Phonological Processing in Parents of Children with Autism.

A review of: Schmidt, G., Kimel, L., Winterrowd, E., Pennington, B., Hepburn, S., Rojas, D. (2008). Impairments in phonological processing and nonverbal intellectual function in parents of children with autism. Journal of Clinical and Experimental Neuropsychology, 30(5), 557-567. DOI: 10.1080/13803390701551225

I have previously reported on studies examining the “Broader Autism Phenotype,” a repeated finding that some parents of children with autism (most often fathers) have mild autistic tendencies themselves. I recently discussed a study on social cue perception and a study on seizure disorder. In the present study, the authors wanted to explore performance on language measures among parents of children with autism when compared to parents of typically developing kids. The study included 22 parents of kids with autism (14 mothers and 8 fathers) from 17 families (some families had both parents participating while most had only one parent). The comparison group included 22 parents that were matched for sex, age, IQ, and socioeconomic status. The two groups completed a battery of neuropsychological tests including the Wechsler Abbreviated Scale of Intelligence, and measures of receptive language, expressive language, phonological processing (processing of sounds), and history of reading difficulties. The authors found that when compared to parents of typically developing kids, parents of children with autism performed worse on measures of non-verbal reasoning and phonological processing. There were no significant differences on measures of verbal intelligence, expressive language, receptive language, verbal fluency, and history of reading difficulties. The findings would appear consistent with the ‘non-verbal disability’ profile that had been proposed as a marker of Asperger’s syndrome, although several recent studies have failed to provide evidence for this profile (see this review on a study on non-verbal learning disabilities in Asperger's syndrome). However, it was surprising to see any differences at all between the groups, in light of their very high intellectual functioning profile. That is, these parents were significantly above the norm in intellectual capacity, with IQ scores of 116 for the parents of children with autism and 120 for parents if typically developing children. Thus, in regards to non-verbal reasoning and phonological processing, we are not talking about “impairment” among parents of kids with autism, but instead slightly worse (but still above average) performance than parents of typically developing kids.

Infant asymmetry in children with Austim

A review of: ESPOSITO, G., VENUTI, P., MAESTRO, S., MURATORI, F. (2008). An exploration of symmetry in early autism spectrum disorders: Analysis of lying. Brain and Development DOI: 10.1016/j.braindev.2008.04.005

Many clinicians who conduct diagnostic assessments of children with suspected autism would tell you that there is something unique, yet difficult to describe, about how children with autism move. Parents often report also noticing something unique in their children's movement, and that they've noticed these patterns since the time their children were babies. Consistent with these clinical observations, some researchers have examined the movement patterns of infants who would eventually be diagnosed with autism. In this article, a team from the University of Trento (Italy) and the Univeristy of Pisa (Italy), reported on a study looking at symmetry patterns in posture among infants participating in a longitudinal study of autism. The study include 18 children diagnosed with Autism via ADOS and ADI, 12 children with a diagnosis of non-autism developmental delays, and 18 typically developing children. The parents of these children were asked to provide video tapes of their children when they were infants. Sections of the videos showing the babies awake and lying in supine position were coded for ‘symmetry’ by trained researchers who were blind to the eventual clinical diagnosis of the child. Symmetry was determined by matching the position of the baby to a standard list of infant asymmetric positions called the Positional Pattern for Symmetry During Lying. The results were consistent with the common clinical observations. Children with autism were rated as infants to be significantly less symmetric than children with developmental delays and typically developing children. Moreover, there were no differences between the typically developing children and those with non-autism developmental delays. The authors found that all of the children with low levels of symmetry were in the autism group, but that these represented only a subgroup of children with autism. This was interpreted as evidence for a possible subgroup of autism that is related to dysregulation in neural pathways associated with balance and motor movements.

The possible future role of antibiotics as treatment of Type 1 Autism?

