupthink. The delusional world views that some NTs have can become extremely compelling to them,, such that they are unable to perceive that it is delusional, particularly when a charismatic leader with a strong ToM (essentially the definition of a charismatic leader) imposes it on his/her followers. More on this later in the discussion of cargo cult science.

ASD individuals developing skills unrecognized as useful by NTs must possess a compulsion to acquire those skills despite peer pressure that such skills are useless. Many ASDs acquire skills that NTs think are useless, fascination with train spotting, bird watching, collecting, virtually every savant ability is acquired to a degree that NTs do not find useful (if they did, then NTs would acquire such skills to that degree and it would not be thought of as savant). Language and communication is the "savant" skill of NTs. NTs possess a skill at communication (with other NTs) that ASDs cannot hope to master. Just as ASDs sometimes have skills that NTs cannot hope to master. Just as elite athletes have skills that non-athletes cannot hope to master. A society with the ability to use the best skills of a highly variable and diverse group would be better able to cope with adversity than a society where all individuals had the same average abilities. Not every individual in the village needs to be proficient at making stone tools, provided there are enough proficient individuals and the tools their skills produce can be traded for other things.

Cognition: Non-algorithmic calculation

Cognition in human brains is done by neural networks, the fundamental details of which are mostly unknown. Some cognitive abilities (such as savant calendar) are known to be non-algorithmic because the errors are not always the same, and the time for performing the calculation is not asymmetric depending on calculation direction the way a computation performed using an algorithm would be. [32] It is likely that most if not all other types of human cognition are non-algorithmic.

I am using algorithm in the sense that an algorithm is what a Turing machine executes. An algorithm is a series of instructions that when acted upon manipulate data and perform a calculation. The computers that people are familiar with are algorithmic. Calculators use a calculating engine (the processor) to operate an algorithm (the software) to manipulate the data. In general the data does not modify the software or the processor while the computation is in process, and given the same data, the same processor running the same software will produce the same output each and every time the calculation is performed.

Neural networks are inherently non-algorithmic in the sense that there is no "algorithm" explicitly being implemented by the neural network. A neural network may be used to implement an algorithm. For example, humans and other animals have the ability to do approximate mathematical operations such as comparison. Two groups of objects can be compared and the one with the larger number can be selected even when the members of each group have not been counted. This selection can be made by individuals unable to count and even by animals. This selection is non-algorithmic. An individual able to count is also able to count the members of each group and then tell which group is larger by comparing the two values. The person, who can count, knows that the counting algorithm produces a more reliable comparison than the non-algorithmic visual comparison. The person who cannot count does not know how to implement the counting algorithm.

Human brains are not optimally configured to run algorithms. A processor that can run algorithms is in essence emulated in a human brain to run the algorithm under consideration, such as counting or multiplication. The form that the data is in may greatly limit what algorithms that data can be manipulated with. For example multiplication using Arabic numerals is easy. Multiplication using Roman numerals is exceedingly difficult. There is essentially no algorithm for multiplying Roman numerals, individuals use a look-up table. Learning algorithms takes considerable time and effort for many individuals.

Communication requires a Theory of Mind

Exactly how neural networks in the brain configure and reconfigure themselves to do the computations that certain cognitive tasks require is unknown. Presumably there is some type of feedback that modifies the network when sub-optimal results are achieved so as to configure the network to produce better results. How this occurs is unknown, but for language acquisition, some conclusions as to how this optimization works can be made which I discuss below. What I want to emphasize the compulsive aspects of language acquisition. People do not choose to acquire the language they acquire as children, their brains acquire it (or synthesize it de novo) for them.

All communication requires two parties, a sender and a receiver. The sender must have a mental concept, translate that mental concept into a communication medium, transmit that message to the receiver, who must receive and then translate that message back into a mental concept. In that sense, all communication is only the transmission of representations of internal mental states. For there to be communication, the mental concept must necessarily be mapable onto the neural structures of both individuals. If one party is not able to represent the mental concept in their brain, the concept cannot be communicated either from them or to them. In a sense, communication is the transmission of data that allows the receiver to identify and map that concept into a mental representation, in effect the receiver is doing pattern recognition on the data stream and generating a mental representation, in effect a pattern of thought either generated de novo, or a familiar pattern previously used.

In this sense, communication can only occur between individuals with a shared Theory of Mind. This is the sense that I am using ToM in this paper, the emulation of the cognition of another individual to achieve a mapping of the mental state of one individual with the mental state of another individual. The possible fidelity of that mapping determines the possible fidelity of that communication. If a mental state cannot be mapped onto another individual's ToM, then that mental state cannot be communicated to that individual.

Pattern recognition is a well recognized ability. All systems encoding pattern recognition are subject to different forms of error. There is the type 1 error, the false positive, the error in wrongly identifying a false instance as positive. There is also the type 2 error, the false negative, the error in missing the correct identification of a correct instance. In a general sense any pattern recognition system can be made more sensitive, that is with a reduced type 2 error, but then there is an increased type 1 error and there are more false positives.

A type 1 error is getting the attempted message wrong; a type 2 error is missing the attempted message. Since communication is a two-party interaction, the "fault" of miscommunication cannot be attributed to either party, the "fault" lies in their interaction.

Many human interactions engender other types of error. There is no generally accepted definition of what is a Type 3 error, but one definition is "the error committed by giving the right answer to the wrong problem". When times are hard, and the culturally transmitted traditional information isn't capable of solving the hard times, that is an example of the right answer to the wrong problem. The time of adolescence and early adulthood is often a time of rebellion against authority, against conventional wisdom, against cultural norms. Young people are testing the limits of their culturally acquired information; testing to see what works and what doesn't. This is somewhat speculative but this might be a mechanism to reduce the cultural transmission of obsolete or dysfunctional practices. In the absence of a written language, the only cultural practices that can be transmitted are those adopted by the next generation. If the older members of the tribe live long enough to transfer their wisdom to adults past their adolescent rebellion period, perhaps the wisdom is worth transferring. If not, then perhaps it isn't and the tribe should try new approaches until that happens.

Communication and language acquisition

Social animals communicate with each other. In humans the ability to develop language is innate and the brain structures to support language and language development must be coded for genetically. Language itself must be learned or is synthesized de novo during certain periods of brain development. This point is quite important. When humans are growing up in a culture, they adopt the language of the culture, provided that the language is "well formed". If the language the adults are using is not "well formed", the children synthesize a new language that is "well formed". That is, when the children of immigrant parents grow up, they do not adopt the pigeon language their parents are speaking, they either adopt the "well formed" dominant language, or synthesize a "well formed" Creole. The various sign languages did not become "well formed" until children grew up with signing as their first language, which they modified into a "well formed" language.

The acquisition of language in this way tells us several things; that the ability to acquire language is innate, that there is a more "primitive" cognitive structure underlying language (by that I mean that the structure of "thought" has a component that is simpler than the linguistic components humans communicate with). Without a simpler and more primitive cognitive structure, the Creole could not be analyzed as it is being formed to ensure the resulting Creole has a "well formed" grammar. However, the ability to form a Creole is lost at a certain age. The immigrant parents of the Creole synthesizing children continue to speak their pigeon language. This implies that the cognitive structure that analyzes language as it is being learned and forces it to be "well formed", i.e. to conform to standard human linguistic patterns is lost (to some extent) with age. It also implies a compulsion to learn the "standard" language and a compulsion to force others to comply with the "standard".

The development of a de novo language, such as a Creole, is a collective outcome produced by a population. It is not produced by a single individual. Another way of describing it is that the population developing the language acquires a shared neural mapping of the medium of the language (sounds, gestures, etc) to neural structures producing the mental states that are the ultimate outcome of communication (that is the ideas being communicated). In this context, there is no arbitrarily correct mapping. The mapping is correct so long as it is the mapping shared by the group. In the sense of the Galbraith quote at the start what ever the majority adopts as the linguistic mapping is the correct mapping. This is a very important point. What ever the majority adopts as correct is correct; everything else is wrong.

For a single majority linguistic mapping to arise spontaneously there must be very powerful mechanism(s) to eliminate deviation from the mapping acquired by the majority. The majority acquire a shared Theory of Mind with respect to linguistic mapping. In other words, the differences between the shared Theory of Mind and that of any individuals in the population are reduced. The deviation is not reduced by changes to the shared theory of mind; the deviation is reduced by individuals adopting the shared ToM as their own. This is an important point. There is no "shared" ToM. There are only individual ToMs which correspond to the shared ToM more or less. The shared TOM can only be shared to the extent that all individuals have the same components and the same structural relationships between those components. The shared ToM reflects the "lowest common denominator"; the ToM that overlaps with everyone else's ToM is all that can be shared. I think this relates to the importance of "peer pressure" in the age group capable of forming a Creole language. If peer pressure were not so compelling, a single coherent language would be difficult to achieve.

The rigidity of an inflexible ToM maintains stability of communication, of information transmitted culturally to the next generation. If your ToM doesn't support an idea, you cannot transmit it, receive it, understand it, or even think it. When times are easy, transmitting the cultural information that led to those easy times is important. It is important to do so with high fidelity because it worked. When times are hard, the culturally transmitted information isn't working, and so needs to be abandoned or modified. The fidelity of transmission must be reduced so what ever is wrong and/or isn't working can be eliminated.

The ToM of NTs that allows them to communicate so easily with each other limits what they can communicate to ideas that are within the shared ToM. This is an extremely important point, but it is a point that NTs have an extremely difficult time understanding because they can only think using ideas that are within their shared ToM. If an individual's ToM is insufficiently flexible to map an idea, that idea cannot be understood unless the ToM changes. But there is tremendous peer pressure to maintain the shared ToM of the group and to not change it.

