Differences in White Matter Fiber Tract Development Present From 6 to 24 Months in Infants With Autism

23 Feb

If you watch for autism related news stories you likely have seen multiple stories on a paper out Friday in the American Journal of Psychiatry: Differences in White Matter Fiber Tract Development Present From 6 to 24 Months in Infants With Autism (full paper available online). The researchers studied brain structure in children and compared those who went on to be diagnosed with autism to those who did not. They found differences in white matter between the two groups. In particular fiber tracks were different.

Here’s figure 1 (click to enlarge) from the paper to give you an idea of what they mean by fiber tracks. Check the brain cartoons on the right. Then check the actual data in the graphs. These are “significantly different” trajectories for these measurements. They are not clear differences that could lead to a diagnostic tool.

Here is the abstract:

Objective:

Evidence from prospective studies of high-risk infants suggests that early symptoms of autism usually emerge late in the first or early in the second year of life after a period of relatively typical development. The authors prospectively examined white matter fiber tract organization from 6 to 24 months in high-risk infants who developed autism spectrum disorders (ASDs) by 24 months.
Method:

The participants were 92 high-risk infant siblings from an ongoing imaging study of autism. All participants had diffusion tensor imaging at 6 months and behavioral assessments at 24 months; a majority contributed additional imaging data at 12 and/or 24 months. At 24 months, 28 infants met criteria for ASDs and 64 infants did not. Microstructural properties of white matter fiber tracts reported to be associated with ASDs or related behaviors were characterized by fractional anisotropy and radial and axial diffusivity.
Results:

The fractional anisotropy trajectories for 12 of 15 fiber tracts differed significantly between the infants who developed ASDs and those who did not. Development for most fiber tracts in the infants with ASDs was characterized by higher fractional anisotropy values at 6 months followed by slower change over time relative to infants without ASDs. Thus, by 24 months of age, those with ASDs had lower values.
Conclusions:

These results suggest that aberrant development of white matter pathways may precede the manifestation of autistic symptoms in the first year of life. Longitudinal data are critical to characterizing the dynamic age-related brain and behavior changes underlying this neurodevelopmental disorder.

If the idea of differences in fiber tracks seems somewhat famiiliar, last year Eric Courchesne at UCSD reported at IMFAR about
Abnormally Accelerated Development of Higher-Order Long-Distance Cerebral Tracts In ASD Infants and Toddlers. The paper was highlighted at the IMFAR press conference (and discussedhere at Left Brain/Right Brain.

At the press conference David Amaral mentioned similar work at the IMFAR press conference last year.

At 51:20 in the video above, Prof. Amaral speaks on the work that precocious brain growth at 4-6 months of age in infants and is most prominently present in children with regression.

“..despite the fact that the regression, the behavioral regression, takes place at 18 months or 24 months, the brain changes actually started taking place at 4 to 6 months. So it actually casts a doubt on the idea that a vaccine, the MMR vaccine for example that’s taken at 12 to 18 months, would be actually the precipitating factor because things were starting much much earlier than that.”

The talk that Prof. Amaral was speaking about was Total Cerebral Volume Is Associated with Onset Status In Preschool Age Children with Autism.

C. W. Nordahl1, A. Lee1, M. D. Shen1, T. J. Simon1, S. J. Rogers1, S. Ozonoff2 and D. G. Amaral1, (1)Psychiatry and Behavioral Sciences, UC Davis M.I.N.D. Institute, Sacramento, CA, (2)Psychiatry and Behavioral Sciences, M.I.N.D. Institute, UC Davis, Sacramento, CA
Background: Autism is a heterogeneous disorder, and multiple behavioral and biological phenotypes likely exist. One well-characterized behavioral phenotype is onset status. While some children with autism exhibit symptoms very early in life, others experience a regression or loss of previously acquired skills. There is currently very little known about the neural substrates associated with these two different behavioral trajectories in autism.

Objectives: We examined the relationship between total brain volume and onset status in a large sample of 2-4 year old children with autism spectrum disorder (ASD) (n = 48, early onset, n = 58, regression) and a comparison group of age-matched typically developing children (TD) (n = 55).

Methods: Diagnoses and autism severity were based on ADOS and ADI-R scores and clinical judgment by trained, experienced psychologists. Developmental quotients (DQ), verbal quotients (VQ) and nonverbal quotients (NVQ) were based on the Mullen Scales. Onset status was categorized based on parent reports from related ADI-R questions. Total cerebral volume was compared between autism onset groups as well as relative to age-matched typically developing controls. Autism severity and DQ were also evaluated in relation to brain volume and onset status.

Results: Children who exhibited regression had significantly larger total brain volumes than children with early onset autism (p = .004). Total brain volume in the early onset ASD group did not differ from the TD group, whereas total brain volume was significantly larger in the children with regression. Moreover, children with regression had significantly lower VQ (p = .03) and higher (i.e. more severe) ADOS social and communication scores (p = .02). Total brain enlargement remained significant even after controlling for these variables. There were no significant correlations between total brain volume and VQ or ADOS scores.

Conclusions: Total brain enlargement has been reported in children with autism under the age of five. However, behavioral associations with abnormal brain enlargement have not been fully explored. Our findings suggest that abnormal brain enlargement in autism is associated with a parent-reported regressive pattern of onset and more severe symptoms involving both developmental impairment and ASD severity.

The idea that autism, even regressive autism, has signs as early as 6 months is challenging to some groups on two levels. First the idea that autism involves physical differences in the brain. Second that these differences are present well before regression, or well before vaccines which are sometimes proposed as precipitating events.

The study itself has limitations, one being generalizability. It makes a lot of sense to monitor siblings of autistics since the recurrence risk is high and the chances of collecting data on autistics is higher than in the general populaiton. However, this leaves us with the question: are the types of autism found in siblings (familial autism) representative of all forms of autism?

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56 Responses to “Differences in White Matter Fiber Tract Development Present From 6 to 24 Months in Infants With Autism”

  1. Harold L Doherty February 23, 2012 at 09:50 #

    “Second that these differences are present well before regression, or well before vaccines which are sometimes proposed as precipitating events.”

    Really? Aren’t vaccines administered to pregnant women? Do some vaccine ingredients cross the placental barrier?

  2. MikeMa February 23, 2012 at 11:32 #

    Next up: The vaccine that travels back in time!

    Interesting addition to the already huge and growing pile of evidence pointing away from vaccines as a cause for autism.

  3. Natasa February 23, 2012 at 14:39 #

    If confirmed/replicated etc findings like these would confirm my suspicion that the main insult in most cases happens very early in life. Prenatal infection and placental pathology seem to be crucial.

    Placental infection and/or inflammation is already highly suspect as behind autism (and has been partially confirmed – raised cytokines and other markers have been found in kids who later regressed). Very promising area of research imo, especially in terms of prevention and early treatment.

    Amniotic fluid inflammatory cytokines: Potential markers of immunologic dysfunction in autism spectrum disorders

    Exposure to prenatal inflammation is a known risk factor for long term neurobehavioral disorders including cerebral palsy, schizophrenia, and autism. Models of systemic inflammation during pregnancy have demonstrated an association with an immune response an adverse neurobehavioral outcomes for the exposed fetus. Yet, the most common route for an inflammatory exposure to a fetus is from intrauterine inflammation as occurs with chorioamnionitis… http://www.ncbi.nlm.nih.gov/pubmed/21382466
    Interesting case study was published recently – mum had active CMV infection during pregnancy – only one of the triplets got infected and later developed autism. The placenta and amniotic fluid of that child showed clear pathology and presence of CMV, which was absent in other two placentas.

    It would also tie in neatly with further regressions kids go through vaccination, natural infections, exposure to allergens etc. This is because prenatal immune insult (either as direct infection or through maternal immune activation) dysregulates the immature immune system and makes it less able to fight off infections and more prone to inflammatory ‘over-reaction’ later on. Perfect fit to what we see in autism.

    • Sullivan February 23, 2012 at 18:15 #

      Amniotic fluid inflammatory cytokines: Potential markers of immunologic dysfunction in autism spectrum disorders

      This is exactly the sort of imprecise statement which was part of an offline discussion I recently had.

      Issues of maternal immune responses being potentially linked to autism causation need to be clearly stated as separate from the claims that there is “immonologic dysfunction” in autistics. All too often people conflate these two to give credence to the idea that autism is related to auto-immune or other issues in the autistic (a position which is not well supported).

      Also, what makes you say this is a dysfunction? Unless you know the cause of the inflammatory cytokines you claim are present, you can’t say that the this is an “immunologic dysfunction”. They could be an absolutely appropriate response to something occurring.

      “Perfect fit to what we see in autism.’

      Hardly. More of a press fit of a square peg into a round hole.

  4. Natasa February 23, 2012 at 14:56 #

    P.S.
    imo no need for the dualistic ‘either-or’ attitude here, as both early insult/signs of autism AND later regression following vaccination are perfectly compatible!

    Early immune/inflammatory insult can easily lead to brain findings such as above, while it would at the same time leave the immune system in a proinflammatory/overreactive state, but less able to fight and permissive to chronic infections. Triggers such as vaccines would lead to more circulating cytokines etc (not to mention the permissiveness ofimmune system to ‘weakened’ viruses) leading to more microglial reactivity, neurotransmitter imbalances etc ==== more symptoms of autism.

    http://www.ncbi.nlm.nih.gov/pubmed/21192986

    • Sullivan February 23, 2012 at 23:42 #

      Natasa,

      I assume you didn’t have access to the full paper? Or did you miss this statement in the conclusions:

      Notwithstanding these marked changes in the brain phenotype, the LPS-exposed monkeys were healthy and appeared behaviorally and physiologically normal until examined under arousing and challenging conditions.