An article was just released pre-publication on the Journal of Autism and Developmental Disorders. It’s not a report of an empirical study. Instead, it’s a letter to the editor of the journal written by Dr. Hari Manev and Dr. Radmila Manev from the University of Illinois. I never discuss letters to the editor on this blog, but this particular letter caught my attention. In this letter the authors present an interesting speculative suggestion of the possible role of some types of antibiotics in treating a specific type of autism. This is the basic argument:
- A number of studies have identified a mutation in the neurexin gene CNTNAP2. Not all cases of autism are related to this mutation, thus the label of Type 1 Autism was proposed by Dr. Stephan on the article “Unraveling Autism” published on the American Journal of Human Genetics (2008). Type 1 Autism would then refer to cases of autism that also have the gene mutation.
- This mutation results in a premature stop codon resulting in a non-functional CNTNAP2 protein. A stop codon is a genetic sequence that signals the end of the process of creating a protein.
- Some antibiotics, such as gentamicin and PTC124, have been shown to suppress the premature stop condons, thus preventing the specific protein deficits associated with such premature codons.
- It is theoretically possible that such antibiotics may suppress the actions of the premature codon in children with this type of autism, possibly leading to a normalization of the levels of protein related to CNTNAP2.

But would this lead to improved symptoms among children already with a full diagnosis? Or will the treatment only be effective before the CNTNAP2 mutation affects protein synthesis during early development, which would argue for early genetic testing? And of course, this assumes that indeed the CNTNAP2 mutation has a causative role in autism and is not simply a comorbid condition. We should note that none of these medications have been approved or studied as a possible treatment for “type 1” autism. Yet, the basic theoretical foundation is there to guide future research to examine the possible role of antibiotics in treating Type 1 autism.

Children with Autism have difficulty recognizing emotions from whole body movements.

A review of: Parron, C., Da Fonseca, D., Santos, A., Moore, D.G., Monfardini, E., Deruelle, C. (2008). Recognition of biological motion in children with autistic spectrum disorders. Autism, 12(3), 261-274. DOI: 10.1177/1362361307089520

A human point-light display is created by filming a set of lights attached to the joints of a person as the person moves. The film is done in a dark room so that only the lights are visible and captured by the camera. By watching these lights as they move in space, typically developing children and adults can identify very specific information about the person, such as the gender and emotional states. In this study, the authors compared 23 children with autism spectrum disorder (7 to 18 years of age; mean IQ = 94; SD=15 Range 85-120) diagnosed based on DSM-IV criteria via ADI against 23 typically developing children matched for sex and age. The children were presented with 20 video clips of point-light displays (10 of a male actor, 10 of a female actor). Five of the clips showed the actor displaying emotional states such as happy, sad, and angry. The children were asked to identify what they see. Responses were coded for accuracy in identifying the object (person vs. other object such as a ball), the action (jumping, running, etc), subjective state (tiredness, bored), and emotional state (sad, happy). There was no statistically significant difference between the children with ASD and typically developing kids in their ability to identify the action, the subjective state, or the object. However, children with ASD displayed significantly more difficulty in identifying emotions from the point-light displays when compared to typically developing kids. This suggests that the reported difficulty in the processing of non-verbal emotional information among children with ASD may be influenced by difficulties in understanding the motional content embedded in whole body movements. Two related comments: The performance accuracy of children with ASD in identifying the action and the subjective states was also below that of typically developing kids, but these differences did not reach statistical significance. However, based on the graph included in the paper, it appears that the mean differences were large and the non-significant finding was most likely a byproduct of the small sample size used. Unfortunately the group means and standard deviations were not provided, which would allow us to test the necessary sample size needed to reach statistical significance. This relates to my second comment. The groups were not matched for IQ. The authors argued that IQ was unrelated to performance in the ASD group, but this analysis is limited by the small sample size of the ASD group, which possibly violated the assumptions of the statistical tool used to examine the effect of IQ (ANCOVA). Thus it is possible that the ‘average’ group differences observed are indicative of group differences in intellectual capacity rather than to something unique to ASD.