This rigidity of the NT ToM is what causes ideas to persist even when those ideas are wrong and the rejection of correct ideas even when well supported by incontrovertible data. Many religious ideas have no supporting evidence and are in fact demonstrably wrong. For example the idea that the Earth is less than 10,000 years old and was created in 6 days as described in Genesis. Similarly the idea of evolution is rejected without a single piece of data inconsistent with it.

Most ToM ideas are transmitted from other individuals, not generated de novo.

Conflicting compulsions for ToM and ToR

A specific ToM is only useful for communication in the context of the group of individuals that share it. The mapping of a data stream (i.e. speech or gestures) into ideas and mental states is arbitrary and the only correct mapping is the one that everyone else in the group shares. There must be a tremendous compulsion to modify one's ToM to conform to that of the group. It is this compulsion that forces the emergence of a single language in a group.

In contrast, a ToR is only useful in so far as it actually corresponds to reality. To eventually develop a robust ToR, the individual must have a compulsion to modify his/her own ToR until it does correspond with reality, irrespective of the ToR of others in the group.

Thus developing and maintaining a good ToR is in conflict with developing a good ToM. A ToM needs to remain static for individuals to be able to communicate with each other. A ToR needs to be dynamic and change when ever it is found to be in error or to be dysfunctional.

I think this is the source of much of the resistance to new ideas in human culture but also in the scientific community. These concepts are laid out by Thomas Kuhn in his book, The Structure of Scientific Revolutions. Most scientists do what Kuhn calls "ordinary science", where they work within the paradigm of their scientific field. It is difficult to work outside the paradigms of a scientific field. Any contradiction of an existing paradigm is considered extraordinary and so requires extraordinary evidence. Some individuals are unable to reject paradigms even when they have been shown to be wrong. In these individuals, their rigid ToM has locked them into a perpetual state of error, and they don't have a sufficiently robust ToC to appreciate that their thinking is faulty and in error. It is mechanisms similar to the mechanisms that enforce a rigid ToM during language acquisition that compel adherence to the faulty ToM in later life, peer pressure, appeal to authority, tradition.

Communication and ASDs

Communication in humans encompasses a number of modalities including speech, sign language, body language, written language, music, artistic expression and perhaps pheromones. Most of these have components that are learned, improve with practice and degrade with disuse demonstrating the involvement of neural structures which retain plasticity (positive and negative) even in adulthood.

Autism is defined by behaviors, behaviors related to social interactions where autistic individuals have what are called characteristic deficits which can be reliably measured. However what constitutes a deficit is a matter of perspective. One example is a "deficit" in the ability to impute anthropomorphic motivation and emotion to inanimate objects as in the work of Frith. In this research, triangles were animated and made to move in three different ways, randomly, goal directed and moving interactively with implied intentions. The two sets of purposeful motions were designed to evoke anthropomorphic responses, e.g. chasing, fighting and coaxing, tricking. Individuals were scored on how closely they matched the scripts the animators of the triangles were trying to portray.

The ASD individuals scored lower than the NTs did, and this was described as a "mentalizing dysfunction". This was taken as a confirmation that people with ASDs have an impairment in attribution of mental states. However, whose "mental state" did the ASDs have an impairment in recognizing? The "mental state" of the triangles? Was this error a type 1 error (false positive), or type 2 error (false negative)? One might say the ASDs had a type 2 error, failure to recognize the "mental state" of the triangles, but one could (more correctly I think) say that the NTs had a type 1 error of falsely attributing a "mental state" to obviously inanimate triangles.

There is no intrinsically correct representation of the mental state of triangles. Triangles do not have mental states. The only way that a mental state can be attributed to triangles is via anthropomorphic projection of human-type intentions onto inanimate objects. In most circumstances this would be a Type 1 error; falsely observing anthropomorphic attributes in inanimate objects. It could also be thought of as a type 3 error, wrongly using a human based anthropomorphic model where it is inappropriate. This type of projection is not uncommon. Imputation of motivation and intentions to inanimate objects was at one time the basis for the religious belief that demons and spirits inhabit and animate virtually every object.

Inappropriate invocation of anthropomorphic feelings is a large part of the entertainment industry. Many cartoons are stylized after humans and many humans develop grossly and dangerously wrong ToR based on these erroneous ideas. In regions where bears are endemic, campers feeding bears is a serious problem. People assume that the anthropomorphic representations they have seen on TV are representative of how bears will react in real life. There have even been cases where a parent has applied peanut butter to a child's face so a bear cub would lick it off to obtain cute pictures.

This relates to the second quote, "If the only tool you have is a hammer, you tend to see every problem as a nail." If the only cognitive structures you have to think with are the cognitive structures of human emotions and communication, trying to figure out the properties of inanimate objects would consist of trying to ascribe human motivations and intentions to those inanimate objects and trying to figure out what they would do next in human terms.

Savant cognitive abilities

A striking feature of some people on the autism spectrum is that in some instances they have narrow and highly superior cognitive abilities. Human mental abilities have distributions in the population, with "normal" abilities being distributed "normally". Usually people with autism are somewhat lower on intelligence tests such as WISC, but with somewhat higher scores in block design. When intelligence tests without a communication component such as Raven's Progressive Matricies are used, some autistic individuals score much higher, in some cases as much as 70 percentile points higher (n=7). [33] That is 70 percentile points higher. Such a lack of congruence between tests is sufficient to show they are not measuring the same thing and we shouldn't use the same label to denote what the different tests are measuring even if there is good correlation among NTs. That correlation can only be spurious.

The distribution of intellectual abilities is "normalized", that is differences are measured and then scaled to fit on a distribution. That scale is arbitrary, and does not reflect any sort of absolute scale of difficulty.

As social animals, humans live in societies, larger communities of humans where there can be specialization and division of labor. It is this specialization and division of labor that has allowed humans to collectively master many technologies. Presumably different mental tasks are optimized by different neural structures. Dispersion in mental abilities requires dispersion in neural structures.

Savant abilities are not rare among people on the autism spectrum, and sometimes occur in individuals with profound disruptions in other cognitive abilities. This shows that to some extent, some cognitive abilities are independent of each other. Presumably superior performance in some cognitive tasks and inferior performance in others represents a trade-off of abilities along multiple spectra. The brain is limited in size, its computation capacity is limited, relative cognitive abilities of individuals will depend on the myriad details of the neurodevelopmental path that individual took.

Communication is "savant" ability of NTs

Many ASDs have savant abilities, which demonstrate that what ever part of the brain is providing those cognitive abilities has superior performance to the corresponding part of NT brains with lesser performance. The one area where NTs are universally better than ASDs is in communication. I suggest that communication is the savant ability of NTs, and that NTs have traded reduced abilities on ToR and ToC for enhanced ability in ToM.

The difficulty in relations between ASDs and NTs is that NTs don't appreciate that the ToM they are using for communication is a savant ability that ASDs don't share, and shouldn't be expected to be able to emulate. An ASD can't emulate the NT savant ability to communicate any more than an NT can emulate an ASD savant ability at mathematics. If you don't have the brain structures that can do the computations, you can't emulate the behavior. You might be able to fake how it sounds, but because the fundamental neural structures are not present, it is just an act and can't have the actual content.

Trying to think about Reality with a ToM is like doing Cargo Cult Science

Richard Feynman coined a term, Cargo Cult Science, to describe the practices of people who may be doing what they call experiments, but they are missing the fundamental intellectual honesty to be actually doing science. The term comes from the observation that tribes in the South Pacific would observe westerners arrive and set up landing strips which would bring aircraft laden with cargo, all sorts of goods that seemed to appear like magic. Along the lines of Arthur C. Clarke's observation that "any sufficiently advanced technology is indistinguishable from magic". They tried to understand the source of this cargo and how to get cargo for themselves using their understanding of reality. They generated a Cargo Cult, and proceeded to adopt rituals to try and cause cargo to appear.

This is really an excellent metaphor for trying to think about a subject with the wrong approach. Their thinking was that such good cargo had to come from the Ancestors, but the Ancestors would only bring such good cargo if they were communicated with in the right way, which the westerners knew how to do, so copy them and the cargo would appear. They built landing strips, control towers and populated them with radio control operators, but to no avail.

Explaining that their approach was wrong would fall on deaf ears. They don't have the background to understand where the cargo actually came from. They had anthropomorphized their observations and reduced them to the human terms they could understand using their ToM. They didn't come to their beliefs via facts and logic, facts and logic won't dissuade them from their beliefs.

Obviously there are multiple individuals involved, a leader and followers and the leader may achieve lots of things even if no cargo shows up. Presumably it is the charismatic persuasion of the leader using the leader's ToM that causes the followers to believe the leader. Simply by leading the effort to obtain cargo the leader achieves status over the others. Even when doing something completely useless and wrong, the society holds together if all of the members share the same ToM. Individuals not sharing the conceptualization of obtaining cargo by building airstrips would not fit in.

To people who have savant mathematical ability, those without it who are trying to emulate mathematical abilities can be seen as trying to do cargo cult mathematics. They can go through the motions, but don't have the ability to generate the content. Similarly, ASDs who try to communicate with NTs are doing cargo cult communication. They can go through the motions, but there is a lot of stuff that is being missed.

Neurological structures required to support an idea

The only ideas that an individual can think about are ideas that can be mapped into that individual's neural network. To learn a new idea, either the neural structure present is sufficiently flexible that the new idea can be mapped into it, or the neural structure must be modified until the new idea can be mapped onto it.

The process of learning a new idea must include as the first steps, the process of modifying the neural networks of the brain such that they can support the new idea being learned. Often the first step is "unlearning" ideas that are wrong. I think that this modification of the brain to support new ideas is why learning takes such a long time. New neural structures need to be made.

All mental representations require some level of neuronal "overhead" to be sustained. The details of how the brain does that are not understood. While the capacities of the brain are large, they are not infinite, and at some point trade-offs must be made.

