Autism and Parental Psychiatric Disorders

A brief review of: Daniels, J.L., Forssen, U., Hultman, C.M., Cnattingius, S., Savitz, D.A., Feychting, M., Sparen, P. (2008). Parental Psychiatric Disorders Associated With Autism Spectrum Disorders in the Offspring. PEDIATRICS, 121(5), e1357-e1362. DOI: 10.1542/peds.2007-2296

The journal of Pediatrics just published a population study based on the national Swedish registry, which examined the association between parental psychiatric history and autism. The authors compared the parental psychiatric history of 1,227 of children with autism spectrum disorder and 30,925 typically developing children. Children were identified as having autism spectrum disorder if they were born between 1977 and 2003 and had a diagnosis of ASD recorded in the registry between 1987 and 2003.

Parents of children with autism were 70% more likely than parents of typically developing kids to have a psychiatric diagnosis. When both parents had a psychiatric disorder, the children were 100% more likely to have a diagnosis of autism. Schizophrenia was more common in both parents among children with autism as compared to parents of typically developing kids (90% more likely for mothers and 110% more likely for fathers). In addition, mothers of children with autism were more likely than mothers of typically developing kids to have depression (70%), and personality disorders (70%).

In summary, the study suggests that in Sweden, during the last 30 years, children with a diagnosis of autism were more likely to have parents with psychiatric diagnoses than typically developing children. This could reflect a non-specific, possibly genetic, predisposition in affected families for psychiatric conditions, including autism. It could also reflect that having a child with autism increases stress in the parents possibly leading to psychiatric diagnoses. However, the association noted by the authors was even stronger if the parental diagnosis was provided before the child’s diagnosis. One important consideration, these results were based only on kids who had a history of inpatient treatment. Those with a history of only outpatient treatment were not included. It is possible that the observed link between parental psychiatric history and autism applies only, or mostly, to the most severe cases of autism requiring hospitalization.

One last comment: It's important to note that the rate of psychiatric conditions among even children with autism were very low. For example, schizophrenia was observed among 0.6% of the mothers of children with autism (compared to 0.2% of the typically developing mothers). 99.4% of the children with autism did not have mothers with schizophrenia. Therefore, the data only suggest that there may be a familial/genetic predisposition that is related to autism among very small subset of children with autism.

Acetaminophen use and Autism.

A review of: Schultz, S.T., Klonoff-Cohen, H.S., Wingard, D.L., Akshoomoff, N.A., Macera, C.A., Ming Ji, . (2008). Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: The results of a parent survey. Autism, 12(3), 293-307. DOI: 10.1177/1362361307089518

A study in the latest issue of the journal Autism examined the possible role of acetaminophen use after MMR vaccine and autism. The authors provided an excellent review of the MMR vaccine-autism research, which indicates that although some clinical studies have found a link, most epidemiological studies have failed to find an association between MMR and autism. The authors noted that acetaminophen is commonly used to treat the adverse reaction of MMR vaccinations such a fever and rash. In addition, one study (Alberti et al, 1999) showed that some low functioning children with autism process acetaminophen differently. Thus, the authors proposed a innovative hypothesis: Does acetaminophen use after MMR vaccination increase the risk for Autism?

The authors recruited parents of typically developing children and children with autism via internet advertisement. The total sample included 83 parents completing the survey for children with autism and 80 parents completing the control survey. The surveys included a variety of questions about the child such as age, gender, what medications were used to prevent or treat reactions to the MMR vaccine, including aspirin, acetaminophen, or ibuprofen. The survey of parents of children with autism included additional questions about their children diagnosis such as whether a regression in development was observed.

The authors found that parents of children with autism reported:
- more adverse effects of MMR vaccine, including fever, diarrhea, irritability
- increased presence of concurrent illnesses with MMR vaccine
- more acetaminophen use after the MMR vaccine among children who had a reaction to the vaccine, children who had a regression in development, and those under 5.
- more acetaminophen use between 12 and 18 months of age
No association was found between ibuprofen use and autism.