Autism Regression: A prevalence study

A review of: Baird, G., Charman, T., Pickles, A., Chandler, S., Loucas, T., Meldrum, D., Carcani-Rathwell, I., Serkana, D., Simonoff, E. (2008). Regression, Developmental Trajectory and Associated Problems in Disorders in the Autism Spectrum: The SNAP Study. Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-008-0571-9

Although most children with autism present very early signs and symptoms and a linear developmental trajectory, a small subset of children present a trajectory characterized by normal development followed by a loss of acquired skills or a failure to use the acquired skills. This pattern has been termed autistic regression. Possible explainations for this phenomenom have varied from a genetic effect on brain restructuring and pruning during the early stages of life, to enterocolitis due to vaccinations, to epilepsy. In this study, the authors explored differences in developmental outcomes for children with and without regressive autism, and the association between regression and enterocolitis and epilepsy. This study examined a population cohort born in the UK in 1990 and 1991. Out of 56,946 children in this cohort, 218 had and ASD diagnosis by age 10. A subset of these children were evaluated via ADOS and ADI and divided into a broad autism (N=105), narrow autism (N=53), and no autism (N=97). The narrow autism group met full criteria for autism based on ICD-10. The broad autism group met clinical consensus for autism but not full ICD-10 criteria. These children were then evaluated for history of epilepsy, gastroinstestinal problems, and developmental regression. 39% of children with narrow autism had a history of regression during development. This compared to 11% of children with broad autism, and 3% of children with no autism. On average this regression occurred around the 25 month of age. There were no differences in IQ or adaptive functioning between those with or without regression. However, those with regression classified in the broad autism group had significantly more symptoms than those without regression also classified in the broad autism group. Regression was not associated with gastroinstestinal symptoms or with epilepsy.

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.

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 the gender gap

Typically developing boys score higher than girls on autism scale.

A review of: Williams, J.G., Allison, C., Scott, F.J., Bolton, P.F., Baron-Cohen, S., Matthews, F.E., Brayne, C. (2008). The Childhood Autism Spectrum Test (CAST): Sex Differences. Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-008-0558-6

This large-scale study examined gender differences in the Childhood Spectrum Test, a parental report of autism symptoms for use in primary schools. The test consists of 37 questions covering communication, social behaviors, and other symptoms of Autism Spectrum Disorder, but more specifically Asperger’s syndrome. A score of 15 or above is considered to be in the clinical range suggesting the presence of an ASD. The test was completed by 3,334 parents of typically developing kids attending elementary schools in England. There were equal number of boys and girls. The results were compelling. Boys had a statistically higher median score than girls (5 vs. 4, p < .001). But most notable, 103 kids (3%) had scores in the borderline range (12-14). This group was composed of 75 boys (73%) and 28 girls (27%). In addition, 102 kids (3%) had scores in the clinical range (>14). As you may expect, 79% (81) of these were boys.

Is the gender gap observed in the parental responses to this particular scale a reflection of true gender differences in the rate of ASDs – as predicted by the Extreme Male theory of Autism? Or do these results tell us more about a possible fundamental bias in our view of expected behaviors as they relate to ASDs? That is, gender differences may exist in communication styles, play preferences, and social behaviors, which are often view as ‘soft’ signs of autism spectrum disorders. Unfortunately this particular study will not give us the answer, for the results are consistent with both theories. It is also possible that both positions are not unique, or orthogonal, since the gender differences in communication styles, etc, may result from the underlying mechanisms proposed by the Extreme Male theory: a male tendency for systematizing and an impairment in empathizing.

Autism and Cerebellar Differences?

Study finds no differences in cerebellar volume in people with autism after controlling for macrocephaly, IQ, and age.

A review of: CLEAVINGER, H.B., BIGLER, E.D., JOHNSON, J.L., LU, J., McMAHON, W., LAINHART, J.E. (2008). Quantitative magnetic resonance image analysis of the cerebellum in macrocephalic and normocephalic children and adults with autism. Journal of the International Neuropsychological Society, 14(03) DOI: 10.1017/S1355617708080594

As I do my weekly literature search on Autism Research for Translating Autism, I noticed a number of forthcoming manuscripts about the role of the cerebellum in Autism. I will likely review some of these new studies and decided to start with Cleavinger et al (2008) MRI examination of cerebellum in children and adults with autism.