Socially isolated individuals develop on an autism-like pathway.

All important physiological systems are under feedback control (that would be all physiological systems). Presumably an organ as important as the brain is also under feedback control, and this is reflected in the improved efficiency obtained through practice at certain mental tasks.

Presumably if there is a trade-off of ToM vs. ToR, then isolated individuals with no need for a ToM would develop a more robust ToR. This does appear to be the case in multiple organisms including humans, monkeys and rodents.

The classic work on socially isolated monkeys was done by Harlow in the 1960's, [34] and present animal welfare regulations would make such experiments problematic. Some monkeys were raised with no social contact at all, even with their mothers. Such monkeys were profoundly affected and exhibited rocking behaviors, self-injurious behaviors and profound disruption in abilities to interact with other monkeys. They were termed autistic by the experimenters.

Surprisingly, some of these socially isolated monkeys exhibited superior cognitive abilities. What is especially interesting is that these superior abilities were termed "deficits" by the experimenters. [35] Socially reared monkeys were conditioned with a tone and a startle stimulus. A redundant lamp was then paired with the tone. Socially isolated monkeys conditioned to the redundant light, the socially reared monkeys did not. The experimenters characterized the non-conditioning of the socialized monkeys to the redundant signal of the light as "blocking" the isolated monkeys then exhibited what was termed a "deficit" in blocking. Why the experimenters chose to use the term "deficit" to refer to a superior ability tells us something about the experimenters and their expectations about the socially deprived monkeys, not the monkeys.

Rhesus monkeys raised in social isolation have superior learning performance to those raised in social environments. [36]

Involvement of nitric oxide in social interactions and communication

The archetypal social interaction in mammals is the bonding of the mother to her infant. All mammals exhibit this behavior and have exhibited it for as long as mammals have suckled their young. The first social interaction all mammals have is with their mother. Even mammals thought of as primarily non-social do have this social interaction.

NO is involved in the development of the bonding and smell recognition that occurs in ewes within 2 hour of giving birth. Inhibition of nNOS blocks formation of that olfactory memory, and this blockage can be reversed by infusion of NO into the olfactory bulb. [37] Oxytocin is essential in the formation of normal social attachment in mice. [38] Reduction in oxytocin release following epidural anesthesia in heifers preceded a reduction in maternal bonding type behaviors[39]. Activation of the oxytocin receptor causes activation of nitric oxide synthase. [40] The connections that mediate maternal bonding can occur in the space of a few hours[41], limiting the distance over which axons must migrate to form these new connections.

Why NO is the signaling molecule that mediated the neural remodeling to cause maternal bonding makes evolutionary sense. Lactation is extremely energy intensive. If a mother does not have the metabolic resources to generate sufficient milk of sufficient nutritional quality to sustain her infant until it is weaned, she (and her infant) is better off not bonding to her infant and abandoning it. Spending metabolic resources on a reproductive attempt that will fail will reduce the success of potential future reproductive attempts. A failed reproductive attempt has no advantage either to the mother, or to the infant. An infant's best reproductive strategy in those circumstances is to do what ever increases the likelihood that the infant's mother will have a successful reproductive event later, so that the non-surviving infant may have a surviving sibling.

I discuss this at length in my blog on infanticide. Using NO as the positive signaling molecule to mediate maternal bonding directly couples maternal bonding to energy status. The low NO of metabolic stress directly reduces the degree and fidelity of maternal bonding. In extreme metabolic stress (the most important states for maternal bonding to be blocked) the maternal instinct turns from nurturing to infanticide. It needs to be appreciated that infanticide under conditions of extreme metabolic stress is as much a "maternal" instinct as is nurturing when times are better. I see infanticide as the brutally hard state that desperate metabolic stress induces in postpartum women.

Social isolation reduces NO generating neurons in the brain

When rodents are raised in a socially deprived setting, the numbers of NO producing neurons in some parts of their brains are reduced. [42] A reduction in basal NO in the brain due to development under socially isolated circumstances makes sense. Many social interactions are mediated via NO mediated pathways, including bonding and other pathways mediated through oxytocin. If the environment one is growing into is non-social, social neural pathways have little or no survival benefit. Better to develop the neural structures that will be useful.

Socially isolated individuals retain sufficient neural plasticity to partially recover

Social isolation at birth produced monkeys with profoundly disrupted social abilities. Experiments demonstrated that some of the disrupted social abilities could be restored. This involved the use of "therapist" monkeys, usually socially raised normal monkeys that were substantially younger than the isolated monkeys. [43] In females, a socially isolated female could recover somewhat and be an improved mother following pregnancy and raising an infant however many times the first born infants did not do very well but mothering did improve with subsequence births[44] demonstrating plasticity in neural networks mediating mothering behaviors during pregnancy and/or mothering activities. Since maternal bonding is the archetypal communication pathway for mammals, this suggests that other fundamental communication pathways have plasticity also.

With NO being involved in bonding, improved bonding and mothering interactions with subsequent births is consistent with increased neurogenic nitric oxide as a causal mechanism. If a non-social environment becomes social, reconfiguring neural structures to cope with social interactions would be advantageous.

Potential for treatment

I suggest an analogous treatment for ASD individuals may be to incorporate them into play groups with significantly younger NT children that are at similar developmental stages, but with sufficient adult supervision that nothing untoward can happen.

Doing this in the context of increasing NO levels via the techniques I am working on my have important therapeutic effects.

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35 comments:

sadunkal said...

It seems interesting...it's also long... :) But I'm willing to read it all when I can find some time.

By the way there is a typo in your last sentence I guess: my - may

Socrates said...
This comment has been removed by the author.
Socrates said...
This comment has been removed by the author.
Socrates said...

Third time lucky:

As an autistic, the idea of no being able to ascribe thoughts and feelings to a triangle on a computer screen, no matter how delightedly it dances when kissed by a square, is not a deficit.

It's what makes me a human and you lot a bunch of evil monkeys ;-)

Jonesy said...

Great article! I spotted a couple typos myself. Search the post for "hominin", and change it to "hominid" (of course). Also, when you say "pigeon" talking about language, it should actually be "pidgin".

I liked this article so much, I incorporated a summary (with relevant quotes) into my latest post over at The Autism Spectrum.

I don't disagree with anything you say here, but I do add a lot to the picture, some of which I know you disagree with me on. Still, I hope you'll give my post a read and leave a comment.

BdN said...

"Search the post for "hominin", and change it to "hominid" (of course)."

Actually, hominin is an appropriate term. See :

http://archaeology.about.com/od/hterms/g/hominin.htm

and

http://www.madsci.org/posts/archives/2003-04/1050350684.Ev.r.html

But writing "Humans are the only extant hominin that manufactures and uses tools." is a mistake since human (homo sapiens sapiens) are the only extant hominin and because some extinct hominins did manufacture and use tools.

daedalus2u said...

I was aware of the change in the definitions when I wrote that sentence.

The distinction I was trying to make was about tool making as well as tool using. Chimps and monkeys use tools, virtually all tools that they have not made or modified themselves. Tool making requires a tool-using-ability that is of a higher order than simply using objects that are already available as tools. I think the understanding that tool making is a tool-using-ability of a higher order is lost on people who don’t have it. I think the same way that an ability to communicate in sentences is a communication ability of a higher order than being able to communicate with only single words or pre-made phrases.

I was trying to convey that there is quite a gulf between the monkeys that can learn to crack nuts with stones after a few years of practice vs. humans who can learn to crack nuts in a few minutes. This is a gigantic difference.

There are no other organisms with even a tiny fraction of the tool making ability of humans. I think that makes it quite difficult for humans to see just how special that ability is.

/s said...

This is a hypothesis with flair and chutzpah. Publish I say, even if in Med Hypotheses (should Nature is not interested this time ;-). Your info about NO and skin is also amazing--totally new to me.

Re autism and NO, would your hypotheses in some way link in with abnormalities of fatty acid and cholesterol metabolism (Am J Med Genet B Neuropsychiatr Genet. 2006 Sep 5;141B(6):666-8., J Nutr Health Aging. 2004;8(3):163-74., Biol Psychiatry. 2007 Feb 15;61(4):551-3., Horrobin "The Madness of Adam and Eve" etc etc), especially in the light of the fat free craze...

And now I am going off tangent!
...where severe confusion is made between "good " and "bad" fat or cholesterol. E.g. not realising that some fats are essential while others are just plain bad (as transfats and saturated fats) (CCM Pond "The fats of life"). (Uffe Ravnskov's cholesterol-skepticism is very interesting.)

And well let's chuck in Martin Pall's ideas on CFS too.

Cheers
/S

daedalus2u said...

In the comments of another post I discuss Martin Pall's ideas.

http://daedalus2u.blogspot.com/2008/06/mechanism-for-mitochondria-failure.html

They are 180 degrees wrong. CFS is caused by not enough NO, not by too much. Not enough basal NO causes the switching from a low NO state (dominated by superoxide) to be sluggish, leading to greater time spent during the transition where NO and superoxide are both produced. That is what causes the build-up of nitrated proteins, not enough NO to rapidly switch from a low NO state to a high NO state. There are links there to more discussion of NO and CFS including details on why the problem is not enough NO.

I looked at the first paper on cholesterol metabolism in the context of autism, and I would consider that to be an “autism-like” syndrome due to a defect in metabolism. The defect in metabolism causes metabolic stress which lowers NO and that invokes the low NO phenotype which has many autistic characteristics.

Low NO does skew cholesterol physiology because NO regulates cytochrome P450 enzymes that are intimately involved with multiple steps in cholesterol synthesis as well as in steroid synthesis. There are ~60 cytochrome P450 enzymes. There is excellent evidence that some of them are regulated by NO, it is likely that all of them are regulated by NO to some degree.