A few caveats:
The finding that parents of children with autism reported more adverse effects of MMR vaccine or more concurrent illnesses with MMR vaccine is not overly informative. Note that these results were based on parental reports via internet with no possibility of verification of accuracy of such reports. So it is completely plausible to argue that given the extended media coverage of the vaccine-autism link, some parents of children with autism are more attuned to their children histories after vaccination and thus are more likely to remember or report complications. What is informative and actually interesting is that there was a significant difference in reports of acetaminophen use as compared to ibuprofen use. This difference can not easily be explained on the basis of some report bias. The problem is that acetaminophen use was reported much more frequently than ibuprofen use by all parents. So it could be argued that since parents of children with autism were more likely to report complications (even if just a by-product of recall bias), the use of acetaminophen will also appear to be different between the two groups.

Mercury Exposure and Autism: Should you check for nearby power plants?

...But this study is compelling in showing an association between mercury exposure and autism rates, and scientists can not just ignore it under the basis of its imperfect design and inability to make causal links – if that is the case, then only carefully controlled laboratory studies, with poor external validity, should be published and accepted as contributors to our greater scientific knowledge.

A review of: PALMER, R., BLANCHARD, S., WOOD, R. (2008). Proximity to point sources of environmental mercury release as a predictor of autism prevalence. Health & Place DOI: 10.1016/j.healthplace.2008.02.001

This fascinating, yet bound to be controversial, study hit the news yesterday as it was made available (pre-publication) by the Journal Health & Place. The study is simple, straightforward, elegant, with some powerful findings. In fact, the findings are somewhat daunting given the simplicity of the design. The researchers reviewed the amount of mercury release reported by industrial facilities and power plants in the State of Texas in 1997 from data provided by US Environmental Protection Agency Toxics Release Inventory. They compared these data against autism rates in 1997 and 2002 as measured by schools' autism classifications provided by the Texas Education Agency. Using a specialized geographical analysis system, the authors were able to locate each source of mercury and calculate the distance between each mercury source and each school. The results:

Industrial release of mercury and distance to industrial sources independently predicted increased rates of autism. The association with industrial release of mercury was not linear, instead the statistical model fit suggested an accelerated risk. This association remained statistically significant after controlling for specific variables such as SES, urbanicity, and race.

Power plant release of mercury and distance to power plant independently predicted increased rates of autism. In this case the association was linear (not accelerated). Again, this association remained statistically significant after controlling for other variables.

It is easy to dismiss these findings as inconsequential because they are ‘correlational’ in nature, or do not really prove anything. Researchers are too often guilty of selective acceptance of research: those studies that fit the consensus are accepted while those that don’t are dismissed for their methodological flaws – even though the studies we accept are equally flawed.

In the spirit of fairness I have to say that these findings are strong. Their methodology and analytical process are not any different from what is commonly seen in social science or epidemiology research. Is it perfect? Far from it. Is it useful or informative? Definitively! The data speak very clearly: In Texas, mercury release from industrial sources and power plants in 1997, and school proximity to these sources, are associated with rates of autism in 2002 as measured by school special education classifications.

Does this mean that mercury causes autism? Not at all. In the last sentence of the previous paragraph you can not replace the words are associated with with the word cause. There is a major difference. The data, albeit strong, have limitations. For example, the most obvious (to me) alternative explanation is that mercury release and proximity to these sources is also associated with another mystery factor that is causing this apparent association and that in fact, mercury release has nothing to do with autism rates in 2002. Let’s hypothesize that these power plants and industrial sources also release another toxin – let’s call this toxin autisimic (this is a made up toxin). These sources release mercury and autisimic at the same rate, so for each pound of mercury released there is a pound of autisimic released. It is possible then that this autisimic toxin directly increases the risk for autism, and this could explain completely the strong (but now obviously inaccurate) association between mercury release and autism.

Does this study show that vaccines cause autism? Absolutely not. I know this question may sound ludicrous to some, but I pose it rhetorically because I am certain that some will make the wide leap and link these findings to the vaccine issue.