The cerebellum is located on the lower back region of the brain and traditionally it has been implicated in the integration of sensory information and the coordination of movement. However, more recent investigations have determined that the cerebellum is also active in various higher-order functions such as language, emotion, and cognition. In the past, studies looking at differences in the cerebellum of people with and without autism have provide mixed results with some showing increased volume in people with autism, while others show no difference, or decreased volume. One possible explanation for these conflicting findings is that people with autism often vary in degree of macrocephaly (large head size) which may affect the results if the samples studied included individuals with and without macrocephaly. To address this question the authors of this study examined 4 groups: a) people with autism and macrocephaly (N=13) b) people without autism and macrocephaly (N=8) c) people with autism and without macrocephaly (N=28) and c) people without autism and without macrocephaly (N=16). In general, after controlling for macrocephaly, age, and IQ, no statistically significant differences in cerebellar volume were found, although a trend was observed in that people with autism who also had macrocephaly showed smaller cerebellar volume as compared to similar macrocephalic individuals without autism. This trend is important because the ‘non-significant’ differences reported here are likely due to the small sample size and unequal group size, which affects the statistical power of the analysis (making it more difficult to show statistical significant differences even when such differences actually exist). But even if the 'non-differences' result is replicated and in fact no differences in cerebellar volume exist between these groups, does this mean that the cerebellum is not implicated in autism? Not at all. Here again I touch the issue of how we should avoid reaching conclusions that go beyond what the data tell us. These results only speak to the size of the cerebellum, suggesting no apparent morphological differences. These results however, do not speak to possible anomalies in the functioning of the cerebellum, which may or may not be present in autism.

Autism and social perception: The possible role of attention

Can the difficulties in social perception in Autism be due to attention deficits?

A review of: Fine, J.G., Semrud-Clikeman, M., Butcher, B., Walkowiak, J. (2008). Brief Report: Attention Effect on a Measure of Social Perception. Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-008-0570-x

The co-morbidity between autism spectrum disorders and attention disorders (ADHD or ADD) is very high, with rates ranging from 49% to 78%. Thus, a significant number of people with autism spectrum disorders also have attention difficulties. Yet, little is known about how these attention problems may contribute to the different social difficulties experienced by people with ASD. In this paper, the authors compared 37 children with ASD (no breakdown of ASD was provided), 30 children with ADHD, and 19 typically developing kids (age 6-16). All kids had IQ scores over 80. 20 of the kids in the ASD group also had a co-morbid diagnosis of ADHD. These children completed a measure of social perception: the Child and Adolescent Social Perception Measure (CASP). This measure consists of 10 video clips of children interacting with an adult. The kids could see the vingnettes but the audio of the video was modified so that the kids could hear the prosody but not the lexical content. Then the kids were asked to tell the story in their own words and then indicate how each of the characters was feeling and how they could tell how the characters felt. Additional measures of attention and cognition were also included.

The results: ASD and ADHD kids did not differ in their ability to correctly identify emotions, but both groups performed significantly worse than the typically developing group. The ASD and ADHD groups also did not differ on measures of inattention or impulsivity, but the ADHD group had higher levels of hyperactivity. Finally inattention was a significant predictor of poor performance on the CASP. Thus, for all groups, lower levels of inattention were associated with better performance on the social perception measure, suggesting that for children with austim spectrum disoder, inattention may play a key role in explaining difficulties in non-verbal social understanding.

Autism and Cholesterol: A possible link?

Low levels of cholesterol associated with autism-like symptoms in Smith-Lemli-Opitz Syndrome.