/s said...

After having read your brilliant hypothesis on ADSs and NO more thoroughly I think there is something missing. The why now? Why this sudden apparent increase in neurological dysfunction that according to Fuller-Torrey has occured during the last 250 years? His research and ideas/hypothesis are summed up in the book (well more of a monograph) "The Invisible Plague: The Rise of mental Illness from 1750 to the Present" that also contain a huge amount of statistics pressing his case.

You state that "the genotype that leads to the ASD phenotype was adaptive under conditions where humans evolved, in the “wild”" and then go on to elucidate by suggesting a ToM/ToR trade off due to environmental stress (i.e. good times/hard times).

The problem with this part of your hypothesis is that a shift towards the ToR phenotype will only have evolutionary value if it increases the chance of either 1) individual survival long enough to a) beget children that b) in their own turn survive etc, or 2) help other members of the hunter-gatherer family group (or tribe) to accomplish 1).

If neither 1b) or 2) will result, any genetic imprinting or mutations selecting for '100% ToR' will be selected against or mankind would just plain have lost the capacity of ToM and thus the ability to have the socially complex society we have (pretty harsh statement, but a hundred individuals solipsistically banging away at stones would soon end up as predator dinner).

You also suggest that the "ToR" individuals would invent superior tools and then come back and regain control over the group. Unfortunately the outcome would be pretty more likely that the group killed the solitary male. Also notice that in e.g. chimpanzee groups the *alpha female* is a player in deciding the "power" of the current alpha male and chance of success of any pretender. Also, alpha male status is only attained by cooperating with other males and a socially unskilled chimpanzee male would, even in the event of superior firepower, be very short-lived. Frans de Waal has written many scientific papers and popular books on this subject.

'100% ToM' is equally fruitless as such a society would most likely just stop being able to adapt to changed environmental challenges.

So evolutionary pressure has for favored the evolution of a more complex ToM, while retaining a high capability for ToR. In sum a balance between ToR/ToM with the genetic mechanism to 'produce' individuals within a range of endpoints of notably less than 100% ‘pure’ ToM or ToR ability. (And an individual with too much of any would hopefully be corrected by his parents -- unless those are morons applying peanut butter to their children’s faces -- or other adults, thus helping mitigate the effects of too much of either.)

That said it is not surprising that ASDs cannot be pinned on any few genes but may involve "perhaps 135 genes". ASDs are as you state not a genetic disease but an effect of something gone amiss with our quite normal genes as you do conclude.

An aside: a 'mild' type of social isolation usually called "sickness behavior" is observed in all sick mammals and birds. The sick animal withdraws from the group and interaction with other individuals is impaired (it could loosely be regarded as ToM regressing in favor of ToR--reality: 'i am vulnerable', 'i spread possible infection' etc). (e.g. www.ncbi.nlm.nih.gov/pubmed/17088043 and /18979053 and /19125209). This reaction is cytokine-induced. This is why mercury, and other vaccine adjuvants, cannot yet be excluded as causatives in ASD or other neurological complications as, at least in murine experiments, cause an autoimmunogen reaction, affect Th1/Th2 balance etc. (e.g. www.ncbi.nlm.nih.gov/pubmed/17084957 and /15990073 and /16443248 and /16512356 and /16870260 and /18771903).

A possible cause to why fever may cause ASD regression may be sought in cytokine etc expression changes concomitant with fever.

Another aside: mammal bonding. Curiously smell bonding (imprinting) is to any (although textbooks usually always point out the mother, despite e.g. K Lorentz animal experiments showing that anything goes) individual that holds the baby during these crucial postpartum minutes to first hour. If it is the father, the child will imprint on the father and seek out the father except when hungry as it learns that another individual, aka the mother, can only provide this (lactation assumed). If the 'initial individual' is 'lost' the baby will re-bond.

To get back on track.

To cut a long story short you suggest "nitropenia" following long time environmental stress triggering neurological change leading up to a higher prevalence of ToR-biased individuals. (Although not quite clear in your text, but I have made that assumption.) By implication certain factors in our current environment cause an exaggerated 'nitropenic response' that cause over-expression of the ToR genotype and phenotype.

You point specifically at modern bathing practices as a causal source.

Hope I have followed you correctly up to this point.

What is left unexplained is why ASD/autism is suddenly seemingly more common. A disorder with such characteristic symptoms should have left some impression in medical records before the eighties, even assuming different diagnoses and/or a broader definition of normal. Especially the upper classes, which can be assumed to have adopted modern bathing practices before the general population, should thus hypothetically have an elevated incidence of ASDs. Which may actually be the case or be it just higher parental awareness (e.g. http://www.pubmedcentral.nih.gov/tocrender.fcgi?artid=1449864 and http://www.springerlink.com/content/m522g204l111445k).
Prevalence studies indicate higher rates of diagnoses in affluent communities and first generation immigrants, which both fit the bill for the hygiene/bath hypothesis.

These groups also fit the bill for the vitamin-d hypothesis of ASD which is described at length here: http://www.vitamindcouncil.org/health/autism/.

Is there some modern change in behavior affecting lower classes that emulates upper class behavior. Indeed there are: bathing, less prevalence of menial and often outdoor jobs and the sun-scare, dictating that sun is bad, leading to usage of sun-block and avoidance of outdoor environments/sunbathing.

Could there be a connection between Vitamin D deficiency and nitropenia? Actually there is. Neuroprotective and immunomodulatory effects of vitamin D metabolites have been described in several experimental models. It can inhibit the synthesis of inducible nitric oxide synthase and increase glutathione levels, dose-dependently inhibited iNOS messenger RNA expression, significantly reduced the gaseous NO release and OONO(-) production, alter brain gene and protein expression, regulate the balance between neuronal stem cell proliferation and programmed cell death in the offspring etc

Details here (this also connects back to Th1/Th2 immune balance etc): www.ncbi.nlm.nih.gov/pubmed/19019042, and /18579197 and /11893522 and /14749681 and /18621414 and /18694980.


/S


PS

I get the impression you have read Pinker's books on language, but if you've not, do so! He makes a brilliant case for language structure being preprogrammed in our brains.

daedalus2u said...

s, very nice comment. You are the first person who has read my stuff sufficiently well and understood it sufficiently well so as to make such well thought out comments. Thank you very much, I greatly appreciate it. It will take several comments to respond.

I see the ToM and ToR spectrum as many dimensioned, at least dozens, probably hundreds. I see it as a characteristic like height. Height is a multi-gene trait, with positive and negative control. You can't have someone who is 100% tall because the rest of physiology can't support that extreme. That the 100% extreme case is lethal does not mean that the partial case is not adaptive. All evolved traits at steady state end up being in balance, where more of the trait and less of the trait both increases death. Behaviors are a lot more complex that physiological traits and their relative survival benefit depends on the other humans around so there is more dispersion in what is good and what is bad because it is context dependent (which is why it is under epigenetic control and modification via neuronal plasticity).

I think there have been multiple hits on NO/NOx status. First, 150 years ago, the germ theory and the advent of industrial level supplies of clean water which people used for bathing. This took a long time to spread throughout the population. That is the earliest time I have data for. The decline could have started earlier. The advent of soap, even the crude home-made varieties may be an earlier hit. 150 years ago the average age of menarche was almost 17.

http://www.biolreprod.org/cgi/content/full/60/2/205

It has gone through a steady decline as people transitioned from isolated and untreated well water (which with virtual certainty has these bacteria) to highly treated municipal water which has near complete removal (some municipal supplies that use chloramine can have quite large populations of these bacteria).

The next hit was the advent of alkylbenzene sulfonate detergents which are toxic to these bacteria at ppm levels. That started in the 1960's.

The next hit was conditioning shampoo which allowed people to wash their hair every day without it turning to straw. That started in the 1970's.

The latest hit is the antibacterial everything fad.

There are characteristic disorders related to nitropenia that increased in that time frame, obesity, diabetes, allergies and asthma. The lead exposure from lead in gasoline may have had a modulating effect, perhaps generating a more violent phenotype (which is controversial) rather than an autistic phenotype, but I haven't really thought about that very much.

There may be other effects too, things that increase oxidative stress also lower NO levels. I think those effects are second order to the main low NO effect.

I have another post about the fever result. I see it as due to NO from iNOS.

http://daedalus2u.blogspot.com/2008/01/resolution-of-asd-symptoms-with-fever.html

There has been some recent work on Etanercept (a TNF-alpha blocker) injected into the CSF to treat Alzheimer's, which it does, causing substantial improvement in minutes. I think that is higher NO from blocking the superoxide production caused by TNF-alpha.

I see there are two components to autism, the neuroanatomy which only occurs due to low NO in utero and early childhood, and the ongoing autism-like symptoms which are only maintained due to ongoing low NO. I think the ongoing autism-like symptoms can be relieved by increased NO, the neuroanatomy can't unless NO is raised while there is still substantial neuronal plasticity.

Anything that lowers NO levels will skew physiology to be more on the ASD spectrum. Social isolation does, work with socially isolated monkeys shows increased mental acuity at some tasks, an effect that is reminiscent of savant abilities that some ASD individuals exhibit.

In rodents socially isolation causes increased mental abilities and also causes a reduction in NO production in the brain. Social isolation programs them to have a lower NO level.

Bonding is two-way. Babies bond to mothers and mothers bond to babies. Human females happen to be promiscuous in their bonding in that they will bond to virtually any baby, not just their own (in contrast to most other mammals).

There are plenty of NO/NOx photochemical reactions that occur in the skin. I suspect this is another reason for the loss of skin color when humans moved away from tropical regions; as NO/NOx was lost due to reduced sweating during winter, more photochemical NO/NOx was needed so skin color evolved to be lighter.