      How exactly does that fit in with your description of “less able to fight and permissive to chronic infections”?

      What logic leads you to believe that vaccines render one’s immune system more permissive to ‘weakened’ viruses? This statement has nothing to do with the paper you cite and is not supported by any research I am aware of.

  5. passionlessDrone February 23, 2012 at 16:00 #

    Hello friends –

    This is a neat study that got some coverage in other areas, but the real world has kept me from poking around it and/or entering a discussion about it. It is sad to me, however, that every discussion I’ve seen about it so far has had commentary about how problematic the findings are towards vaccine causation theories.

    I’ve tried to read this paper a few times, and a few things of interest popped out to me. The temporal timeframes that were observable due to the longitudinal nature of the study are pretty interesting; i.e., the white matter changes were different both spatially and over time in the autism group.

    Had the present study included only cross-sectional data centered at 12 months, for instance, it might have followed that the anterior thalamic radiation is uniquely relevant to the early development of ASD.

    Secondly, there is some discussion as to potential mechanisms by which this could be occurring:

    Both highly experience-dependent and less environmentally mediated processes contribute to the functional and structural organization of the brain, and the dynamic interplay of these processes over time yields specialized cortical circuits designed to optimally process complex information (51). For example, differences in structural organization prior to a period of experience-dependent development related to social cognition (52–54) may decrease neural plasticity through limitations on environmental input, preventing typical neural specialization (52). These alterations could have a ripple effect through decreasing environmental responsiveness and escalating invariance,thus canalizing a specific neural trajectory that results in the behavioral phenotype that defines ASDs. In typical
    development, the selective refinement of neural connections through axonal pruning (55) along with constructive processes such as myelination (56) combine to yield efficient signal transmission among brain regions. One or both of these mechanisms may underlie the widespread differences in white matter fiber pathways observed in the current study.

    This reminds me a little of the increased neurons paper that came out a while ago in that the possibility of impaired removal of neurons was part of the ‘problem’. I am saddened, but not particularly surprised, by support for the notion of a experience/neurobiological feedback loop that could result in decreasing environmental responsiveness and escalating invariance. :(

    @Sullivan – Very nicely done pushing in older, related data. Thank you.

    @Natasa –

    imo no need for the dualistic ‘either-or’ attitude here, as both early insult/signs of autism AND later regression following vaccination are perfectly compatible!

    I am largely in agreement with you on this, at least in some subsets of the autism population.

    That’s a pretty interesting link you’ve got there, especially nice seeing a primate model. Regarding the possibility of a ‘two hit’ (or multi hit) mechanisms of a the effect of a neuroinflammatory state, I think you might find this study pretty interesting.

    http://www.ncbi.nlm.nih.gov/pubmed/19501063

    – pD

  6. passionlessDrone February 23, 2012 at 20:47 #

    Hi Sullivan –

    Also, what makes you say this is a dysfunction?

    I think that Natasa may have experienced a link failure, the paper she was referring to uses that term in the title:

    Amniotic fluid inflammatory cytokines: Potential markers of immunologic dysfunction in autism spectrum disorders

    Issues of maternal immune responses being potentially linked to autism causation need to be clearly stated as separate from the claims that there is “immonologic dysfunction” in autistics.

    OK. But I think it is more than just a “claim” that there is immune dysfunction in autism; the literature on this is very, very clear. Maybe this is a semantics issue. (?) [see below]

    Unless you know the cause of the inflammatory cytokines you claim are present, you can’t say that the this is an “immunologic dysfunction”

    Do you think ‘dysregulation’ is a better term? I’ve seen it used in many instances. Any argument that there is no evidence of aberrant immune responses in the autism population, or differential levels of baseline cytokines, chemokines, or related molecules is in direct contradiction to dozens of studies. The only line of argument involves whether or not these findings rise to the qualification of ‘immunologic dysfunction’ or not.

    But this argument still would seem to ignore what we can learn from the literature, namely that an inflammatory insults during development are sufficient to persistently modifying the immune system (and interrelated systems), and behavior of the offspring. Your argument mandates that there is another cause, but the evidence tells us this does not need to be the case. For example,

    Early life activation of toll-like receptor 4 reprograms neural anti-inflammatory pathways.

    Which found that early life challenge of the immune system reprograms the neuroimmune axis by priming peripheral tissues to create a novel, prostaglandin-mediated activation of the HPA axis brought about by increased constitutive expression of TLR4 and COX-2.

    I guess the question is, do you think that differential neuroimmune responses and/or ‘increased constitutive expression of TLR4′ qualify as ‘immunologic dysfunction’ or not? These animals didn’t even actually get sick; they were just fooled into thinking there was a bacterial infection, but a single insult was sufficient to persistently modify expression of TLR4 and COX2 into adulthood. Do you think these changes could be ‘appropriate responses to something occurring’? What? There wasn’t anything except the immune challenge.

    The concept of developmental programming of a variety of systems by early life experience is terrifying, but the supporting evidence is extremely robust.

    Sooner or later the argument that there might be a nebulous other thing that causes both autistic behaviors, and immune dys-whatever concurrently is going to have to be more precise in what that other something ‘might’ be because there are biologically plausible mechanisms by which immune dysfunction (or whatever) can modify behaviors.

    – pD

    • Sullivan February 23, 2012 at 22:06 #

      “Do you think ‘dysregulation’ is a better term?’

      No. Further, how was that not clear? This is where the discussion goes off the rails all the times. With apologies in advance, I’ll go into more detail and be more direct:

      The presence of an immune response is not automatically evidence for “dysfunction” or “dysregulation”. This is basic, simple logic. The immune system exists for a reason. The statement I made previously was simple and clear: Unless you know why an indicator of immune system function is present, you can’t say that it is a sign of dysfunction. Simple example to make the point–I have a fever. Is that my immune system acting dysfunctionally? Well if I have an infection, the answer is no. The fever is a sign of a functional and appropriately responding immune system.

      Are pro-inflammatory cytokines an automatic sign of immune system dysfunction? If we don’t know why they are there, the answer is no. they could be there to serve a valuable purpose, with the immune system acting appropriately.

      Somehow in the autism world anything about the immune system is “dysfunction” and it’s causal to autism. It’s such a bad logical leap that I don’t see why we need to keep having this discussion.

      Consider what Andrew Zimmerman wrote as part of his expert report for the Omnibus Autism Proceeding:

      My colleagues and I have also described signs of immune activation in both the cerebrospinal fluid (CSF) of living children, and in postmortem brain tissue from children and adults with autism. There is no evidence in brain tissue or CSF of infection,9 and the immune activation we observed contained pro-inflammatory as well as anti-inflammatory elements.8 Further research is needed to determine if the immune activation in the brain in autism is harmful or beneficial to the brain (it may be either or both), is a residual immature pattern of development from an earlier age, or results from abnormal regulation of brain cells (neurons or astroglia) or a genetic abnormality affecting the immune system, among other possibilities.

      Immune activation–not immune dysfunction. Are the “anti-inflammatory elements” a sign of immune system dysfunction? The answer is we don’t know without understanding the root cause. And this is why translating immune system “activation” into immune system “dysfunction” is incorrect.

      “But I think it is more than just a “claim” that there is immune dysfunction in autism”

      You are certainly allowed to think that. It would help if you were precise in what you are saying though. With apologies for the directness–The statement is so vague as to be nearly meaningless. What is “immune dysfunction in autism”? Immune dysfunction in the etiology of autism? If so, is it ongoing immune dysfunction, or is it immune dysfunction prenatally? Immune dysfunction in autistics, which could be comorbid condition with the autism? Is it the dysfunction the same in all autistics?

      Once again, Dr. Zimmerman:

      In the immune system, a variety of atypical findings have been reported in children with autism, as measured in the blood.3 These have been difficult to characterize, because of variability among findings in different studies, most of which cannot be compared due to small numbers of patients and their different techniques and measurements. In spite of
      these findings, severe immune deficiencies typically do not occur in autism, and there is no evidence that correction of mild immune deficiency states (e.g., with administration of
      immunoglobulins) provides benefit for autistic symptoms.

      “Any argument that there is no evidence of aberrant immune responses in the autism population…” An example of the imprecise language of the discussion. There is evidence of aberrant immune responses in ALL populations (unless you chose one so small and specifically filtered for no aberrant immune responses). Also, while Dr. Zimmerman also used the phrase “in autism”, he is much more precise in stating “atypical” rather than “aberrant”, in my opinion. Not all atypical findings are aberrant.

      When one discusses brain antibodies, again, Dr. Zimmerman:

      Although antibodies to a variety of brain antigens have been described in the blood from children with autism, they have also been found in normal “control” children and have
      not been proven to play a role in causing or contributing to autism. 5 Indeed, a current focus of immune research is on the mother’s immune system, which shows that maternal
      antibodies directed to the developing human fetal brain may be pathogenic (cause pathology) before birth.6 The effects of these human maternal antibodies have been
      demonstrated following placental transfer in animal models, producing abnormal behaviors and changes in the brain of the offspring.7 This implies that differences in the
      immune system in autism are likely to be important before birth, acting between the mother and fetus.