There are other problems and limitations with this study, such as how autism rates were calculated (using all children instead of only those born inor after 1997), whether the autism rates are truly climbing and not explained by other factors, whether there are other variables that could be explaining this relation, etc, etc --- and yes, this study does not prove or directly indicate that autism is caused by mercury exposure (click here for a much more critical review of this study). But this study is compelling in showing an association between mercury exposure and autism rates, and scientists can not just ignore it under the basis of its imperfect design and inability to make causal links – if that is the case, then only carefully controlled laboratory studies, with poor external validity, should be published and accepted as contributors to our greater scientific knowledge. This is study is far, far, from perfect, and many changes should have been requested prior to publication, but I can say the same of 90% of what is published today.

Autism and Perfect Pitch?

Title: Autism and pitch processing splinter skills: A group and subgroup analysis.
Source:Heaton, P., Williams, K., Cummins, O., Happe, F. (2008). Autism and pitch processing splinter skills: A group and subgroup analysis. Autism, 12(2), 203-219. DOI: 10.1177/1362361307085270

Anecdotal as well as experimental studies have suggested that a sub-group of persons with autism have specific skills that are significantly above what is expected in the general population. Music abilities, and specifically pitch recognition, is one of these abilities. In this study the authors wanted to assess pitch recognition and memory in children (11 to 19 years of age) with Autism with various levels of intellectual abilities (as measured by a non-verbal test, namely: the Raven’s Progressive Matrices) and typically developing children of equal intellectual abilities. The first experiment involved the identification of pitch intervals (major fifths, thirds, etc). However, in order to make this test appropriate for non-musically trained children, the experiment used a computer screen to present a staircase of 8 steps representing the 8 standard tones of a western musical scale (think C, D, E, F, G, A, B, C). The children were trained to recognize each pitch as representing a specific step on the staircase by having a stick figure go up and down the stairs as the pitch changed. After training, an interval was presented (two tones at the same time) pairing the middle C (C4) with another tone. The children were presented with the stick figure anchored on the C step and were asked to move the stick figure to show the other step that represented the second sound in the interval. In the second study, a similar procedure was performed but no anchor was presented, so the children had to remember the pairings of tones to steps, which the authors suggested, was a better measure of traditional “perfect pitch”. The results indicated that as groups, the children with autism did not perform better than typically developing children. However, within the autism group, a subgroup of ‘statistical outliers” was noted. Outliers are data points that are so significantly different than expected based on the performance of the entire group, that statistically they represent anomalies in the data. Often these ‘outliers’ are interpreted as possible errors of measurements, data entry, etc, etc. But this is a great example of when outliers are not errors in the data and actually provide meaningful information. The outliers observed in this study represented a small group of children with autism that scored up to 5 standard deviations above the mean of all groups. None of these children had received music training or were receiving music therapy. More likely, these were children with perfect pitch and the rate of these children in the autism group was disproportional to what is expected in the general population. That is, the data suggest that children with autism are more likely than typically developing children to have significantly above average pitch recognition --- perfect pitch.

Autism, Monkeys, and Maternal Antibodies

Title: Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism
Authors: Loren A. Martin, Paul Ashwood, Daniel Braunschweig, Maricel Cabanlit, Judy Van de Water and David G. Amaral
Source: In press. Journal Brain, Behavior, and Immunity

You can find a more complete description and review of this paper based on the press coverage here. Thus, I’ll limit this to a micro summary and a few related thoughts. The researchers wanted to experimentally test the hypothesis that exposure to maternal neuronal antibodies (IgG) during the PREnatal period could be one of the causes of at least some variants of Autism. To test this hypothesis the researchers exposed 4 prenatal rhesus monkeys with IgG taken from human mothers who had multiple children with ASD. They also exposed 5 prenatal monkeys with IgG taken from human mothers who did not have any children with Autism. Once the monkeys were born, these two groups were also compared to monkeys that had not been exposed to any antibodies. The researchers found that the monkeys that had been exposed to the antibodies of human mothers of children with autism engaged in much higher levels of unique whole-body stereotypic behaviors and less social contact with familiar peers, than did the monkeys exposed to IgG of mothers of typically developing kids or monkeys not exposed to any antibodies. Furthermore, these stereotypic behaviors increased when the monkeys were exposed to novel environments or peers. As I understand how controversial this paper will be for some people, I want to say that the authors are very clear and explicit in stating that this is NOT an animal model of autism. That is, they did not intent to say that they were able to “cause” autism in these monkeys via exposure to IgG. Instead, their data presents some evidence that exposure to IgG before birth leads to unique patterns of stereotypic behaviors, similar to those observed in some children with ASD. This is a very small preliminary study, but the results are fascinating in that it will guide future research to explore exposure to IgG as a potential cause (one of many) of ASD.