Regarding sickness behaviors, the brain self-regulates in the near percolation threshold. Around that threshold, the functionality of the network changes exponentially with connectivity in both directions. Below the threshold increased NO increases connectivity and exponentially increases functionality above the threshold increased NO increases connectivity and decreases functionality because the network becomes less susceptible to change. This could explain a difference between the sickness behaviors of people with ASDs and NTs. For the NTs, higher NO decreases their brain functionality.

Mercury doesn't fit. There was much higher exposure to mercury 70 years ago. At that time, many children were given teething powders that contain a grain of calomel, 65,000 micrograms of HgCl per dose Over 1000 children died of pink disease, which we now know was mercury poisoning. Many millions of children were given many thousands of times more mercury via teething powder than ever received from thimerosal. All of the in vitro tests are complete crap because mercury partitions into the cells (by ~1000x) over the media. You can't use the mercury concentration in the media to estimate the dose the cells receive because of that partitioning.

Then there is the Faroe Islands. The incidence of autism in the Faroe Islands is no higher than elsewhere.

http://dx.doi.org/10.1007/s10803-006-0178-y

This study overlaps the extremely extensive study on mercury in cord blood, where ~1000 consecutive births were tested for mercury and then followed up.

http://dx.doi.org/10.1289/ehp.7842

In the 1400 child cohort that overlapped the 1000 child cohort tested for mercury, there were 5 children on the autism spectrum, 2 with autism and 3 with Asperger's. There were 250 children that had documented cord blood mercury measurements of over 200 nM/L at birth. At most 5 of them had autism. That is more than an order of magnitude higher than the values in the DeSoto re-analysis.

There are some pathways by which mercury could interfere with NO physiology, but there is no evidence that mercury is at all responsible for autism and lots of evidence that it isn't. The "mercury causes autism" hype is being pushed by quacks and lawyers out of greed to exploit vulnerable parents, not by science or data. Sorry to be so harsh, but the "mercury causes autism" hype really has damaged the autism field. So has the anti-vaccine hype.

I do have a couple of posters on autism that I haven't yet put into blog form, one on the physical symptoms and one on NO as the final common pathway. Send me an email and I will send them to you.

PS, chutzpah? I don't see it that way. If you are right, it isn't chutzpah. If I am wrong, I would abandon it in a heartbeat. That isn't chutzpah.

daedalus2u said...

s, I looked at the abstracts of the immune/mercury papers you cited. Low NO does cause immune system effects. The immune system is turned on by low NO caused by the respiratory burst. Low NO activates NFkB and low NO also increases the sensitivity of mast cells. Xenobiotic chemicals lower NO when they are metabolized by the cytochrome P450 enzymes. Those enzymes are highly uncoupled and make lots of superoxide (as much as 50% of the O2 they consume goes into superoxide). That superoxide pulls down the NO level and disinhibits those enzymes (which are tonically inhibited by NO). The superoxide they then produce causes a positive feedback which accelerates their activity. (Incidentally I think this is the mechanism for multiple chemical sensitivity, if you have a very low NO level you will be hypersensitive to reductions in NO due to xenobiotic chemicals.)

Mercury was once used as a cure-all. It was one of the most widely used pharmacological agents. I suspect that it worked by reducing NO levels and lowering the threshold for triggering the immune system. 100 years ago, many diseases were infections. With no antibiotics or specific anti-microbial agents the only treatment for infections was to activate the immune system. I suspect that the decline in infectious diseases that has occurred in the last 100 years or so, and which preceded vaccines may be due to lower NO levels from increased bathing. Low NO will increase the activity of the immune system and counter infectious disease, but that higher immune system activity will then cause autoimmune disorders, allergies, asthma, the chronic inflammation of the metabolic syndrome, inflammatory bowel disease, rheumatoid arthritis and so on. My hypothesis is that these bacteria are the agent of the hygiene hypothesis which has been suggested to explain the differences in health between the developed world and the rural undeveloped world. Allergies, asthma, heart disease, diabetes, hypertension, obesity, are virtually unknown in the rural undeveloped world.

Mercury is not the cause of autism. Reducing exposure to mercury will not prevent autism. Reducing mercury will not relieve the symptoms of autism. Mercury does lower NO levels and may (to a very slight extent) exacerbate disorders associated with low NO. In the context of autism I think any potential exacerbation will be too small to measure even in extremely large populations even with deliberate mercury exposures. The people pushing the "mercury causes autism" idea are not doing so based on science, on facts or on logic. They are beyond being reasoned with because they did not arrive at their belief via facts or logic, facts and logic will not change their beliefs. I don't want anything I say to be used (misused) to exploit gullible parents into injuring their children by chelating them to remove mercury which isn't there.

If the people working on the mercury causes autism idea were working in good faith and were being intellectually honest, I would have no problem discussing some of the similarities in mercury physiology and low NO physiology. I am afraid that any discussions regarding the similarities between mercury physiology and low NO would get me branded as a quack as the mercury causes autism advocates are known to be.

The mercury causes autism idea has killed a few children, no doubt has caused neurological damage in many others due to chelation. Some of the quacks pushing it have made a lot of money, but no children have gotten better due to chelation. It is a dead end, a dead end that every intellectually honest scientist has abandoned long ago. The only hangers on are those unable to understand the science, or those who don't care about the science and are only in it for the money they can get by exploiting those who don't understand the science.

Again, I am sorry to be so harsh, but children's lives are at stake, and the anti-vaccine quacks don't care. I do care.

Jonesy said...

I agree with you that exposure to mercury doesn't explain the whole thing. And I understand you don't want to lead people in what you see as the wrong direction. But if exposure to mercury lowers nitric oxide levels, it's certainly not helping matters, right? There are just bigger contributing factors that should be considered causal way ahead of mercury exposure. Is that your position?

Not enough NO early on is the key, right? What do you see as the primary cause(s) of lowered NO levels these days? Just stress in general?

About all the modern advances in germ-killing power, how exactly does that affect NO levels again? (I'm sorry if I've missed/forgotten something. I really don't have your background; I'm just extremely interested and personally invested.)

daedalus2u said...

I am not saying that mercury is good for anyone. It isn't. Mercury exposures should be reduced as low as is feasible. Canned tuna has ~0.5 ppm mercury in it. 100 grams of tuna has about 50 micrograms of mercury. Ingested methyl mercury is better absorbed than is injected thimerosal, in that ingested methyl mercury results in higher blood and brain levels than does the same dose of injected thimerosal. It makes no sense to blame mercury from vaccines when people receive orders of magnitude more mercury from other sources. The only reason mercury from vaccines is being blamed is because pharmaceutical companies have deep pockets. Now that thimerosal is removed from vaccines, there is not the slightest hint of a reduction in autism cases. Why? Because mercury in vaccines never had the slightest thing to do with autism.

There is not a bit of science driving the mercury causes autism idea. It is driven purely by greed by quacks exploiting curebie parents and by lawyers trying to win the legal lottery by scamming the court into ruling for them. There is no science behind the mercury causes autism idea, no amount of science is going to stop the quacks and lawyers from pushing it so long as they continue to make money off the naïve and gullible.

They are wasting resources trying to enrich themselves while providing nothing useful. Those resources could be better utilized with treatment or with research that had a chance of leading somewhere. Mercury is a complete dead end.

The source of NO that I am working with is from a surface biofilm of ammonia oxidizing bacteria. Bathing removes those bacteria and reduces the NO/NOx status. I see that mechanism as the normal physiological pathway by which humans regulate their basal NO/NOx status. Disrupt that biofilm and you disrupt basal NO/NOx status. Disrupt basal NO/NOx status and you skew physiology to a high stress state and exacerbate all disorders that are exacerbated by stress. I don't see them as disorders per se, I see them as normal physiology that is invoked under stress. They are adaptive in the short term. They become maladaptive in the long term when pushed to an extreme level by chronic low NO/NOx status.

Jonesy said...

Thank you so much for that clarification! I gleaned some of that information from your responses to /S, but I hadn't yet seen this post where you sum it up nicely. It's almost two years old; does it still represent (in brief) your position pretty well? I'd like to link to that post and quote that last comment you made here on my blog if you don't mind.

You've certainly adjusted my view of the whole thing. I feel much better about not using soap every time I give my two-year-old daughter a bath now. I thought it was unnecessary, and I had a vague suspicion it might actually be harmful somehow, but I hadn't seen this kind of information about the ammonia oxidizing biofilm anywhere before. Very interesting!

daedalus2u said...

The ammonia oxidizing bacteria are very well known in soil chemistry and in waste water treatment. I am the first to find that they are commensal and important in physiology. It is hard for some to accept that concept because they are obligate autotrophs and so don't grow on any media used to isolate pathogens.

The bacteria are quite slow growing, so it can be difficult to recover a biofilm once it is lost through bathing. Once you have a biofilm, bathing is optional. These bacteria suppress the heterotrophic ones that cause disease and odor.

s said...

Hi again, thanks for your kind consideration of my response and compliments for the 10000 hits.

I would like to add that I liked your suggestion that communication skills (essentially ToM as you propose it) as being "savant" skills of "NT"'s. Actually visualizing ToR, ToM and ToC on a ternary diagram is quite interesting as 100% of any can be visualized as zero of the other. OK 100% ToC is difficult to envisage if ToR and ToM are zero. The opposite is easier as it would implicate the inability to choose/understand when the choice of ToR or ToM is appropriate.

/S

PS
Yes chutzpah was a badly chosen descriptor.

PPS
Comment on mercury under your mercury thread

daedalus2u said...

That is quite all right. I have Asperger's, and to be described as having chutzpah was incongruous to me. I appreciate it probably can happen, but I think of chutzpah as more of a ToM characteristic.

There are likely many analogous mental modules (but I don’t really like that term as applied to physiological systems). Selecting the proper brain volume(s) to activate has to be an especially critical brain activity.