      As to my statement above that one needs to be clear about what immune system one is speaking about–mother, child, systemic or brain. I again bring up Dr. Zimmerman:

      There is also no evidence for correlations or causal connections between findings in the “systemic” immune system (in the blood and lymph glands) and immune or other findings in the brain in autism

      But people persist in conflating these findings.

      As to your reference, what’s the point in discussing LPS exposed rats when the very basic language of the discussion is so imprecise?

      As to Natasa’s statement, let’s look at that last paragraph again:

      It would also tie in neatly with further regressions kids go through vaccination, natural infections, exposure to allergens etc. This is because prenatal immune insult (either as direct infection or through maternal immune activation) dysregulates the immature immune system and makes it less able to fight off infections and more prone to inflammatory ‘over-reaction’ later on. Perfect fit to what we see in autism.

      Serious logical failures. Multiple failures. Note how “inflammatory” is basically a buzz-word now. No evidence is given for “inflammatory” over-reaction, or that this would mean anything. How we got from different trajectories of brain fiber connections to the above paragraph is an great demonstration of how any findings are forced to fit with the vaccine-causation model.

  7. passionlessDrone February 24, 2012 at 03:03 #

    Hi Sullivan –

    No. Further, how was that not clear?

    You were clear, I just was figuring that I hadn’t understood you correctly.

    While I don’t have any court transcripts where someone describes immune dysfunction, or immune dysregulation, I do have tons of literature that makes this claim. There is a lot of data up and above Vargas on the immune abnormalities observed in autism, and for one reason or another, the authors of these studies, editors, and peer reviewers of the journals in question don’t seem to have the same concerns you do over specificity of language.

    Andrew Zimmermanm, whom you quote here, didn’t seem to have a problem recognizing the potential for immune dysregulation in the Vargas paper;

    Other genetic loci associated with autoimmune and inflammatory disorders appear to cluster with those for autism (as well as Tourette’s syndrome) and suggest a genetic relationship based on immune dysregulation (Becker, Freidlin, & Simon, 2003).

    Perhaps you should take issue with Zimmerman for writing such an imprecisely worded paper.

    From Macrophage Migration Inhibitory Factor and Autism Spectrum Disorders

    At present, views of possible immune dysfunction in ASD range from conclusions that it may contribute to manifestations of the disorder in some patients18 to hypotheses that neuroimmunopathogenic responses play a fundamental role in ASD.

    This paper was, indeed, founded on the hypothesis that Thus, the central hypothesis underlying this research was that a genetic predisposition to a particular level of MIF production may lead to a proinflammatory profile of cell activation that, if present during a neurodevelopmentally sensitive period, might contribute to the etiopathogenesis of autism., and reported that, Collectively, these data identify MIF as a potential ASD susceptibility gene and support earlier suggestions of a role for innate immunity in the etiopathogenesis of this disease.

    From Immune transcriptome alterations in the temporal cortex of subjects with autism

    Again, many of the genes showing a higher variability in the autistic cohort were related to the immune system and cytokine signaling, suggesting that the increased diversity present in autistic brains is due to a dysregulation of the immune response.

    and

    Many of the genes altered in the temporal cortex of autistic subjects are part of the cytokine signaling/regulatory pathway, suggesting that a dysreactive immune process is a critical driver of the observed ASD-related transcriptome profile.

    Or, what about,Decreased cellular IL-23 but not IL-17 production in children with autism spectrum disorders, which states:

    Evidence of immune dysregulation has been observed in some individuals with ASD, including increased levels of pro-inflammatory cytokines in brain tissues, CSF and plasma, and increased production of pro-inflammatory cytokines by peripheral blood mononuclear cell (PBMC) cultures when compared to typically developing controls (Ashwood et al., 2008; Ashwood and Wakefield, 2006; Enstrom et al., 2009a; Jyonouchi et al., 2001; Molloy et al., 2006; Vargas et al., 2005; Zimmerman et al., 2005).

    Or, in Differential monocyte responses to TLR ligands in children with autism spectrum disorders the authors state:

    Dysregulated immune function is a recurrent finding in ASD, including evidence of brain reactive antibodies; skewed T cell responses to mitogens; altered cytokine levels in the brain, CSF, and periphery; and altered function of innate immune cells such as monocytes and NK cells (Ashwood et al., 2009; Ashwood and Wakefield, 2006; Cabanlit et al., 2007; Denney et al., 1996; Enstrom et al., 2009b; Garbett et al., 2008; Gupta et al., 1998; Li et al., 2009; Molloy et al., 2006; Sweeten et al., 2003; Vargas et al., 2005; Wills et al., 2007).

    Their discussion section starts with:

    Our results indicate notable differences in cytokine production following TLR stimulation in monocyte cell cultures from ASD children including increased proinflammatory cytokine production following exposure to the TLR 2 ligand, LTA with increased production of IL-1ß, IL-6 and TNFa (3.3-, 3.1-, and 2.9-fold increases, respectively) relative to TD controls. In addition, there was an almost 2-fold increase in IL-1ß responses following TLR 4 stimulation with its ligand LPS. Our current findings are consistent with previous reports of enhanced innate immune activity in ASD (Croonenberghs et al., 2002; Jyonouchi et al., 2001), and further indicates that a dysfunctional innate immune response may occur in a number of individuals with ASD.

    Or, from Increased serum levels of high mobility group box 1 protein in patients with autistic disorder.

    Increased oxidative stress and immune dysregulation are other important feature in ASD (McGinnis, 2004; Cohly and Panja, 2005; Blaylock, 2009), and HMGB1 protein plays important roles in both processes (Bianchi and Manfredi, 2007; Klune et al., 2008).

    Note: All links (except Enzo, the last one) included are to full versions of the available papers. If you actually believe there isn’t ample and overwhelming evidence for immune dysregulation in the autism cohort, I’d recommend getting to know some of these papers a bit better.

    Does anyone out there really believe that all of these papers (and others?) somehow have it wrong? I could go on and on with non-court transcript based references, but I’ve got the beta drink to chase and the real world to handle.

    I can’t speak for Natasa, but my thoughts towards the presence of immunogical dys*.* is based on a thorough reading of the available literature and zero reading of Omnibus proceeding court transcripts. If you really believe that a state of immune dys-*whatever are simply a function of imprecise language, your concerns go far beyond Natasa or myself, and extend deep into the published, and repeatedly referenced literature.

    As to your reference, what’s the point in discussing LPS exposed rats when the very basic language of the discussion is so imprecise?

    While crude instruments, animal models can inform us in many ways. In that instance, I was simply attempting to demonstrate that immune disturbances in development are capable of persistently modifying immune function (and behavior) throughout the lifespan, something with parallels towards the double hit notion forwarded by Natasa. If we would like to entertain the the notion that there may be another underlying process capable of causing both immune alterations, and behavioral alterations, ideally, we would have some idea of it’s nature before we overturn readily available and biologically plausible models.

    As towards derailing of a conversation, do you have any thoughts towards my first post on this thread on the specific sections of the paper I found intriguing? I would be interested in your thoughts.

    – pD

    • Sullivan February 24, 2012 at 06:24 #

      “At present, views of possible immune dysfunction”

      You bold “immune dysfunction”

      I would bold “possible”

      In a nutshell, there is the discussion. At least between you and me.

      The next step is the *open* question of immune dysfunction in the autistic as cause or effect in autism.

      Natasa supplies a prime example of why there is a need to be pedantic here. Why to see how the researchers think their work should be interpreted rather than stringing together disparate quotes from studies to give the semblance of a well reasoned argument.

      Aside from the people who seem to think that any mention of immune system in autism research somehow gives credence to the failed notion of a vaccine induced epidemic, we have the alternative medicine practitioners who clearly misinterpreted the research. Recall this paragraph from an article in the Chicago Tribune:

      Meddling with neuroinflammation could actually be a terrible mistake, said co-author Dr. Andrew Zimmerman, director of medical research at the Center for Autism and Related Disorders at the Kennedy Krieger Institute in Baltimore.
      “It may actually be an attempt of the brain to repair itself,” said Zimmerman, a pediatric neurologist. Suppressing the immune response “could be doing harm.”

      Who knows where research involving autism and the immune systems will take us. Perhaps some very valuable understanding of subsets if the population.

      What we can say with certainty is some very bad misinterpretation of the existing research has happened and us still going on. Those misinterpretations are not benign academic debates. They have real direct and indirect effects on autistics and their families. Read some of the yahoo groups where reports of adverse reactions to alternative therapies are rampant. The slippery logic and imprecise use of terminology based on immune activation results in the literature has done harm.

  8. dr treg February 24, 2012 at 05:51 #

    It is now recognised that all psychiatric diseases are characterised by immune dysfunction.

    On that matter all physical diseases are also characterised by immune dysfunction.

    One of my colleagues remarked that “all diseases are allergic”. Let us not make autism unique.

    At present research is heading towards

    immune dysfunction
    genetic abnormalities
    structural abnormalities

    in autism

    I find it interesting that autism is associated with increased numbers of dendritic spines of neurons (or leaves as I call them) and reduced pruning of these spines compared to normal children.

    95% of the volume of a neuron is dendritic arbor (tree).

    Perhaps this is why there is an association with large head circumference in children with autism.

    To deny that there is no immune dysfunction in autism because of lack of evidence is argument from ignorance or argumentum ad ignorantiam or “appeal to ignorance” (where “ignorance” stands for: “lack of evidence to the contrary”), is a fallacy in informal logic. It asserts that a proposition is true because it has not yet been proven false, it is “generally accepted” (or vice versa).