Diminished Cingulate Respose in Children with High Functioning Autism: A possible neural marker?

Title: Self Responses along Cingulate Cortex Reveal Quantitative Neural Phenotype for High-Functioning Autism
Authors: Pearl H. Chiu, M. Amin Kayali, Kenneth T. Kishida, Damon Tomlin, Laura G. Klinger, Mark R. Klinger and P. Read Montague
Source: Neuron 57, 463–473, February 7, 2008

I first heard about this article at the Autism Vox, which led to an interesting discussion on the difficulty in applying findings from basic science into the creation of diagnostic tools. This was a very interesting piece, but as I mentioned on the Autism Vox discussion, I think we are far from the creation of an FMRI test of autism (see the Autism Vox discussion). In summary, the researchers examined 16 adolescents with high functioning autism and 20 typically developing adolescents in their responses to a computer game called the Multi-round Trust Game. In this game the children received computer money (points) from another player in the form of an investment. During the transaction, the investment increased, so the receiving child obtained more than what the “investor” actually sent. Then the receiving child must decide how much of what he received should be returned to the investor. The key finding was that both groups of kids (Children with autism and typically developing) looked the same, in regards to their brain activation as seen on an fMRI, when the “Other” person was making a decision. The authors refer to this as the “Other Response”. However, when the children were making their own responses (called “Self Response”) the children with Autism lack a particular activation in the Cingulate Cortex (located deep in the center of the brain and usually activated during some social interactions including TofM tasks). This pattern of response was similar to the pattern presented by typically developing kids when playing against a computer instead of an actual person. The conclusion from the authors is that these children with autism may be “impaired in the capacity to represent the social intend of their OWN behavior” while understanding the actions of other (but not necessarily the intentions of others).

Commentary: Here is where the logic gets fussy. Since the two groups of children had a similar response patterns to the “Other” response, the authors argued that such “other” response must refer to a representation of the simple actions of others, but not the “intentions” of others. So the lack of cingulate cortex activation during “self” responses are interpreted as a diminished capacity to understand you own social “intentions” (or I interpret this that as “consequences”) and this is used to explain why children with autism have difficulty on theory of mind tasks. The authors argued that if you can’t represent your own social intentions, it will be difficult to represent the social intentions of others. Now, the problem is that in this game there was no difference between the two groups of kids when the “Other” was responding. Why? If children with autism have difficulty representing the social intentions of others, you would expected to see a difference between these two groups, unless you assume that 1) the typically developing kids also had problems representing the social intentions of others OR 2) during this game there was no need to represent the social intentions of others. In conclusion, what this study clearly shows is reduced Cingulate Cortex activation during “self” responses, suggesting that children with autism have a different brain activation pattern when performing actions that have social intentions, or consequences on someone else. Here is a review from MIT.

Autism and Mercury: The Pediatrics thimerosal study

Title: Mercury Levels in Newborns and Infants After Receipt of Thimerosal-Containing Vaccines
Authors: Michael E. Pichichero, MDa, Angela Gentile, MDb, Norberto Giglio, MDb, Veronica Umido, MDb, Thomas Clarkson, PhDc, Elsa Cernichiari, MSc, Grazyna Zareba, PhDc, Carlos Gotelli, PhDd, Mariano Gotelli, PhDd, Lihan Yan, MSe and John Treanor, MDa
Source: PEDIATRICS Vol. 121 No. 2 February 2008, pp. e208-e214