S said...

Hmm, whatever I propose you manage to implicate NO levels ;-)

What you say is that NO levels are vital for basal cellular biochemistry, energy balance etc etc. I was not quite aware of that fact.

If thus correctly understood by me, NO regulation should be tightly regulated in the body to avoid adverse outcomes and also that regulation may differ in different organs?

One obvious question is of course, as I noted before, why now and why some individuals. As there are mothers (and fathers) that are exaggerated users of body detergents and do not get obviously neurologically impaired children and quite the opposite.

Or is this just a statistical error caused by subjective diagnosis criteria or parents wish to explain their kids sub-average intellectual skills?

In my opinion it is both diagnostic criteria, parents and a real increase. But I also believe some additional precipitating, possibly environmental, agent is not unreasonable.

Among these are not only bath and soap, but also changes in usage of perfumes, sunscreen (both skin effects and vitamin D deficiency), dietary fat amount and composition, dietary sugars, fibre (from fruit/vegetable fibre to wheat fibres), increased gluten consumption (higher amounts of wheat from previously more rye and wheat) and needless use of antibiotics and anti-microbials in consumer products.

The second question is if the pathway through which these causes act. Are they postnatal effects caused by epigenetic effects in maternal (or paternasl) germcells or in utero effects or postnatally?

The third question is what the ultimate cause is? Can it be such an elegant solution as your NO proposal?

I am obviously far from knowledgeable of the matter, but this means that experimental animal models should be possible to set up to study the mechanisms proposed by you and others.

One basic experiment would be to e.g. eliminating the nitrogen fixing skin/hide bacteria and observe the outcome after provocation with various substances.

I did a quick check on the web and I could not find any experiments of that sort. Are there any?

/S

daedalus2u said...

As far as I know, I am the only researcher working with these bacteria as surface commensals. I have shared them with a number of other researchers, but none that I know of are doing anything with them at this time. One in particular said it would be too much of a "business conflict" for him to do research on them (the conflict was with one of his funding sources). I have presented at some conferences (including a Gordon Conference on NO), and a number of posters. I would be happy to send them to you. I have instrumental data showing NO production by these bacteria coincident with instrumental data of a physiological effect known to be mediated by NO, in vivo (human). I haven't "published" anything other than abstracts and this blog. It would be quite feasible to look at the effects of these bacteria in animals. I have found surface biofilms on many different organisms and I think this is a generic mechanism for setting the basal NO/NOx level in eukaryotes (vertebrates, invertebrates, plants and animals). At present I don't have the resources to do that research. It doesn't involve DNA; so many researchers are simply not interested in it.

NO is involved in thousands of pathways. It directly couples to ATP through sGC, and ATP couples to everything. As a signaling molecule it is extremely well regulated. The basal NO level is a control parameter that physiology uses to keep everything "in sync" and to regulate the myriad NO pathways together. The basal level is set (mostly) by these bacteria, or rather physiology evolved to have a biofilm of these bacteria so that when ammonia is released onto the skin NO/NOx would be produced. There are a number of physiological reasons why that makes sense; the external skin is protected from infection by heterotrophic bacteria by a biofilm of ammonia oxidizers. Making NO inside the body requires O2 and arginine and excess ammonia has to be gotten rid of anyway, easier to get rid of it while making something useful. The basal NO level is quite low, ~1 nM/L, that is difficult to produce and (and especially) regulate using any of the NOS enzymes. Because all NO sensors only sense the sum of NO from all sources, the basal NO level is an important parameter in all NO mediated pathways. If the basal NO level is low, all NO pathways are skewed in the low NO direction (that is the high stress direction). Any change in basal NO will affect those pathways with no threshold (because it is already in the active range).

There are a lot of idiosyncratic differences between individuals. I think that one of the large differences associated with skin color is that because individuals with light skin had ancestors who lived many generations in regions where there were cold winters where sweating did not occur year round, I suspect they evolved compensatory pathways to deal with the loss of NO from these bacteria during winter. I think that is why the low NO disorders seem to hit people of color more severely, including hypertension, kidney failure, heart disease, diabetes and so on. I have no idea what those compensatory pathways might be. I think the culture practice of sauna arose to cope with reduced sweating in winter. The modern custom of bathing afterward is (I think) non-physiologic.

I think that many of what are called "complex genetic disorders" are not disorders at all. They are normal physiology working the way it is supposed to work, but with too low a basal NO level. I see them as being characterized by good regulation around a bad setpoint. Physiology will do things that in the short term are bad, but which are better than the alternative. An example I use a lot is "running from a bear". If the bear catches you, you are dead, so any injury your body needs to sustain in order to escape from the bear is better than being caught. The triggering of the "fight or flight" state is what allows you to run from the bear until you drop dead from exhaustion. Your heart rate goes up, your blood pressure goes up, you get hyperglycemia, your immune system is turned off, and you don't feel tired. Your body can't sustain that state indefinitely, but it doesn't need to, it only needs to sustain it until the bear has been escaped from, or until you drop dead from exhaustion. Being caught by the bear and dying from exhaustion are "the same" from an evolutionary standpoint. The capacity to run yourself to death is a very strong survival feature because you can use it to escape from a bear.

I think the effects of antibiotics in animal feed may be due to the suppression of the ammonia oxidizing bacteria and a reduction in basal NO levels. Lower NO will mimic the effects of stress, which skews physiology to accelerate things. I think that explains the faster growth, more efficient feed conversion into body mass, greater muscle mass, and earlier sexual maturity. NO inhibits the enzyme that is the rate limiting enzyme for androgen synthesis, so low NO will cause hyperandrogenic effects. I think that is what produces the larger body size in farm animals given antibiotics. One hyperandrogenic effect is increased hair growth; that expands the niche where these bacteria live, increasing NO/NOx from them. I think that is one of the feedback mechanisms that regulates NO/NOx status. I think that bathing does to humans what antibiotics in animal feed does to farm animals.

I think the main effect of low NO is to activate stress pathways. In the short term these are adaptive, in the long term they are not.

NO is known to modify epigenetic programming in utero.

http://ajprenal.physiology.org/cgi/content/full/288/4/F626

Many aspects of adult physiology are known to be epigenetically programmed in utero.

http://www.ncbi.nlm.nih.gov/pubmed/10799412

The focus of research has been on nutrition because that is something that can be measured and is pretty straightforward. Basal NO has to be important, and that may be part of how nutritional status gets transduced into fetal epigenetic programming.

There has been research done on exposure to stress in utero, and that research is all consistent with what I am proposing. Stress in utero does increase brain size in experimental animals and it also increases the incidence of ASDs.

http://dx.doi.org/10.1007/s10803-005-5037-8

Any kind of maternal "stress" including nutritional stress is going to change the NO/NOx status but in complex ways. The effect that these have on the developing fetus should not be thought of as "damage" per se, rather as programming the fetus to survive better in the world it is going to be born into. If food is scarce, it is better to have a small body that doesn't need as much food, and better to grow fast, mature fast, and reproduce fast and spend fewer resources on maintaining your body for a long life span (so a larger fraction is devoted to reproduction). Similarly if you are being born into a violent world, better to initiate violence than to have violence initiated on you. This is what is known as the cycle of violence, and because it happens, there must be physiology that supports that epigenetic modification of humans via exposure to violence. I think that low NO plays a key role in that.

I don't think that modification of germ-line cells is a big issue in autism. Because women carry their eggs with them, those eggs (in theory) could integrate a life-time of environmental effects and be epigenetically programmed to match what ever environment seems most appropriate. That seems to be overkill to me. If the environment changed back and forth, the programming would have to change back and forth too. It would seem most efficient to simply reprogram everything once, during oocyte maturation. It seems even more plausible that rather than programming the oocyte before conception, that programming the individual tissue types during first trimester differentiation a few months later seems a lot easier, more powerful and much more likely. It makes more sense to use present day environmental conditions to epigenetically program a fetus while it is differentiating and growing rather than what the environment was like 20+ years ago when the mother was a child or in utero. There could easily be multi-generation effects; I just think they are going to be second order to effects during that pregnancy. Over evolutionary time, women averaged having only 2 children survive and reproduce. Without birth control they would have gotten pregnant many times. I think that immediate environmental effects would influence infant survival much more than effects 20+ years ago.

Epigenetic programming of sperm is (I think) a more likely explanation for paternal age than is genetic mutations in that sperm. There are some studies suggesting that very young as well as very old fathers have an increased incidence of ASD children. Having a father who is unable to protect you (either because he is too young, or has died of old age) means you have to grow up fast. That effect might be mediated through epigenetic programming of sperm, or (perhaps even more likely) through stress experienced by the mother during pregnancy because of the father of her fetus being too old or too young. If it is epigenetic modification of sperm that is likely mediated through low NO (i.e. paternal stress during sperm formation). That might be reduced by increasing NO levels. Certainly lots of cell-cycle stuff is regulated by NO and the proper NO background will increase the fidelity of DNA replication, and perhaps even improve post cell division deletion of damaged genomes.

Sylvie said...

I am not a scientist by inclination, but am an animal lover by nature. Therefore, when I read about the superiority of the human brain over the animal brain, I am always a bit uncomfortable. I think it's because there is more to being alive in the universe than being able to think, create and use tools, create a symbolic system leading to language and writing and mathematics and so forth and so on.

I admire animals because they simply are. A cat wishes to jump up to a counter six feet high, it looks up, it jumps. An elephant mourns the death of another elephant. Dolphins have assisted humans in trouble in countless scenarios for no "logical reason." Bees act for the benefit of their colony, with no teaching, no apparent mode of collective communication. It just is.