    The fact is that immune dysfunction is being decribed in autism.

    On another point it has been discovered that a non-direct brain insult (LPS) can cause abnormalities in the immune system in the brain.

    I find the research fascinating and realise that these are very early days.

    Perhaps autism will turn out to be many diseases rather like rheumatism in the 1800s turned out to be a whole number of joint diseases.

    • Sullivan February 24, 2012 at 06:29 #

      pD–

      As if on cue, we have Dr Treg.

      “It is now recognised that all psychiatric diseases are characterised by immune dysfunction.”

      Do I need to point out that he is wildly wrong?

      I couldn’t have asked for a better example of the misinterpretations and the potential for harm than the comments by Dr Treg. He’s so far off the mark one might suspect me if creating him as a sock puppet (I didn’t)

  9. dr treg February 24, 2012 at 05:58 #

    This paper shows how the brain`s structure and immune system may respond to a peripheral immunogen:

    “Long-term changes of spine dynamics and microglia after transient peripheral immune response triggered by LPS in vivo”

    http://www.molecularbrain.com/content/4/1/27/abstract

  10. Science Mom February 24, 2012 at 16:19 #

    Does anyone out there really believe that all of these papers (and others?) somehow have it wrong? I could go on and on with non-court transcript based references, but I’ve got the beta drink to chase and the real world to handle.

    I don’t think the issue is with these studies that directly examine immune function and have parameters which allow them to classify them as “immune dysfunction/dysregulation”. The problem is what Sullivan really did state quite clearly and that is laypeople and pompous self-interested others extrapolating any mention of immune function to dysfunction or dysregulation when that is not the case.

  11. passionlessDrone February 24, 2012 at 20:39 #

    @Dr T-reg:

    You might find this study of interest:

    http://www.sciencemag.org/content/333/6048/1456.abstract

    Also, anyone interested in learning about how the immune system participates in the process of synaptic pruning might find it interesting.

    @Science Mom –

    I’d be interested in your thoughts on the white matter paper. The paper I linked to T-reg above, in particular, found a specific flavor of genetic knock out mice showed a transient impairment in synaptic pruning by microglia, something conceptually not entirely dissimilar to what seems to be observed in the axonal tracts here. I haven’t seen anything specific on microglia participation in axonal pruning, but it does not seem an unreasonable possibility based on their participation in synapse management. (?)

    The problem is what Sullivan really did state quite clearly and that is laypeople and pompous self-interested others extrapolating any mention of immune function to dysfunction or dysregulation when that is not the case.

    OK. I guess the point I was trying to make is that researchers seem to be making the claim that there is evidence of immune dys* in autism; we shouldn’t pretend that the only people making such claims are predators out to bilk money from parents.

    @Sullivan –

    Do I need to point out that he is wildly wrong?

    I think the fact that you believe this would be a simple task shows your unfamiliarity with the appropriate studies on the intersection of the immune system and pscyiatric conditions.

    Schizophrenia:

    Investigation of serum cytokine levels and cytokine production in whole blood cultures of paranoid schizophrenic patients

    In summary, increased serum levels of some cytokines such as IL-6, IL-8 and IFN-gamma indicate an activation of the inflammatory response in schizophrenia, while the in vitro assay indicates significant changes in the Th1 (decreased production of 1L-2 and IFN-gamma) and Th2 (decreased production of IL-4) cell system responses.

    Neuroinflammation in schizophrenia especially focused on the role of microglia

    An accumulating body of evidence point to the significance of neuroinflammation and immunogenetics also in schizophrenia. Recent genome-wide studies in schizophrenia suggest immune involvement in schizophrenia.

    Immune and neuroimmune alterations in mood disorders and schizophrenia

    This chapter reviews the evidence, which suggests that a proinflammatory state of the cytokine network induces psychopathologic symptoms and may be involved in the pathogenesis and pathophysiology of these major mental illnesses. The authors also present recent data, which relates immune activation to present theories on the influence of activated immune cells in altering brain function.

    Intracellular monocytic cytokine levels in schizophrenia show an alteration of IL-6

    Several studies have shown an involvement of the immune system, in particular the monocytic system, in the pathophysiology of schizophrenia. Beside others, the monocyte-derived cytokines TNF-a, IL-6 and IL-10 were found to be affected.

    Here are two DBRPC studies that show different anti-inflammatory agents (aspirin/cox2 inhibitors improve features in schizophrenia)

    Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial

    Aspirin given as adjuvant therapy to regular antipsychotic treatment reduces the symptoms of schizophrenia spectrum disorders. The reduction is more pronounced in those with the more altered immune function

    Celecoxib as adjunctive therapy in schizophrenia: a double-blind, randomized and placebo-controlled trial

    Although both protocols significantly decreased the score of the positive, negative and general psychopathological symptoms over the trial period, the combination of risperidone and celecoxib showed a significant superiority over risperidone alone in the treatment of positive symptoms, general psychopathology symptoms as well as PANSS total scores

    Depression:

    Inflammation, glutamate, and glia in depression: a literature review

    Multiple lines of evidence suggest that inflammation and glutamate dysfunction contribute to the pathophysiology of depression. In this review we provide an overview of how these two systems may interact. Excess levels of inflammatory mediators occur in a subgroup of depressed patients. Studies of acute experimental activation of the immune system with endotoxin and of chronic activation during interferon-alpha treatment show that inflammation can cause depression.

    Cytokines: abnormalities in major depression and implications for pharmacological treatment

    The role of cytokines in depression was first considered when the cytokine interferon resulted in “sickness behaviour”, the symptoms of which are similar to those of major depression. The latter is associated with an increase in pro-inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-alpha). These cytokines are potent modulators of corticotropin-releasing hormone (CRH) which produces heightened hypothalamic-pituitary-adrenal axis (HPA) activity characterized by increases in ACTH and cortisol, both of which are reported elevated in major depression. Antidepressant treatment has immunomodulatory effects with increases in the production of IL-10, which is an anti-inflammatory cytokine

    The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine.

    Signs of an inflammatory process, in particular increased pro-inflammatory cytokines and increased levels of prostaglandine E(2) (PGE(2)), have repeatedly been described in major depression (MD). As cyclooxygenase-2 (COX-2) inhibitors inhibit the PGE(2) production and the production of pro-inflammatory cytokines, we performed a therapeutic trial with the COX-2 inhibitor celecoxib.

    Bi-Polar:

    Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder

    During mania, proinflammatory cytokines, IL-2, IL-4 and IL-6, were increased in comparison with healthy subjects. Patients in depressive episode showed only increased IL-6 levels. There were no significant differences in cytokine levels between patients in remission and healthy subjects, except for IL-4

    Immune variations in bipolar disorder: phasic differences

    Our results show the existence of phasic differences in the serum levels of cytokines in BD.

    Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder

    These findings suggest that the increased activity of pro-inflammatory cytokines and an imbalance between pro-inflammatory and anti-inflammatory cytokines may play a role in the pathophysiology of bipolar disorder.

    Dr T-reg says, “Let us not make autism unique” Indeed.

    I could go on and on, but why? Clearly, major subsets of psychiatric disorders do, indeed, show evidence of immune dys*. If I was border, we could add links for addiction, or ptsd, and plenty of others.

    There are a few possibilities when considering the scope and depth of the findings from the associations between the immune system and conditions classically diagnosed behaviorally:

    1) All of these studies are false. An exceedingly unlikely possiblity.

    2) All of the conditions listed above, and autism, have something else that is causing both the neurological condition and the observed immune changes. While possible, we need an agent, or agents that have eluded all investigations, and seem to be able to span across many disorders. So far, the best I’ve ever seen from someone is that such a situation is possible, but nothing of more substance than this.

    3) Having a neurological conditions creates the immune profiles we see. To me, this is more plausible than our first options, and likely a participatory force in some instances. But that doesn’t help us if we try to incorporate the findings that modifying the immune system also affects the behavioral condition, and cannot address the fact that animal and human studies tell us behaviors can be modified by immune system challenge.

    4) The molecules of the immune system are capable of participating in nueriobiological chemical milieu, affecting the wealth of biological functions within the brain, including excitation balances, seizures, neurotransmitter availability, and even brain structure, ultimately impacting behaviors. This is consistent with all of the studies I have listed above, and tons of others.

    5) Something else. (?)

    The correlation != causation argument and the ‘we must understand the underlying cause’ argument don’t really help your position much; both rely on an increasingly antiquated model of a brain and an immune system that operate distinctly and cannot accomodate the observations of crosstalk between very tightly coupled systems. If our world view accepts the concepts of integrated communications and feedback loops, which I think an honest reading of the literature mandates, the question of a chicken or the egg coming first is largely moot; what matters is can these systems interact with each other? The answer to that question is clearly, ‘yes’.

    Whatever other problems might arise from this, once you accept the reality that modifying the immune system can affect what happens inside the brain, and vice versa, the notion that there must be a singular, other, cause of observed immune irregularities within psychiatric conditions is very difficult to defend. In the face of the avialable evidence that no other such phenomena is necessary, sooner or later, it will become incumbent on someone wanting to make that argument to provide a more cogent defense than ‘it might be’.

    – pD

    • Sullivan February 24, 2012 at 20:52 #

      “I think the fact that you believe this would be a simple task shows your unfamiliarity with the appropriate studies on the intersection of the immune system and pscyiatric [sic] conditions.”