The famous Thimerosal study from the American Academy of Pediatrics journal finally was released this morning. This short review could not possibly do justice to the major controversy about mercury and autism, so I will limit the commentary to the results of THIS STUDY ONLY. Given that Thimerosal is commonly used in vaccines in other countries outside of the US and Europe, the researchers teamed with a research group in Argentina to examine how infants and toddlers process Thimerosal when injected as part of their standard vaccination procedures. The researchers examined newborns, 2 month old babies, and 6 month old babies. The infants received a birth dosage of BCG and HBV vaccines that contained 32.5 ug of mercury (ethyl mercury). The 2-months-olds received the first dosage of diphtheria-tetanus-whole-cell pertusis and Hib, the first dosage of polio, and the second dosage of HBV, providing a total of about 40-50 ug of mercury. Finally the 6-month-olds received the additional dosage of diphtheria-tetanus-whole-cell pertusis, Hib, and HBV for a total mercury intake also between 40-50 ug. Then the researchers examined mercury levels in the blood, stool, and urine 1, 3, 5, 11, 21, and 30 days after the vaccinations. The 1/2 life of mercury was found to be 3.7 days in new born, 2 days for 2-month olds, and 2.2 days for 6-months olds. Blood mercury levels returned to baseline by day 11 after the vaccination. The 1/2 life refers to the time it takes for the drug to reach 1/2 of its original value (max in the first cycle). Why is this significant? Because part of the argument against the use of Thimerosal in vaccines was based on the effect of Methylmercury in adults. Methylmercury has a 1/2 life of about 50 Days with studies reporting as long as 180 days! This long 1/2 life of Methylmercury means that the person is exposed to levels of mercury for extended periods of times (weeks), which has many potential side effects. The argument made by the authors of this study is that the 1/2 life of Ethyl Mercury as found in children is only about 3 days, significantly reducing the exposure to mercury in these babies. Now, the authors correctly state that this study does not address the "toxicity" of thimerosal, so it could be argued that exposure to ethyl mercury even for a short period of time (3-4 days)could be enough to cause maturational changes in the brain leading to permanent impairments.

Autism and Vaccines: The California Thimerosal Study

Title: Continuing Increases in Autism Reported
to California’s Developmental Services System
Authors: Robert Schechter, MD, MSc; Judith K. Grether, PhD
Source: Arch Gen Psychiatry. 2008;65(1):19-24

While we wait for the release of the new Academy of Pediatrics study on Thimerosal (see last blog entry), I thought this recent article from the Archives of General Psychiatry was worth reviewing, especially given the current controversy regarding ABC “Eli Stone” episode. This study was simple and elegant. It follows a straightforward logic. If the use of Thimerosal in vaccines has a causal role in the development of autism, the elimination of Thimerosal in vaccines should result in a drop in the rates of autism, or at the very least, a pause in the accelerated increase of these rates. To test this hypothesis the authors reviewed the rates of autism in the State of California from 1995 to 2007. The found a consistent increase in rates during these 11 years without any indication of a slowdown or a drop in autism rates. One particular finding is worth mentioning. The rates of autism in 3 to 5 year old kids increased from 3 to 4.1 per 1000 live births from 2004 to 2007, which represented a higher increase than those observed for all other developmental disabilities. This is of major importance because during this same period all but trace amounts of Thimerosal had been eliminated from vaccines in the State of California. If the link between Thimerosal and autism were "causal" and strong, the rates of autism during the 2004-2007 year should have dropped. Instead these rates increased. Now, although strong, this is far from conclusive evidence, since people could argue that rates continued to increase because of vaccinated babies moving to California or that such trace amounts of Thimerosal were enough to continue the increase in autism. But this last hypothesis will likely be answered by the Pediatrics article due to come out next week.

UPDATE: I found an interesting post at Autism in New Brunswick about a University of Kentucky professor’s (Dr. Boyd Haley) skepticism of this research based on the idea that mercury exposure continued after thimerosal was supposedly removed from vaccines in California (see the press story here). The difficulty with Dr. Haley's argument is that I can't find any reliable data showing that the levels of mercury in vaccines continued to be higher than trace amounts after Thimerosal was taken out of vaccines. At least I can’t find any published studies in scientific journals of such effect. It is difficult to believe that after Thimerosal was removed there was not a reduction in mercury exposure. Arguing that mercury exposure remained stable implies that either Thimerosal was not actually removed, that the new non-Thimerosal vaccines were so delayed to reach Drs offices as to not affect the overall mercury exposure, or that somehow these children continued to be exposed to mercury through a difference source. Otherwise, the most rational conclusion is to assume that mercury exposure was significantly reduced after Thimerosal was pulled from the market and therefore a parallel reduction in new cases with autism is expected. Sadly this didn't happen.