As humans, the majority of us have lost the ability to simply be. There is an increasing disconnect with the earth. The messages we get on media, television, social enculturation all teach about revenge, me first, that there is a right and a wrong and nothing in between, all sorts of capitalistic consumeristic values, the spectrum of normalcy, and that it's okay to destroy the bad guy and to step on others to attain success.

We have much to learn from animals, and from engaging in nonverbal thinking, induced by practicing meditation.

I know I have not presented a research-based "argument" here. I am speaking more from intuition and the heart, which I hope has a place here.

Sometimes words get in the way. What we wish to communicate is before the words come. But on the internet, the words are the only way, I guess.

Silent tranquility to all,

Sylvie

TheOtherGuy said...

I think your use of citations here is VERY misleading. You say that calls to abandon the search for a single cause of ASDs are premature and cite a paper (Happe et al. 2006), from Nature Neuroscience no less, that says the exact opposite.

I think your essential premise is flawed. My understanding is that you think low NO in utero leads to ASDs. I read through your paper, but you have not provided a single indication that this is the case.

While you have plenty to say about the link between defects in brain development and ASD diagnosis - the only study where you link it to 'stress' (and, by extension, low NO) is a written survey of parents of autistic and Downs Syndrome children (Beversdorf et al. 2004). I am sorry - but this is a very long bow to draw.

The one possible tenuous link is a comment by Gustaffson - a comment notably lacking any empirical evidence when one reads the full article (which I suspect you have not)

Why is low NO the culprit? and not, say, calcium? Another important signalling molecule in foetal development. There may well be low amounts of NO in brains that go on to develop ASDs - but what makes you think this is the cause and not merely another symptom? Especially when, by your own admission, its level is modulated by hundreds of different chemical pathways.

What you have is a classic case of equating correlation with causation: a famous logical fallacy.

Why isn't the cause adrenalin levels, or insulin? Or any other hormone that fluctuates in times of stress. Are you sure you understand the difference between oxidative stress and psychological stress?

I don't doubt your passion for this subject. But if you want to have your work discussed by a link to a noted skeptic (Steven Novella)- you are going to have to account for this.

daedalus2u said...

What exactly is it you want me to account for? This is a work-in-progress.

The paper I linked to did call to abandon the search for a single cause. That was exactly why I linked to it. Their call to abandon the search for a single cause is premature. How is that misleading? Perhaps I should have put the citation mark after the word “premature” and not at the end of the sentence. Anyone who looked at the paper would not have been confused. I put the whole title in the citation, to reduce the likelihood that anyone looking at the citation would have been confused. I am sorry that you were confused.

You missed the major conclusion of my post; that ASDs are not caused by “defects in brain development”. They are caused by normal brain development pathways operating in a parameter space that causes the neurodevelopment path that leads to the characteristic neuroanatomy, behaviors and physiology of ASD individuals. Those characteristics are not “defects”, they are “features”. Any “feature” taken to an extreme can/will cause a pathological outcome. Evolution can and will take any “feature” to an extreme where disadvantages due to that feature balances the advantages. What evolution minimizes is the sum of death/non-reproduction due to too much and too little of the feature. There is no other evolutionary endpoint. I would expect to see pathological levels of every evolved trait, too much and too little.

Are you familiar with Simon Baron Cohen’s work on testosterone levels in utero and autism-like characteristics? Testosterone decreases NO levels in the brain, estrogen increases NO levels. Testosterone synthesis is regulated by NO. Low NO increases testosterone synthesis, high NO inhibits testosterone synthesis. Low NO in the brain explains the reduced brain blood flow observed in ASD individuals. NO is what causes acute vasodilation in the brain, and acute vasodilation is what the BOLD fMRI technique measures.

I do know the difference between oxidative stress and social stress. Do you? Oxidative stress is local because superoxide is blocked by lipid membranes. NO passes through lipid membranes, so it is low NO that transduces the local signal of superoxide between cell compartments isolated by lipid membranes.

You should look at my earlier posts on resolution of autism symptoms with fevers, and also my post on how high NO during immune system activation can cause mitochondrial shut-down.

NO is what regulated neurogenesis. NO is what regulates blood flow in the brain, and is what regulates synaptogenesis. NO regulates long term potentiation and long term depression. The largest class of transcription factors are zinc finger proteins. Metallization of zinc finger proteins is regulated by NO.NO regulates carbon flow through the folate pathway, which is a major pathway for DNA methylation and epigenetic programming of DNA during differentiation. Aberrant readout of DNA methylation accompanying MeCP2 deletion in Rett Syndrome is sufficient to cause autism-like symptoms. In the mouse model, restoration of MeCP2 activity rescues the phenotype.

NO regulates many other DNA expression pathways. It also regulates the cell cycle by a number of different pathways.The archetypal mammalian social behavior is maternal bonding, a behavior that all mammals exhibit, even those that are non-social. Maternal bonding has to be coupled to energy status because lactation is so energy intensive. Low NO inhibits maternal bonding. Sufficiently low will cause psychosis and infanticide. My hypothesis is that is the mechanism for postpartum psychosis. It is not a “bug”, it is a “feature”, a feature to preserve the reproductive capacity of a mother by inducing infanticide when she lacks the metabolic resources to sustain her infant until it is weaned. If she lacks the metabolic resources to sustain her infant, the “evolutionary correct” response is infanticide and attempt to reproduce again.

Social isolation leads to epigenetic modification of the brain which leads to low NO. Exposure to stress in utero in experimental animals causes neurodevelopmental changes. Why should humans be different? What neurodevelopmental changes are observed in humans from exposure to stress in utero? Movement on the ASD spectrum. Not a surprise when low NO increases androgen levels and increased androgens produce autism-like characteristics.

You should read up on Harry Harlow’s isolated monkeys. Social isolation made them profoundly “autistic” (as described by the researchers). Socially isolated monkeys have superior cognitive abilities in non-social environments. Very much like humans with ASDs often have savant abilities in non-social environments. What is very interesting is that the researchers looking at the socially isolated monkeys found their superior abilities to be “deficits”, just the same way that neurologically typical clinicians often find superior cognitive abilities in ASD individuals to be “deficits”.

There is an association of low NO with ASDs. This is because low NO is the final common pathway that links all of the different physiological pathways.

If you have specific questions, ask away.

Jay Gordon said...

Your posts are brilliant. I'm leaving this here and not "there" for all the reasons you can imagine. Thanks for any help you can give me.

Jay

jay@drjaygordon.com

Scotlyn said...

Hi Daedalus2u - I've spent the last couple of hours reading and thinking about this very thought-provoking post.

Here are some random thoughts.
1) Your very clearly articulated distinction between ToM and ToR makes a lot of sense of things I have experienced and observed but never thought about in this way - thanks. You also make the excellent point that: "A society with the ability to use the best skills of a highly variable and diverse group would be better able to cope with adversity than a society where all individuals had the same average abilities." It would seem to me that there is not a complete dichotomy between individuals with a ToM on the one hand, and individuals with a ToR on the other, but rather that both ToM and ToR may be found to a varying degree throughout the population, with some individuals exhibiting the extremes at either end, but most having a potentially average ability (although your treatment also seems to suggest that ToM may be more adaptive for most humans in most situations - or perhaps is the default, all else being equal). I appreciate your reading here of ASD as arising from (paraphrase) "normal development in response to an altered setpoint", but a key word in the term ASD is "spectrum." I suspect that those you term NT's (probably including myself) could also be profitably viewed as occupying places along a Neuro-typical "spectrum" - clearly the word "typical" could have no real meaning otherwise. Taken together, ASD and NTS (my amended term) could be seen to form a single human-wide spectrum where every individual could be placed somewhere along your ToM map, and somewhere along your ToR map.

2) "The Mountain People" by Colin Turnbull - probably published sometime in the '70s, describes an ethnographer observing a society going through such "bad times" as you postulate might help drive the adaptive switch towards an increased ToR at the expense of ToM. I'd be interested in your thoughts sometime on his observations if you ever tracked this book down. He nowhere uses the term autism, or NO deprivation. Nevertheless he closely observed what he perceived as the total breakdown of family and social bonds in the face of severe starvation, with high mortality at every age, in the population he had gone to study (I've forgotten which).

3) I remember reading somewhere (sorry I've no link for this), about a Russian study of breathing techniques, which concluded that nasal breathing was superior to mouth breathing, as it allowed more NO to be retained?/created? something like that. Just a hint, but if you can track it down, it may interest you.

Scotlyn said...

4) I now understand a lot more about your use of IT-related metaphors in your recent comments on Greg Laden's blog. And though they are a bit strange to me (not very IT-literate), trying to think about your use of them is good for stretching the mind - just like learning another language. It's true that adults don't learn new languages easily, but language learning is not impossible either.

5) I do think that you make a lot of sense when you say that how truly difficult it is for people to think about things that are not mapped onto their shared ToM. But I disagree that it is impossible. Ok maybe it might be impossible to think about such things as well as someone with a more natural ability, just as it would be impossible to run a race as well as a naturally endowed athlete. Nevertheless, with great effort, we can run a bit, and we can think about new "unmapped" things a bit. What is needed in order to expend the required effort, is some good reason to look outside of the current shared ToM - and such a reason might be the sheer discomfort provoked by the cognitive dissonance we have spoken about over at Greg's. Most of us must have some (even if poor and underdeveloped) ToR, otherwise we would be walking off buildings. But probably most of us do not have compelling reasons to seek to develop even that which we have. (I thought your discussion of the "obvious" lack of mental states of triangles was brilliantly enlightening - I mean - duh - and yet, I would certainly be among those easily "able" to assign putative "purposive" behaviour to any number of animated non-human objects). Nevertheless, there are ways in which my own upbringing - for example - has positioned me as a perennial "outsider," something which obliges you to learn several different ToM "maps" and thus become aware of the fact that there can be different ToM "maps" and therefore a natural suspicion of the content of any particular one. One is then forced to seek some outside Reality, or means of testing one's own "map."