      Wow. You buy into ““It is now recognised that all psychiatric diseases are characterised by immune dysfunction.”

      remarkable. As demonstrated-I just remarked on it.

  12. passionlessDrone February 24, 2012 at 22:10 #

    Hi Sullivan –

    Wow. You buy into ““It is now recognised that all psychiatric diseases are characterised by immune dysfunction.”

    Giving the available studies an honest evaluation isn’t ‘buying into’ anything, it is simply accepting what our observations tell us. What I don’t buy into is the idea that all of those findings, and more, are false, and base this conclusion solely on your increduilty that such a thing is possible. If you can read the studies I posted above and think that schizophrenia, depression, autism, and bipolar are not characterized by immune dys*, you have come to conclusions to the opposite of a great number of researchers.

    It used to be, when someone came around here and said a bunch of stuff that was simple to demonstrate as false by evaluating the literature, you’d take them to task on it, show them where the studies were incongruent with their assertions and ask them if they had any studies to back their point. Now, faced with a slew of studies that are in alignment with what Dr. T-reg asserted, the totality of your defense is that I’ve gone off the deep end for reading the literature. What happened?

    – pD

    • Sullivan February 24, 2012 at 23:33 #

      My last comment was too terse. I apologize for that. I should have waited until I could write more.

      Read the statement in it’s entirety. I will emphasize a word that I find critical in this discussion: *All* psychiatric diseases are characterized by immune dysfunction.

      Giving examples of a few (even if we accept that they are all valid) links between psychiatric illness and immune system is not demonstrating all. I will admit that I have not checked “all”. I have checked a few which I would consider highly probable candidates for a lack of association with the immune system. Perhaps my searches were not exhaustive. Should you have counterexamples to these, I would like to see them.

      What immune dysfunction “characterizes” (or is even linked in some way) to, say, Narcissistic Personality Disorder? I don’t find any hits with “Narcissistic Personality Disorder” with immune or with inflammation. Same for delusional disorder. Pyromania.

      It used to be, when someone came around here and said a bunch of stuff that was simple to demonstrate as false by evaluating the literature, you’d take them to task on it, show them where the studies were incongruent with their assertions and ask them if they had any studies to back their point. Now, faced with a slew of studies that are in alignment with what Dr. T-reg asserted, the totality of your defense is that I’ve gone off the deep end for reading the literature. What happened?

      If someone makes a broad statement–say, “all autism is linked to gastrointestinal disease”–a single example disproves the statement. However, when someone says “*All* psychiatric diseases are characterized by immune dysfunction”, a number of possible examples of links does not prove the statement. As I believe I have demonstrated with the examples given above.

      So, if I many, your assertion that “the totality of your defense is that I’ve gone off the deep end for reading the literature” appears to be based on a misread of what was written and/or a misunderstanding of what was written, both by dr treg and myself.

      “dr treg” did exactly what I have complained about–extrapolated a few possible datapoints into a single sweeping conclusive statement that is wrong. This is why I find his statement objectionable. This is why I find much of the over-extrapolation of immune system findings in autism research objectionable. Not the straw man “you deny there are immune system findings in autism” type of argument that dr treg tried to make.

      I find this sort of over-generalization problematic. Just as with dr treg’s: “On that matter all physical diseases are also characterised by immune dysfunction.” Right. If I get a cold and my immune system is activated to fight the cold, that is now “dysfunction”? When exactly did any activation of the immune system become “dysfunction”? Do I need to bring in more physical illnesses to show that they are not “characterized” (whatever he may mean by that term) by immune *dysfunction*?

      I hope you accept my apology for the way the last comment was written. But at the same time I hope you understand my point now. The statement “It is now recognised that all psychiatric diseases are characterised by immune dysfunction.” is false. It is an over generalization and the sort that can lead to real harm.

  13. dr treg February 25, 2012 at 02:03 #

    Good point on borderline personality disorders.

    However, to deny that there is no immune dysfunction in BPD because of lack of evidence is argument from ignorance or argumentum ad ignorantiam or “appeal to ignorance” (where “ignorance” stands for: “lack of evidence to the contrary”), is a fallacy in informal logic. It asserts that a proposition is true because it has not yet been proven false, it is “generally accepted” (or vice versa).

    Pyromania is an impulse-control disorder and may be related to dependency.

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2222549/

    Dependency is associated with increased/decreased inflammatory measurements.

    Quite recently it has been discovered that glia are firmly wrapped around dendritic spines of neurons. Decreasing ensheathment is associated with increased spine density and synaptic puncta.

    http://www.ncbi.nlm.nih.gov/pubmed/21044397

    In another study “microglia had extensive interactions with tiny lollipop-shaped structures called dendritic spines, which are essential for a neuron’s ability to connect with other nerve cells that transmit excitatory signals. Eliminating dendritic spines is one way to destroy synapses.
    Scientists found that dendritic spines that were touched by microglial processes during the first imaging session were more than three times as likely to be eliminated within the next two days compared to spines that were not. And microglia interacted more often with smaller dendritic spines, which generally indicate synapses that are either in the early stage of formation or that can easily be broken.”

    http://www.urmc.rochester.edu/news/story/index.cfm?id=3019

    And so it seems that there is a close relationship between the immune system and neurons.

    Perhaps instead of the emotional term immune dysfunction one could just describe increased or decreased immune system activity compared to people without the condition.

    Say for example the inflammatory measurements are increased with a viral sore throat.

    The inflammatory measurements are increased in autism and other psychiatric diseases, of that there is no doubt.

    I find some nomenclature in medicine/psychiatry is counter-productive to advances in helping people who are suffering.

    PD`s reference to the immune system and neurons (2011) is later than mine.

    I think Sullivan knows that autism is associated with altered inflammatory markers.

    You cant BS a BSer?

    • Sullivan February 25, 2012 at 02:40 #

      “However, to deny that there is no immune dysfunction in BPD because of lack of evidence is argument from ignorance or argumentum ad ignorantiam or “appeal to ignorance””

      You don’t understand the appeal to ignorance argument.

      You stated previously that “It is now recognised that all psychiatric diseases are characterised by immune dysfunction.”

      The data are not there to support your claim. It is not “now recognized”. Rather than misapply the “appeal to ignorance” you should be considering the “shifting goalposts” argument. You just did it.

  14. dr treg February 25, 2012 at 03:06 #

    You should read the evidence of my internet references/ PD`s references on immune system abnormalities in psychiatric diseases.

    Ignorance is bliss.

    • Sullivan February 25, 2012 at 03:27 #

      I did read them dr treg. You need to read–and understand–what I wrote.

      You made two false statements. One about “all” psychiatric diseases and one about all physical diseases.

      I don’t know if you are ignorant, incapable of understanding simple logic or trolling at this point. Frankly I don’t care. What I do know is that you continue to support blatantly false comments.

  15. RAJ February 25, 2012 at 11:46 #

    Few psychiatric or physical ‘diseases’ follow a Mendellian pattern of inheritance. All human ‘diseases’ have a strong genetic component and a strong environmental component which may include higher rates of auto-immune disease and immune deficiencies and ‘autism’ cannot be excluded.
    One of the most intriguing findings is that advanced paternal or maternal age is associated with increased autism risk. De novo gene mutations is associated with advanced paternal age and the effect is seen in girls with autism in simplex families and older fathers have a six times increased risk for fathering a daughter with increased rates of de novo gene mutations in simplex families with no history of autism.
    What are the causes of de novo mutations associated with increased autism risk and do environmental factors influence the risk of de novo sperm or egg mutations in severe genetic syndromes and CNV’s as seen in girls with autism?

    There is an extensive discussion of the phenomena discussed at the SFARI Autism blog which published an article on the effect of advanced paternal age seen in girls with autism:

    http://sfari.org/news-and-opinion/news/2012/effect-of-paternal-age-seen-in-girls-with-autism

  16. passionlessDrone February 27, 2012 at 03:06 #

    Hi Sullivan –

    Well, first off, you have no need to apolgize to me for anything.

    Secondly, I guess I should have been more clear, my position isn’t that pyromania, and Narcissistic Personality Disorder have been evaluated for immune biomarkers per se, but rather, our available evidence points us towards the conclusion that all psychaitric conditions will have an immune component as a result of the breadth and robustness of findings in a spectrum of well studied conditions.

    You mention pyromania, which I show only 410 hits in pubmed all together; by way of comparison, schizophrenia results in 96,000+ hits, and schizophrenia cytokine comes back with over 1600. Do you think the lack of findings may be an artifact of a relative amount of studies in the two conditions?

    I do not believe that we must start from a position wherein each time we evaluate a psychiatric condition, there is only a blank slate. You mention pyromania, I think we can probably agree that there are broad overlaps between someone with uncontrollable tendencies towards starting fires and someone with a obsessive compulsive disorder; and sure enough, when we look for ocd, our findings are largely similar to what we saw when we evaluated schizophrenia, depression, autism, and bipolar disorder; i.e.,

    A cytokine study of adult patients with obsessive-compulsive disorder

    The levels of certain immune markers are increased in adult patients with OCD and seem to vary according to predominant symptoms dimensions. Other studies are required to establish whether our findings truly reflect immunologic dysfunction in OCD or are the result of other hidden confounding factors.

    Or

    Plasma levels of tumor necrosis factor-alpha and interleukin-6 in obsessive compulsive disorder

    OCD patients showed increases in TNF-alpha and IL-6 levels compared to the healthy controls. This study provides evidence for alterations in the proinflammatory cytokines which suggest the involvement of the immune system in the pathophysiology of OCD.