A review of: Aneja, A., Tierney, E. (2008). Autism: The role of cholesterol in treatment. International Review of Psychiatry, 20(2), 165-170. DOI: 10.1080/09540260801889062

The Smith-Lemli-Opitz Syndrome (SLOS) is a genetic disorder characterized by alterations in the processing of cholesterol. Specifically, people with this disorder do not produce enough cholesterol resulting in a variety of morphological, physiological, and behavioral symptoms. Of interest to autism researchers is that people with SLOS have many of the same symptoms that characterize autism spectrum disorders, including language impairments and stereotyped behaviors. How is cholesterol related to ASDs within and outside the SLOS syndrome? In this article, Aneka and Tierney (2008) present a succinct summary and conceptualization of the possible role of cholesterol in the phenomenology of Autism. The authors reviewed the physiological mechanisms by which low levels of cholesterol may play a role in the behavioral phenotype found in kids with SLOS. The following mechanisms were discussed:
1. Cholesterol is necessary for normal embryonic and fetal development.
2. Cholesterol is a precursor of neuroactive steroids (possibly affecting anxiety)
3. Cholesterol is required for the growth of myelin membranes (affecting brain maturation).
4. Cholesterol can be a modulator in oxytocin receptor functioning (Oxytocin plays an important role in social behaviors).
5.Cholesterol is a modulator of the ligand binding activity and G-protein coupling of the serotonin1A (5-HT1A) receptor (affecting serotonin neuron development).

An examination of these factors is beyond the scope of this review, but they represent a sensible theory regarding the possible mechanisms by which low levels of cholesterol may lead to many of the behavioral symptoms present in autism. The authors then discussed the implication of these findings for assessment and possible treatment interventions. First, most comprehensive evaluations of autism may include genetic and laboratory testing, including testing for fragile X, heavy metals, etc. The authors stated that biochemical testing can be utilized to assess for low level of cholesterol (actually low levels relative to another compound - 7DHC). In my experience, requesting this test within a neuropsychological evaluation is not common. Actually I don’t remember ever conducting an evaluation of someone who had been recommended this test by anyone (neurologist, pediatricians, psychologist, etc). Finally, the authors reviewed previous studies that have examined the effectiveness of cholesterol supplementation in children with SLOS. Previous studies have found that children with SLOS that receive cholesterol supplementation show a reduction of autistic behaviors, irritability, attention problems, and improved affect.

Should cholesterol testing become a part of the standard assessment procedures of children with Autism?

Brain Differences in Autism 2: Fusiform Gyrus

A review of: van Kooten, I.A., Palmen, S.J., von Cappeln, P., Steinbusch, H.W., Korr, H., Heinsen, H., Hof, P.R., van Engeland, H., Schmitz, C. (2008). Neurons in the fusiform gyrus are fewer and smaller in autism. Brain DOI: 10.1093/brain/awn033

The fusiform gyrus is an area of the temporal lobes of the brain that has been extensively associated to people’s ability to recognize faces. The authors of this paper proposed that abnormalities in the fusiform gyrus may explain some social deficits in Autism. Although people with autism can correctly complete face processing tasks, the authors noted that people with autism display reduced activation of the fusiform gyrus during these tasks. This alteration could be responsible for atypical behaviors such as reduced eye contact. To examine the underlying hypothesis further, the authors examined the post-mortem brains of 7 children and adults with autism as compared to 10 matched controls. They found significantly reduced neuron density and total neuron number in areas of the fusiform gyrus but not in other cortical areas. The authors presented a very interesting alternative interpretation. Although the reduced neural density and number in the fusiform gyrus could reflect neurodevelopmental impairments in the fusiform itself resulting in specific functional impairments, it is also possible that this atrophy is related to ‘loss of targets’ to which the fusiform gyrus projects. That is, the fusiform gyrus sends neural projections to the amygdale, which play an important role in monitoring eye gaze and other social behaviors. Thus, is the finding of reduced neural density and total number of the fusiform gyrus a reflection of dysfunction of this area of the brain, or simply a byproduct of alterations in other related areas such as the amygdale?