American Academy of Pediatrics Study on Thimerosal and Autism

It seems that due to the ABC decision to air the court drama "Eli Stone", the American Academy of Pediatrics released one study from their February journal issue a week early. This study apparently contradicts the theory that Thimerosal is linked to autism. Here is the link to the news release. I just checked our university online journals and the issue is not available yet. I suspect they made the issue available mostly to the press. As soon as I obtain a copy of the study I will post my commentary and summary as usual.

UPDATE: As of today (1/31 at 10:45am) the study has still not been made public. See the ABC news about the controversy here.

UPDATE: I finally reviewed the article HERE.

Autism and Genes in the News.

Title: Linkage, Association, and Gene-Expression Analyses Identify CNTNAP2 as an Autism-Susceptibility Gene
Source: The American Journal of Human Genetics 82, 150–159, January 2008
Authors: Maricela Alarcon, Brett S. Abrahams, Jennifer L. Stone, Jacqueline A. Duvall,
Julia V. Perederiy, Jamee M. Bomar, Jonathan Sebat, Michael Wigler, Christa L. Martin,
David H. Ledbetter, Stanley F. Nelson, Rita M. Cantor, and Daniel H. Geschwind.

As probably some of you have seen in the press today, the North American Journal of Behavioral Genetics just published 3 studies linking specific Genes to Autism. I just finished reading all three articles and I can say the results are fascinating (from a research perspective). I will limit this review to the main article “Linkage, Association, and Gene-Expression Analyses Identify CNTNAP2 as an Autism-Susceptibility Gene“ In this large study the researchers explore specific SNIPS (Single nucleotide polymorphism). SNIPS are rare genetic variations that represent our individual differences. That is, SNIPS are the variations in our genetic sequence that makes us different. Why are these important in bio medical research? Because if you can identify specific variations (SNIPS) that are more commonly or uniquely transmitted from one generation to another, and these generations also happen to have a unique disorder, it is possible to assume that the disorder may be affected or even caused by such specific genetic variation.

So this study explored a very rare genetic variation in a specific gene: the CNTNAP2. This is a gene that has been previously related to language delays and believed to play an important role in language development. This study found that a specific variation in the CNTNAP2 gene contribute to variability of “Age at first word” (How old was the child when he/she said the first word) in boys with autism (but not girls!). That is, the groups included in the study consisted of boys and girls with autism who had an average age at first word at around 30 months (typically developing kids say their first words at around 12 month). The researchers found that a particular variation in the CNTNAP2 was most commonly transmitted amongst these boys than amongst the girls or than amongst what is expected if such variation was random (like it is in the general population). The authors mentioned a similar study with Amish families that found this particular gene to be related to the presence of seizures, language delays, and social deficits. They argue that this particular gene may affect the development of ASD during the embryonic phase by affecting the way our brains change during early development. It is interesting to note that a similar process (disruption in normative brain development – specifically the way our cells migrate in our brain) has been proposed as the explanation of the “regressive” variant of autism.This is a variant experienced by many children consisting of normal development up to the age of 2 followed by a rapid regression and loss of abilities.

This is not the first study linking specific SNIPS to ASD, but provides more evidence to the genetic roots of autism. However, by no means this disputes or undermines other bio-social theories, such as the EP-M or Broken mirror reviewed yesterday, because these simply represent different levels of analysis. For example, we know that Down's syndrome is caused by a an extra 21st chromosome. However, this only defines the syndrome. People with Down's have specific deficits, such as intellectual impairment and delayed motor skills. But these impairment can be mapped to specific brain regions that have been compromised. So we have 3 levels of analysis in this case, the genetic anomaly is the cause the syndrome, which leads to compromised brain development, which leads to particular intellectual and motor difficulties. A similar process is likely in play in Autism. A series of genes anomalies are likely to be responsible for the disorder, leading to compromised brain development in specific regions (maybe mirror neuron system for example), leading in turn to social deficits.