    Genetically, promoter regions of tnf-alpha genes appear to be related to OCD

    Association study between functional polymorphisms in the TNF-alpha gene and obsessive-compulsive disorder

    We found that the A allele of the TNFA rs361525 polymorphism was significantly associated with OCD subjects, according to the allelic ?² association test (p=0.007). The presence of genetic markers, such as inflammatory cytokines genes linked to OCD, may represent additional evidence supporting the role of the immune system in its pathogenesis

    So while it is technically true that there are no direct studies of pyromania and immune biomarkers, for there to be no association, we must speculate on a scenario wherein patients with obsessive compulsive disorder show these different immune profiles, but persons with pyromania do not. Do you really think this is very likely? Even more problematic for this argument are the wide ranging and repeatedly replicated findings in a great number of other conditions, as previously demonstrated. Why make pyromania unique?

    How many psychaitric disorders must be demonstrated to have different immune profiles before Occam’s Razor mandates that we accept that Dr. T-reg’s statement is very likely accurate, even though we have not necessarily performed evaluations on every possible condition?

    “dr treg” did exactly what I have complained about–extrapolated a few possible datapoints into a single sweeping conclusive statement that is wrong.

    Well, I cannot speak for Dr T-reg, but as for myself, it wasn’t about extrapolating a few possible datapoints, but rather, a lot of reading, with only some of it comprised of the type of population studies above. Here is where a lack of studies in pyromania really run into problems, the underyling science that doesn’t care about DSM level behavioral manifestations tells us the same thing; the same molecules the immune system uses as messengers in the case of immunological activation affect the neurochemical balance, and ultimately, brain function.

    Here is an example: Architectural changes to CA1 pyramidal neurons in adult and aged mice after peripheral immune stimulation

    After IP LPS administration, expression of IL-1ß, IL-6, and TNFa mRNA was higher in hippocampus of aged mice compared to young adults whereas NGF and BDNF mRNA was reduced similarly in both age groups. The basal dendritic tree was not affected by LPS in either adult or aged mice 72 h after treatment; however, length and branching of the apical tree was reduced by LPS in aged but not adult mice. The present findings indicate that a peripheral infection in the aged can cause a heightened inflammatory cytokine response in the hippocampus and atrophy of hippocampal neurons. Architectural changes to dorsal CA1 hippocampal neurons may contribute to cognitive disorders evident in elderly patients with an infection.

    Check that out, not only does a mock infection initiated outside of the CNS initiate a state of increased ctyokines in the brain, in some animals, the physical structures of parts of the dendritic trees were modified. These mice did not get sick, there was no pathogen, just a pretend infection, and yet, there were differences in neuron shape in older mice. In a very real sense, the structure of the brains of the aged mice were diffferent after pretend infection. Similarly, from the same author, we could look to

    Cognitive deficits in interleukin-10-deficient mice after peripheral injection of lipopolysaccharide.

    Taken together the results are interpreted to suggest that during peripheral infection IL-10 inhibits sickness behavior and tribulations in hippocampal-dependent working memory via its propensity to mitigate inflammation. We conclude that IL-10 is critical for maintaining normal neuro-immune communication during infection.

    Check that out! Inhibiting the ability to regulate the inflammatory response by knocking out IL-10 altered hippocampal dependent learning and memory formation after mock sickness. Considering this alongside what we learned in the previous study, that a peripheral immune challenge initiated an increase in inflammatory cytokines in the brain, we might ask ourselves, how are these results possible except within a framework wherein there is intimate cross-communication between the immune system and the brain? There are hundreds, or thousands of studies with generalizably similar findings; the closer we look at the interweavings of the brain and the immune system, the more difficult it is to figure out where on stops and the other begins. [If you carefully read some of the papers I referenced earlier, espcially Garbett, you will see references towards an inability to regulate an inflammatory response as a likely candidate to explain the profile of immune activation observed.]

    If I get a cold and my immune system is activated to fight the cold, that is now “dysfunction”?

    Well, I guess it would depend on how your immune system reacted to the cold; and in the autism realm, we have a ton of studies that tell us that the degree and qualities of that immune response is qualitatively and quantitatively different; i.e.,

    Differential monocyte responses to TLR ligands in children with autism spectrum disorders

    After in vitro challenge with TLR ligands, differential cytokine responses were observed in monocyte cultures from children with ASD compared with TD control children. In particular, there was a marked increase in pro-inflammatory IL-1beta, IL-6, and TNFalpha responses following TLR 2, and IL-1beta response following TLR 4 stimulation in monocyte cultures from children with ASD (p<0.04). Conversely, following TLR 9 stimulation there was a decrease in IL-1beta, IL-6, GM-CSF, and TNFalpha responses in monocyte cell cultures from children with ASD compared with controls (p<0.05). These data indicate that, monocyte cultures from children with ASD are more responsive to signaling via select TLRs. As monocytes are key regulators of the immune response, dysfunction in the response of these cells could result in long-term immune alterations in children with ASD that may lead to the development of adverse neuroimmune interactions and could play a role in the pathophysiology observed in ASD.

    I don’t know if you want to characterize increased inflammatory responses from bacterial TLR ligands as ‘dysfunctional’ or not, but they certainly are different, as are responses to some viral TLRs. Now, previously you said that there may be a good reason for this unrelated to the childs condition of autism, and this is possible, but what the studies above tell us is that there are biologically plausible mechanisms by which this type of difference can have an effect on the functioning of the brain. Further complicating your analogy of a cold, are the findings in the autism population that indicate that even unchallenged there are differences in the immune profile of the autism cohort; i.e.,

    Associations of impaired behaviors with elevated plasma chemokines in autism spectrum disorders

    In the current study, we determined whether there were differential profiles of chemokines in the plasma of children with ASD compared to age-matched typically developing controls and children with developmental disabilities other than ASD. Increased MCP-1, RANTES and eotaxin levels were observed in ASD children compared with both control groups (p<0.03), and increased chemokine production was associated with higher aberrant behavior scores and more impaired developmental and adaptive function.. Elevated MCP-1, RANTES and eotaxin in some ASD children and their association with more impaired behaviors may have etiological significance.

    Again, you can state that this might not qualify as dysfunction a statement to which I would agree in principle, but it is a difference.

    When exactly did any activation of the immune system become “dysfunction”?

    If the qualities and quantities of an immune response compared to other people differed, then, perhaps? Again, I guess you would need to ask the researchers who wrote the papers, the people who reviewed the papers, and the editors of the journals why they felt the term dysfunction was appropriate (it was also in some of the abstracts I snipped out above). I can only say that my thought processes have been formed by reading these studies and a great many of the types of studies I have posted above. You will have to come to your own conclusions, but my recommendation would be that you do so after a careful consideration of the available literature. If you were to do this, I beleive that what you will find is broad agreement that the immune system can modify the brain in ways unimaginable just a decade ago, frequent use of the terms dysregulation and dysfunction, increasingly rare mentions of the possibility that such associations may be coincidental, and even fewer instances where the people conducting research posit a benificial effect of immune differences.

    The reality is that I could go on and on and on with studies like these, the lack of a study on narcissism does nothing to make any of these finding less robust.

    Note: I am somewhat saddened by the accusations of ignorance that have come into this thread, my intention over time has been to try very hard to tone down my use of ‘inflammatory’ language. Though I doubt it needs to be said, I do not think you are ignorant.

    – pD

  17. Roger Kulp February 27, 2012 at 05:06 #

    Sorry guys,autism is not completely unique in this area.Don’t know about pyromania,but I do know there are families,like ours,where one sibling,usually a male,has autism,and another sibling,usually a female has childhood onset bipolar,or schizophrenia that is present before the age of eighteen.In such families,all the siblings also share problems with autoimmune disease.Something that is common in autism,organic schizophenia,AND bipolar disease.

    Ever heard of something called 22q11.2 deletion syndrome that can have all of these problems?

    Something else that is very common to both autism,schizophrenia,and bipolar disorder,are problems with folate,and B12 metabolism,or transport.MTHFR mutations or polymorphisms are a common thread in all these disorders.If our family is any indication,there is a strong maternal inheritance,and family history of all these problems.The immune, the folate problems,etc.

    Not to drop a brand name,but ever heard of L-methylfolate?It’s a fairly new form of folate,designed for use in schizophrenia and bipolar.Many doctors are now using it in autism,where there are problems with MTHFR,folate,and homocystinemia.I am trying to switch myself.My leucovorin isn’t controlling my seizures,immune problems,etc,like it used to.

  18. Julian Frost February 27, 2012 at 07:27 #

    @Roger Kulp: Citation Needed, especially since I’m Autistic, my sister’s dyslexic and neither of us has an immune disorder.

  19. RAJ February 27, 2012 at 17:18 #

    Roger Culp asked:
    ‘Ever heard of something called 22q11.2 deletion syndrome that can have all of these problems.

    There are a number of groups (MIND Institute and SFARI Autism) that have recruited large groups of children diagnosed with the 22q11 deletion syndrome. This is an interesting group since so many risk factors for autism can be present in most individuals carrying a diagnosis of co-occurring autism. This genetic syndrome is not inherited as 93% of cases are caused by a de novo gene mutation. Immune deficiences, autoimmune disease and mito-chondrial dysfunction cab be present with the 22q11 deletion syndrome.