Brain Differences in children with Autism: White Matter – Gray Matter

A review of: BONILHA, L., CENDES, F., RORDEN, C., ECKERT, M., DALGALARRONDO, P., LI, L., STEINER, C. (2008). Gray and white matter imbalance – Typical structural abnormality underlying classic autism?. Brain and Development DOI: 10.1016/j.braindev.2007.11.006

The authors of this study discussed the relative inconsistent results from studies trying to examine brain differences in children with and without Autism. For example, although many post-mortem studies have found brain differences, the differences they find vary significantly between studies. The same is true of studies using imaging techniques such as MRI. However, the most consistent finding is an overall larger brain volume in children with autism, leading some researchers to propose deficits in cell pruning as a possible cause of autism (more of this below). In this study the authors used MRI (Magnetic Resonance Imaging) to compare 12 children with Autism (average age 12) to 16 matched typically developing children. The results showed that children with autism had increased generalized bilateral gray matter. Specifically increased gray matter was observed in the cingulated gyrus, caudate, cerebellum, claustrum, cuneus, fusiform gyrus, inferior, middle and superior frontal gyri, inferior and superior temporal gyri, inferior and superior parietal lobules, pre and post-central gyrus, precuneus, putamen, thalamus, insula and occipital cortex. The results also showed decreased generalized bilateral white matter in the cuneus, medial and superior frontal gyri, pre- and post-central gyri, inferior parietal lobule, supramarginal gyrus, cingulote gyrus, middle occipital gyrus, parahippocampal gyrus, and the middle and superior temporal gyri. The authors concluded that their data provides strong evidence for increased gray matter and reduced white matter in children with autism when compared to typically developing kids. Similar results have been used as evidence of the cell pruning theory of autism. This theory indicates that children with autism have an atypical brain development process during early infancy. Specifically, during a typical post-natal period, there is considerable removal of connections between cells in the brain leading to more efficiency in cell connectivity and cell communication. Researchers argue that abnormal brain growth during early development in autism is due to limited pruning of such synaptic connections.

Executive dysfunction in Adults with ASDs.

A review of: Barnard, L., Muldoon, K., Hasan, R., O'Brien, G., Stewart, M. (2008). Profiling executive dysfunction in adults with autism and comorbid learning disability. Autism, 12(2), 125-141. DOI: 10.1177/1362361307088486


In this well designed study, the authors first reviewed the basic theory of Executive Function. Executive function (EF) refers to neurocognitive processes associated with the planning and implementation of actions. Some researchers have proposed that autism is directly linked to anomalies in EF. Deficits EF lead to difficulty in the planning and initiation of action, inhibition of inappropriate responses, and difficulty with strategy monitoring. One issue in assessing EF in children and adults with autism is that deficits in EF are also present in other developmental problems, such as learning disabilities, which are common in people with autism. In order to control for this possible confound, the authors compared 20 adults with autism and co-morbid learning disability against 23 adults with learning disability only. These two groups were matched for age and IQ. The authors compared their performance on a battery of neuropsychological tests of EF*. The authors found that although the group with autism performed consistently worse than the group with learning disabilities on all tasks, none of these differences reached statistical significance. The authors then created a composite score of different domains of EF and found significant differences between the groups. Specifically, the group with Autism had significantly lower scores on ‘working memory’ and ‘planning’. A few specific factors about this study are worth mentioning. The study was conducted with adults with intellectual impairment (Average IQ = 67), thus the findings may not generalize to people within the normative range of intellectual functioning. The sample size was also extremely small, which affects the ability to find statistically significant differences. Finally the authors discussed one interesting point regarding "causality". It is difficult, if not impossible, to understand the direction of the causal factors at play. Is executive functioning one contributing factor to autism (a possible cause), or is it simply a byproduct of other impairments related to autism (caused by)?

*For those interested in the specific tasks used, these included the: Tower of London, Mazes, the Knock and Tap task, Verbal Conflict, WCST, COWA, Non-verbal Fluency, and the WMS-III.

More evidence against the Leaky Gut theory of Autism?

A review of: Cass, H., Gringras, P., March, J., McKendrick, I., O'Hare, A.E., Owen, L., Pollin, C. (2008). Absence of urinary opioid peptides in children with Autism. Archives of Disease in Childhood DOI: 10.1136/adc.2006.114389

Should parents of children with autism stop purchasing commercially available test of opioid-peptides?