Anyway, thanks for getting my "thinking juices" flowing - I will no doubt be back to ponder some more.

daedalus2u said...

I think “impossible” is the right term. If your brain does not have the neurological “hardware” to think a thought, then it is impossible to think that thought. These are very awkward terms to use because the brain is not at all like an electronic computer. Computers, as in Turing equivalents are very different than neural networks. There isn’t the complete dichotomy between “hardware” and “software” with the hardware being immutable over time. The “hardware” of neural networks does remodel itself continually. It is only through that remodeling that memories are formed and new ways of thinking are learned. That is why learning takes a long time and is difficult or even impossible for some people; the brain has to remodel itself into a state where the ideas can be instantiated. If there is insufficient plasticity for the brain to remodel itself into a certain state, then that state can never be reached.

I think this is one of the major differences between electronic computers and biological brains. Electronic computers can store information exactly, biological brains for the most part do not.

This is the problem of the denialists. Their brains do not have the capacity to instantiate the ideas that they are denying. That is why they can’t really argue against the real idea, only against the straw-man of the idea that they are able to think about.

The neuronal remodeling that is necessary to learn something is to some extent under conscious control. That is why the denialists actively refuse to learn about what they are denying. That is why the GOP is refusing to talk to liberals. If they let the littlest bit of rationality into their minds, it may take over, like red matter.

Aki_Izayoi said...

"I suggest an analogous treatment for ASD individuals may be to incorporate them into play groups with significantly younger NT children that are at similar developmental stages, but with sufficient adult supervision that nothing untoward can happen. "

Daedalus... let's assume your hypothesis is correct and that there is a trade off between social intelligence, and being able to properly discern reality. If you are correct, then why would treatment be a good thing? Surely, it might be benefit some people if they had a little more social competence to do basic tasks, but as a person who has autistic spectrum like symptoms and who is generally socially incompetent, I would prefer social incompetence and have a perspicious view on reality. But speaking ex ante as a person who is not a NT, I do not like trading having a good theory of reality over having a good theory of mind. If I could have both, that would be great, but you emphasize that it is a trade off.

Donquixote5 said...

Dear DAEDALUS2U,


hi, here's Don Quixote 5. After the very busy last week I could at last manage to read your terrific post.

My first thought - there are no "psychically healthy" people or - the other way round - it is practically impossible to define what "psychically healthy" in fact is ...

Every human being is "microcosm" - a truism. But there was/is/will-be a lot of "collective phenomena" - just as physicists like 'em - in the society (taken as a set of human beings), when we cease to act as "microcosms" and start to be the "scums of the earth" (the history and the present time delivers a plenty of examples), the "nits" which deserve nothing else but "picking" ...

Where is the true clear border between the compliancy/accompliceship and a "healthy" conformism ?

Can the autism, which was in my eyes - before reading your insightful blog - a definite personal disorder, be a panacea against the "social" disorders ?

What do you think about the meditative practices of Buddhists ?

To my mind - and according to my experience - the only country where the people - at least superficially - try to respect each other in the everyday life is Japan.

Although my closer examination of them has demonstrated that they are possessed of the same merits and demerits of being human as all of us upon Earth ...

Oh, my God, give me another globe !

----------

A propos, did you know that we are in fact neighbors:

http://donquixoteundwissenschaft.blogspot.com



Respectfully yours,

Donquixote5

daedalus2u said...

Dear Don, Welcome to my world.
I can't get to this blog during the work day, blogger is blocked at work. Your SB blog is not blocked.

I am working on a post to pull together how this causes xenophobia to be triggered via the uncanny valley effect, but it will be a couple of weeks probably.

Might-o'chondri-AL said...

Hi Daedalus2u,
U gave this link on Small
Things Considered and I've been reading several of your old posts and comments on NO.

Beets have gotten in the news since they contain nitrate. First U.K. reports they improve active exertion capability. Then in U.S.A. publication touts beets lowers blood pressure, via NO downstream.

Latest heralding is beets increases NO perfusion into brain. Yet most NO generated going into dorso-lateral prefrontal and anterior cingulate cortexes (ie: not all brain sees elevated NO).

Dosage suggested is juice of 2 - 3 beets for nitrate content + mouth bacteria yields nitrite for significant NO rise. Process decreases ATP/ADP translocase(a proton conductance enzyme); upshot is less oxygen used (better oxidative phosphorylation). Results in decrease of state 4 respiration and no need of adenylates involvement.

Statement I last saw says food nitrate sources are beets, cabbage, celery, spinach and some (not all) lettuce. Big plate of spinach was equated with 2-3 beets. My questions to you are regarding the use of beets for NO.

Beets are a less finicky crop than your favorite lettuce and the other sources. Last year I even bought a liquid N-P-K plant fertilizer with nitrogen from beets (presumably nitrate culled from sugar beet industrial production left overs).

? Can you tell me if the bio-availability to our mouth bacteria of the beet nitrates is altered by cooking the beets ?

? Would liquid fermenting the raw beets as "Kvass" be a way to bypass the mouth bacteria bio-transformation mastication step ? (Beet Kvass is water diluted with some innoculation yogurt drained whey or kefir drained whey that you put sliced beets into for a few days.)

Annecdotally, about a year ago I was (but stopped) making fresh mixed vegetable juice with beets included. Repeatedly, after drinking a lot of it at once(easily 1/2 liter of blend with varied proportions of carrot, beet, celery, ginger) I felt a personal disassociation. It would come over me in a while (+/- half hour?) and last for a surprisingly long time (+/- 2 hours?).

I remember asking my big shot neuro-psychiatric sister in law if the alert self-watchful perception was a dopamine altered state of mind (she surmised seratonin). Since I don't take any medication, booze or recreational drugs (and am what you call, I think, NT) it was not an interaction with those.

In hindsight, now I think the hyper awareness was from the NO activity cascades. The first few times it came over me I tried to stop the spatial expansivity ;
since thought it was an alcohol conversion making me walk around drunk. Anyway, consider my preceeding questions when you've
a chance to.

daedalus2u said...

Might, nitrate is well absorbed and is highly leachable. Cooking won't affect the nitrate content except by extracting it into any water used for cooking (which it will certainly do). If you boil your beets in a lot of water and then discard it, you are discarding a lot of nitrate too.

The nitrate comes from nitrate in the soil. Many plants can take up both nitrate and ammonia. Ammonia in soil gets oxidized to nitrate but this takes some time. If you are growing your own vegetables, you need to make sure there is nitrate in the soil they are grown in.

Fermenting vegetables can reduce the nitrate content. Many microbes can use nitrate as a source of nitrogen, they reduce it to ammonia and incorporate it into amino acids. Some can also use nitrate as an electron sink and reduce it to nitrite, NO, N2O, N2. When silage is made, they harvest maize plants, grind them up and inoculate them with lactic acid bacteria. That is the same fermentation that is done when making fermented cabbage. I have an earlier post about Autism Diva's Curing Vegetables as a possible source of NO/NOx. In making silage, the fermentation can produce what they call “silo gas”, which has toxic levels of NO2 (nitrogen dioxide). NO2 is highly toxic and forms from NO and O2 in air. At very low NO levels (ppm), the reaction is slow. 500 ppm NO is non-toxic, 50 ppm NO2 is highly toxic. A single breath of a high NO2 atmosphere can be fatal. I am pretty sure the NO2 comes from the reduction of nitrate to nitrite which is then reduced to NO which is then oxidized by air to NO2.

Fermenting vegetables can only reduce their nitrate levels. How much is going to depend on a lot of things. If you do ferment vegetables there may be a risk of formation of nitrosoamines if high protein things are put in there too (like fish).

Might-o'chondri-AL said...

Thanx daedalus2u,
I just measured my homemade Beet Kvass as having 3.92 pH; while the 100% pure extracted Beet Juice reading was at 6.52 pH. They are both of +/- the same refrigerated age (2-3 days).

The pure beet juice still makes the back of my mouth feel like a sore throat; annoyingly astringent and even the swallow reflex irritates repeatedly. I regret again trying some when did these pH measurements. To use fresh beet juice it would have to be heavily diluted with other juice and my goal is sourcing an unadulterated substrate for NO.

The Beet Kvass is of course much more of a diluted solution of beets. At +/- 72*F it takes about 3 days before some white cells from the Kefir whey innoculant show up floating on top; I filter them out. I am led to believe those are in the same family of white fungi growing beningly on Camembert cheese.

Correct me if I am wrong, but I think the low pH of Beet Kvass indicates the kefir whey did not metabolize ammonia. Of course, there is no animal protein involved in the process and so nitrosoamines not in play.

You specify nitrite is unstable at low pH; Beet Kvass' 3.92 pH is low. I would somehow like to believe the kefir whey bacteria have nitrate reductase and converted most of the beet nitrate into nitrite; since most people drink without repeatedly swishing things on their tongue.

When you get a chance to consider it I'd like to know if there is any way to gauge the stability of my theoretical Beet Kvass nitrite. On "Diva" post you said the conversion to NO happens in the stomach and due to pH the NO % was low.

Maybe it's more efficient to just
cook beets & drink their water (Borsht?)for nitrates and let the tongue/stomach process NO. Do you think the Beet Kvass concept for NO is a step in the wrong direction? Thanks again.

www.muebles-en-albacete.com said...

In my view everyone have to glance at it.

pdl1 said...

It is possible the Autism is an evolutionary event. Like most evolutionary events, Autism is both good and bad and natural selection is supposed to decide if the change is overall beneficial.
But from a teleological point of view, humans need more intelligence to master the tasks we have created. Autism may be a first effort.
BTW this would explain why Autism is so widespread in the world, and does not cluster.