    One of the findings sure to make Sullivan react like listening to the scratching of nails on a blackboard is that vaccinations with live vaccines are not recommended in this group because of a high rate of immune deficiencyies (77%) in children with the diagnosis:

    http://www.ncbi.nlm.nih.gov/books/NBK1523/

    • Sullivan February 27, 2012 at 22:17 #

      RAJ,

      did you click on the link to the full review, or just read the abstract? I ask because the full review states:

      Infants with lymphocyte abnormalities should not be immunized with live vaccines (i.e., oral polio, MMR). Their immune status should be re-evaluated in childhood before receiving live vaccines. In addition, antibody studies to assess results of immunizations are warranted.

      So, your statement “live vaccines are not recommended in this group” is not accurate. Live vaccines are recommended to be delayed and reassessed later. Very different statement. Note that the studies I quoted above were all written after the review article you linked to.

  20. Science Mom February 27, 2012 at 21:04 #

    One of the findings sure to make Sullivan react like listening to the scratching of nails on a blackboard is that vaccinations with live vaccines are not recommended in this group because of a high rate of immune deficiencyies (77%) in children with the diagnosis:

    A strawman and a red herring. Really RAJ, can’t you do better? Vaccinating immunocompromised children, particularly with live vaccines is often contraindicated for what should be obvious reasons. So what happens if one of these children also have autism and find themselves in the midst of the anti-vaxx autism crowd? Children like these, and adults rely upon the good graces of others to provide herd immunity.

    • Sullivan February 27, 2012 at 22:07 #

      “Vaccinating immunocompromised children, particularly with live vaccines is often contraindicated for what should be obvious reasons.”

      I won’t take the time to search for how many times I’ve mentioned people who can’t be vaccinated for one reason or another. And exactly the point you make, that these individuals are one big reason for the rest of us to vaccinate.

      RAJ is welcome to read “Safety and efficacy of measles, mumps, and rubella vaccine in patients with DiGeorge syndrome “. They found no moderate or severe reactions to the vaccine, even allowing for 60 days post vaccination followup period.

      In summary, we have demonstrated here that MMR vaccination is safe in patients with 22q11.2 microdeletion who have at least near or more than 500 circulating CD4+ cells/mm3. However, sustaining long-term protective MMR antibody levels, even after repeat vaccination, appear far lower than those in age-matched control subjects. On the basis of this study, we propose that patients with 22q11.2 microdeletion should be periodically assessed for antibody levels and reimmunized accordingly.

      Other studies I’d hope RAJ would have considered before making his comments is “Live viral vaccines in patients with partial DiGeorge syndrome: clinical experience and cellular immunity” and “Safety of live viral vaccines in patients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome).”

      As well as “Safety and immunogenicity of measles–mumps–rubella vaccine in children with congenital immunodeficiency (DiGeorge syndrome)” which states “MMR vaccine is immunogenic and can be safely used in patients with DiGeorge anomaly, so preventing severe complication due to wild virus infection.”

  21. RAJ February 29, 2012 at 16:40 #

    Also read this article on auto-immune disease linked to gene variances:

    http://sfari.org/news-and-opinion/in-brief/2012/clinical-research-autism-genes-linked-to-autoimmune-disease

  22. RAJ February 29, 2012 at 22:56 #

    Or this recent article:

    http://www.molecularautism.com/content/2/1/13

  23. passionlessDrone March 13, 2012 at 18:15 #

    Hello friends –

    I ran into this study this afternoon and it made me think of this discussion.

    The evolutionary significance of depression in Pathogen
    Host Defense (PATHOS-D)

    Given the manifold ways that depression impairs Darwinian fitness, the persistence in the human genome of risk alleles for the disorder remains a much debated mystery. Evolutionary theories that view depressive symptoms as adaptive fail to provide parsimonious explanations for why even mild depressive symptoms impair fitness-relevant social functioning, whereas theories that suggest that depression is maladaptive fail to account for the high prevalence of depression risk alleles in human populations. These limitations warrant novel explanations for the origin and persistence of depression risk alleles. Accordingly, studies on risk alleles for depression were identified using PubMed and Ovid MEDLINE to examine data supporting the hypothesis that risk alleles for depression originated and have been retained in the human genome because these alleles promote pathogen host defense, which includes an integrated suite of immunological and behavioral responses to infection. Depression risk alleles identified by both candidate gene and genome-wide association study (GWAS) methodologies were found to be regularly associated with immune responses to infection that were likely to enhance survival in the ancestral environment. Moreover, data support the role of specific
    depressive symptoms in pathogen host defense including hyperthermia, reduced bodily iron stores, conservation/withdrawal behavior, hypervigilance and anorexia. By shifting the adaptive context of depression risk alleles from relations with on specifics to relations with the microbial world, the Pathogen Host Defense (PATHOS-D) hypothesis provides a novel explanation for how depression can be nonadaptive in the social realm, whereas its risk alleles are nonetheless represented at prevalence rates that bespeak an adaptive function.

    Note: This type of thing may also provide insight, tangentially, into a question I’ve seen RAJ pose on several occasions, namely, the problematic paradox of a condition mediated primarily though genetics when said condition, in general, is associated with outcomes that are less likely to produce offspring.

    Food for thought.

    – pD

  24. Tom March 14, 2012 at 15:10 #

    “This type of thing may also provide insight, tangentially, into a question I’ve seen RAJ pose on several occasions, namely, the problematic paradox of a condition mediated primarily though genetics when said condition, in general, is associated with outcomes that are less likely to produce offspring.”

    I’m not sure there’s a paradox. Copy number variations and de novo mutations likely account for the lion’s share of autism.

    Given that all known gene variants are rare, it’s very likely that those that are truly Mendelian and result in severe phenotypes are eliminated from the gene pool.

    In other phenotypes where people are able to function in society, the variants are conserved. And these people fit a phenotype where the variant confers a modern day survival benefit (scientists, IT techs, inventors) despite some social deficits.

  25. jim March 18, 2012 at 01:49 #

    To date, we still have no immunological testing prior to imposing a large load on patient immune systems. Seems that this work should give us more pause to be careful about what we are doing with vaccines, to whom, and when – whenever the pathway begins. We cannot know that vaccine application is not a tipping point for any number of conditions related to learning and function. Its proximity to so many etiologies must cause us to question this undefensively. Not all patients are equal, but most practice ignores any need for a immune system tests similar to our blood tests. We impose more and more burdens, including legal and school system requirements, on an increasingly unwell population to address the known without knowing whether we often do more harm than good. Increased levels of epilepsy remain largely unexplained as well, and the connection between autism and epilepsy is not well understood but is now supported in the literature.

  26. jim March 18, 2012 at 01:57 #

    Regarding genetic mutations, have you looked at Teresa Deisher’s work on homologous recombination and hotspots related to embryonic stem cell DNA base pair strands in MMR, MMRII, and chickenpox? you might also be interested in the RNA coupling in nervous system development that can be interrupted by human RNA from another human host being introduced, and Theo Theoharides work showing mitochondrial peptides within these embryonic stem cell vaccine adjuvants that cause massive mast cell inflammatory response and opening of the blood brain barrier within 10 minutes of application. These may be significant issues for children who are already on a different development path related to any number of pathologies.

  27. jim March 18, 2012 at 01:59 #

    Georges St. Laurent, George Washington Univ Med School has published a number of papers on the RNA coupling and development of the nervous system, comparing it to connecting the body’s digital and analog systems for experience with the outside world.

  28. Chris March 18, 2012 at 02:35 #

    jim:

    To date, we still have no immunological testing prior to imposing a large load on patient immune systems. Seems that this work should give us more pause to be careful about what we are doing with vaccines, to whom, and when – whenever the pathway begins.

    How does a baby avoid bacteria during vaginal birth?

    • Sullivan March 18, 2012 at 07:39 #

      Sorry, Chris,

      your first of these two comments got held back by spam. I think I know what word triggered that.

  29. Chris March 18, 2012 at 03:45 #

    jim:

    To date, we still have no immunological testing prior to imposing a large load on patient immune systems. Seems that this work should give us more pause to be careful about what we are doing with vaccines, to whom, and when – whenever the pathway begins.

    When a baby is born, is the whole process sterile? When babies learn to crawl, is every floor sterile? Is the beach sand a toddler plays on sterile?

  30. Chris March 18, 2012 at 07:57 #

    The moderators are prudes! ;-)

    Thanks.

  31. Science Mom March 18, 2012 at 08:53 #

    Regarding genetic mutations, have you looked at Teresa Deisher’s work on homologous recombination and hotspots related to embryonic stem cell DNA base pair strands in MMR, MMRII, and chickenpox?

    I have looked at her “work” and it is nothing more than a literature search and hand-waving, no experimentation whatsoever. Her “work” also remains unpublished and she has a vested financial interest in developing vaccines that aren’t cultured on human cell lines.

    you might also be interested in the RNA coupling in nervous system development that can be interrupted by human RNA from another human host being introduced,

    Show the work.

    and Theo Theoharides work showing mitochondrial peptides within these embryonic stem cell vaccine adjuvants that cause massive mast cell inflammatory response and opening of the blood brain barrier within 10 minutes of application.

    Show the work. Your attempt at science-speak is rather telling.

  32. jim March 18, 2012 at 15:07 #

    Science Mom: :) I love your direct approach. Neurotensin is increased in serum of young children with autistic disorder. Angelidou et al. Journal of Neuroinflammation 2010, 7:48. http://www.jneuroinflammation.com/content/7/1/48
    JOURNAL OF NEUROINFLAMMATION. Neurotensin is in the adjuvants.