In this previous POST I reviewed a simple study that examined the intestinal system of children with autism in order to test specific hypotheses related to the “Leaky Gut” theory. As is mentioned before, this theory suggests that children with autism have increased permeability of their intestinal track leading to faster absorption of peptides which could disrupt neural development during the early stages of life. However, the Robertson et al. (2008) article did not find evidence that would support the Leaky Gut theory. In this similar study, the authors compared 68 males with autism between 4 and 11 years of age to 202 typically developing males of similar ages. Autism was diagnosed via ADI-R based on ICD-10 diagnostic criteria. Only 6 of the children with autism were on special diets (gluten free or gluten and casein free). The researchers compared the levels of putative opioid peptides in the urine of all participating children. There was no significant difference between the peptide levels of children with autism when compared to typically developing children. The authors concluded that, given this apparent normative absorption and processing of peptides in children with autism, the presence of high opioid -peptides should not be used as a marker for autism or as an estimate of the possible effectiveness of gluten free diets. The researchers also indicated that previous studies showing high levels of opioid peptides in children with autism prior to the start of a gluten free diet (See for example Knivsberg et al 2002), have not been replicated mostly because of possible inadequate methods used in previous studies. The authors feel strongly that “Children with autism should not be subjected to investigation of urinary opioid peptides or their parents to the expense of the assays which are still widely advertised on the internet by commercial laboratories around the world”.

UPDATE: After I reviewed this study I received several emails from parents with different perspectives on the Gluten Free diet issue. I want to briefly note two things. The data from the Cass article do not directly address the issue of effectiveness of the gluten free diets or the issue of the use of peptide tests to predict treatment effectiveness (despite their strong statement against such tests). Their data simply fails to find support for one of the underlying assumptions of the Leaky Gut theory.

Someone also pointed me to what seems to be the only clinical controlled study of these treatments:

Elder JH, Shankar M, Shuster J, Theriaque D, Burns S, Sherrill L.( 2006) The gluten-free, casein-free diet in autism: results of a preliminary double blind clinical trial. J Autism Dev Disord. 36(3):413-20.

In this study, the authors also failed to find statistical evidence for improvement in children exposed to the gluten free diet for 12 weeks. However, this 2006 study was very preliminary with an extremely small sample size. There is no doubt that additional research is needed to help clarify the possible effectiveness of these diets.

“Leaky Gut” revisited: Intestinal problems in children with autism.

Title: Intestinal Permeability and Glucagon-like peptide-2 in Children with Autism: A Controlled Pilot Study.
Source:Robertson, M.A., Sigalet, D.L., Holst, J.J., Meddings, J.B., Wood, J., Sharkey, K.A. (2008). Intestinal Permeability and Glucagon-like peptide-2 in Children with Autism: A Controlled Pilot Study. Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-007-0482-1

One of the many theories that have been proposed to explain possible causes of autism is the "leaky-gut, opioid-excess" theory. This theory suggests that children with autism have increased permeability of their intestinal track leading to faster absorption of peptides which could disrupt neural development during the early stages of life. To test this theory, the authors measured intestinal permeability in a group of 14 children with autism (diagnosed via DSM-IV criteria by a developmental pediatrician), 7 typically developing siblings of these children, and 8 typically developing additional children. They tested the leaky gut theory in two ways. First they observed the levels of a hormone (GLP-2) in response to feeding, which is believed to control satiation. Low levels of this hormone could lead to, or reflect, dysregulated peptide absorption. Second, intestinal permeability was assessed via a differential sugar-absorption test. They used different types of sugars that have different molecular weights. In a normal intestinal system, sugars with small molecular weight will pass through the walls easily as compared to heavy sugars, leading to high levels of the small sugars in urine. However, in a highly permeable intestinal system, the ratio of these two sugars in urine will change as the sugars with large molecular weights pass through the intestinal barrier at a higher rate. Results: The authors found no differences between any of the 3 groups of children in GLP-2 response to feeding or the ratio of sugars in urine. The authors concluded that in this small sample of children with autism there was no evidence of increased intestinal permeability as hypothesized in the ‘leaky-gut’ hypothesis.

Side note: I always thought "Developmental Pediatrician" was a completely redundant label, and comparable to 'heart cardiologist' or 'eye ophthalmologist'. Although sadly, my experience with some pediatricians does suggest that some really don't know anything about human development.

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.