    You’ll have to look up Georges St Laurent’s work in pub med. It’s fascinating, though.

    I’ve been in Deisher’s lab and looked through her scopes. You rip yourself off by the broad assertions. Her experimental background is first-rate, her science is hard, and she’s on the cutting edge though underfunded. Check out homologous recombination and hotspots and consider the implications of same species pulverized DNA, RNA, mitochondria and neurotensin cocktails. You know the genes don’t just start to mutate.

    What do you say about her PhDs epidemiology by country and date of intro and it’s coordination Timing of Increased Autistic Disorder Cumulative Incidence Michael McDonald adn John Paul, Environ. Sci. Technol. 2010, 44, 2112–2118?

  33. jim March 18, 2012 at 15:14 #

    Chris,
    what’s that got to do with immune system evaluative protocols before these injections? why even have vaccines if the bacteria and virus may be in the birth canal? are you saying let’s let that be their vaccine?

  34. Chris March 18, 2012 at 17:18 #

    jim, if you are going to say the immune system is not developed enough for the small amounts of antigens in the vaccines used prior to a year or eighteen months, then you will have to tell us how to keep babies in a sterile environment.

    And since we know that infants do get pertussis, infected with hepatis B, Hib, tetanus, measles, rotavirus and diphtheria, your next step is to tell us how do we protect them from those particular pathogens with supporting documentation (actually published in a first rate journal).

  35. Chris March 18, 2012 at 17:20 #

    Sully, your moderation system hates me.

    In short, jim, show us how the antigens in vaccines are worse than the ones babies are exposed to, and then explain how we protect babies from vaccine preventable diseases prior to age one.

    • Sullivan March 18, 2012 at 20:10 #

      “Sully, your moderation system hates me.”

      Remember–when things don’t work, it’s Kev’s blog ;)

  36. Science Mom March 19, 2012 at 00:16 #

    Science Mom:

    :) I love your direct approach. Neurotensin is increased in serum of young children with autistic disorder. Angelidou et al. Journal of Neuroinflammation 2010, 7:48. http://www.jneuroinflammation.com/content/7/1/48
    JOURNAL OF NEUROINFLAMMATION. Neurotensin is in the adjuvants.

    Neurotensin was found to be increased in their cohort of autistic children, no other neuropeptides tested and at this juncture, they can’t even be sure of any clinical nor biological relevance of such a finding. But most importantly, nothing to do with adjuvants at all and adjuvants do not contain neurotensin. It is embarrassing for bona fide investigators to have their work abused by people like you. It’s so easy to verify anyway so you are trying to fleece the wrong audience.

    You’ll have to look up Georges St Laurent’s work in pub med. It’s fascinating, though.

    No, you look it up. You made the claim; the onus is upon you to supply the source for that claim.

    I’ve been in Deisher’s lab and looked through her scopes. You rip yourself off by the broad assertions. Her experimental background is first-rate, her science is hard, and she’s on the cutting edge though underfunded. Check out homologous recombination and hotspots and consider the implications of same species pulverized DNA, RNA, mitochondria and neurotensin cocktails. You know the genes don’t just start to mutate.

    Whoop de freakin doo; I have scopes in my house. The fact remains that she doesn’t have any research to make her claims and neither do you. I read what she presented at IMFAR last year or the year before (I don’t care to remember) and remain remarkably under-whelmed by her silly abuse of the literature.

    What do you say about her PhDs epidemiology by country and date of intro and it’s coordination Timing of Increased Autistic Disorder Cumulative Incidence Michael McDonald adn John Paul, Environ. Sci. Technol. 2010, 44, 2112–2118?

    This: http://leftbrainrightbrain.co.uk/2012/01/comment-on-timing-of-increased-autistic-disorder-cumulative-incidence/

  37. McD March 19, 2012 at 08:08 #

    I would take that Neurotensin study with a grain of salt. I found the results impossible to decypher. They report doing at least 9 tests and left the significance level at .05 – no reported adjustment for multiple testing (although if they did actually restrict it to 9 tests, at .004 it may have barely scraped in). The trouble is they report doing both t-tests and MWU, but don’t say which one obtained the significant result. Eye-balling the graphs, the range displayed by the ASD group for neurotensin almost completely envelops the control group, only one data point in the control group is outside the range for the ASD group. The data doesn’t look likely to be normally distributed – hence the MWU test – so why report doing t-tests? I don’t have a lot of confidence in the review process, they could have done better on the stats.

    After I wrote the above. I re-read the conclusion of the report again. One sentence came out of left field:

    “NT could be released from the brain, the intestines or dorsal root ganglia and could act together with environmental triggers such as mercury [30] or …”.

    So I looked up [30], and discovered it was published in the same journal only a few months earlier by the same corresponding author. Boy is that one a doozy; same approach to stats, n=5, in-vitro study that whacks cells with mercury, reports the unsurprising fact that they don’t like it, then discusses that that’s how vaccines injure kids. The Geiers are in the references at #2:

    http://www.jneuroinflammation.com/content/7/1/20

    Then, the lead author “is the inventor of US patents No. 6,624,148; 6,689,748; 6,984,667 and EPO 1365777, which cover methods and compositions of mast cell blockers in neuroinflammatory conditions, as well as US patent application No.12/534,571 for diagnosis and treatment of ASD.”

    The research was funded by “Safe Minds (Huntington Beach, CA) and the Defeat Autism Now Coalition (San Diego, CA), as well as Theta Biomedical Consulting and Development Co., Inc.”

    So, wow. I guess we will be getting a treatment for ASD any minute now.

  38. McD March 19, 2012 at 08:38 #

    Another problem that someone might be able to clarify for me is that in the paper I link to above, the author states that “Results are presented as mean ± SD.”

    In the neurotensin study (short report) jim links to, the use of “±” is not specified that I could find. Looking at the figures, I had worked out that it must be some sort of measurement error, because there is no way that the SD is .5 and .7 in Fig 3 at least. Although less blatant, it looks the same for Fig 1, the significantly different one.

    So I cant see any indication of variance in the report at all. I don’t think they have presented enough data to indicate that there really is a difference between ASD and controls. Is there some sort of convention for the use of ± in these bio-med journals?

  39. Science Mom March 20, 2012 at 01:24 #

    McD, I do have to hand it to you for being so thorough. I merely skimmed the paper that Jim referred to, something I learned to do so as to not waste too much of my time with the pie-in-the-sky claims that the likes of Jim often make. I don’t know what makes the Jims of this world think they can deceive an educated and savvy audience.

  40. McD March 20, 2012 at 10:17 #

    Hey Science Mom, I wish I could leave it alone!

    I’ve been working with some older cog-psych papers recently – famous for doing batteries of tests without adjusting the significance level, so it was a bit of a reflex to check that first. And a bit of a surprise to find it looking shady until I saw the second paper. But wait, there’s more. I have been compulsively following cites since; now I wish I had not been so obsessive.

    The lead author is also lead author for this advertisement for his own products for which he has a patent and for which he also gets funded by the advocates noted above (hence the parents of autistic children). Seriously, if these advocates were really acting for the parents they would not be funding this sort of nonsense. And what sort of journal publishes this stuff? Click on the little figure and prepare to be stunned:

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3293070/?tool=pubmed

    (I was going to be clever and call it “adveresearch”, but didn’t want to imply there was any actual research involved with the production of the paper)

    The lab website is also very interesting. They have not only solved autism, but Fibromyalgia and Chronic Fatigue too. Amazingly the same stuff can treat all of these, and a raft of other disorders as well. The published work “supporting” using the stuff for fibromyalgia is completely research-free, and like the other stuff is free access. Unlike stupid scientists who put up pay walls, these guys know where the real money is. The “review” dates back to 2006. Heaps of time to do some actual research.

    I have wasted way too much time on this. The whole situation resembles the cosmetic industry – conducting shonky in-house “research” (at least they tend to “publish” in in-house journals). It is quite sickening to see parents of special-needs kids targeted like this.

  41. Science Mom March 20, 2012 at 13:21 #

    McD, And to think, Tufts used to be a top-tier university. My alumni colleagues would hang their heads in shame if they wallowed in the same mire I do.

  42. McD March 20, 2012 at 23:48 #

    I see the Prof (President and CEO of the bio-med company selling the “stuff”) has been noticed before on LBRB:

    http://leftbrainrightbrain.co.uk/2009/11/johns-hopkins-faqs-the-meaning-of-neuroinflammatory-findings-in-autism/#comment-70553

    I really hope the stuff-for-autism research gets past the culmination point of research for the raft of other disorders the stuff is sold for – a couple of small open-label pilot studies, looking at subjective pain symptoms, over the past 10 years (one was a retrospective study presented as a poster that was basically an ad for the stuff). The first autism “review” was 2008.

    The stuff would cost me just over $1 a day for my boy (without shipping charges). Older kids cost more. Apparently it will take 3 months before any relief of symptoms is seen (did they pluck that from one of the studies on cystitis, one of which had a duration of 11 months ± 8 months?).

    How the hell would any parent know whether any improvement in a three month period was due to the stuff, normal development, or other therapy? More likely than not there will be some sort of improvement. And repeat orders.

    Safe Minds are doing their parents are real dis-service funding advertisements for this stuff, and not funding proper independent trials. If it really works both the company and these “advocate” organisations have nothing to lose doing this.

    I apologize for hijacking this thread. I have to stop this now. It gets worse the further I go, and I get so angry seeing this sort of thing.

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