Autism is a spectrum disorder , better referred to as ASD, It has been known for some time that differences like autism are, multi-dimensional and not readily reducible to a single set of mechanisms or genetic causes. In the past we have discussed how the disorder may be related to structural differences in the brain like those due to minicolumnar differences.
A new study looked at structural differences in brains of people (adults) with ASD and instead of focusing piece-meal on one feature (like minicolumns) combined a multitude of structural features and used a multi-dimensional classification system to determine the accuracy and specificity of the structural differences to predict/aid in diagnoses.
They came uyp with five dimensions- two based on volumetric measurements (surface area and cortical thickness) and the other three on geometric features (average convexity/concavity, mean radial curvature and metric distortion. (the article is open access, so go read it to find what these mean:-) )
What they found was that cortical thickness was the strongest predictor and that predictive power was greater for Left hemisphere measures than for right hemisphere measures.
They also talk about what these measures may mean in terms of underlying neurons and substructures and I reproduce that here:
There is already evidence to suggest that several aspects of cerebral morphology are different in people with ASD—including both volumetric (i.e., cortical thickness, regional area) and geometric (i.e., cortical shape) features (Levitt et al., 2003; Nordahl et al., 2007); and that different morphological features may have different neuropathological and genetic underpinnings (Panizzon et al., 2009). For instance, cortical thickness is likely to reflect dendritic arborization (Huttenlocher, 1990), while cortical surface area has been linked to the number of minicolumns in the cortical layer (Rakic, 1988). Geometric features such as cortical folding pattern, on the other hand, may reflect an abnormal pattern of intrinsic as well as extrinsic connectivity (Van Essen, 1997). Thus, examining the relationship between such multiple cortical features could provide invaluable insights into the multifactorial etiology of ASD.
We know form previous work that all of the above (arborization, minicolumns, local and global connectivity) have been implicated in Autism. The important take-home for me from thi sstudy is the fact that all these are governed by possibly separate underlying genetic mechanisms and may thus be independent of each other. On its own variations in one dimension may not lead to full blown autism, but when variations in all five or more dimensions combine they may make one more susceptible to ASD diagnosis.
Remember we are only talking about structural change sin brains here; we haven’t even touched upon functional differences (default mode network?) and there is plethora of evidence that functional changes are also very important. Overall I believe the multi-dimensional nature of underlying structural and functional differences lend autism the spectrum property and also a continuum with normality. As always I would be eager to know how the SVM they used to classify Autistics fared when asked to classify Psychotics …did the pattern they see was reverse of Autism and inline with the Schizophrenia/psychosis as opposed to Autism theory?
Ecker, C., Marquand, A., Mourao-Miranda, J., Johnston, P., Daly, E., Brammer, M., Maltezos, S., Murphy, C., Robertson, D., Williams, S., & Murphy, D. (2010). Describing the Brain in Autism in Five Dimensions–Magnetic Resonance Imaging-Assisted Diagnosis of Autism Spectrum Disorder Using a Multiparameter Classification Approach Journal of Neuroscience, 30 (32), 10612-10623 DOI: 10.1523/JNEUROSCI.5413-09.2010
Yesterday I wrote a post about ADHD and creativity and how the frontal lobes hypo-function and dopamine may be the mediating factors involved. Today I serendipitously came across this article by Thomson-Schill et al in which they posit that frontal cortex hypofunction during childhood is beneficial, on average, as it enables convention learning and thus linguistic acquisition.
What they basically mean is that frontal cortex has been found to be involved in cognitive control i.e. in higher cognitive functions like planning, flexible thinking etc ; and the frontal cortex does this by biasing the competitive responses elicited by a stimuli by goals /existing beliefs / other task related information that is maintained in the working memory. To take an example, cognitive control is often measured by tasks such as the stroop task. the strrop task measures how well you are able to suppress the prepotent response tendency of naming the color-term itself by the task-relevant constraint that you name the color of the term instead. when a color term like ‘green’ is presented in Red color, then the green as well as red linguistic response compete with each other. In the absence of frontal biasing in teh direction of color ie.e red, we are apt to name the color-term itself i.e green by default which is the habitual response. Children , who have less well-developed frontal cortices generally perform poorer at the stroop task than adults as their frontal cortex does not bias or tilt the scales in favor of the color used rather than the color-term presented.
The authors claim that this inability to bias results on the basis of pre-existing knowledge/beliefs leads to a greater ability to learn. They posit that learning conditions (that maximize competition ) are different from performance conditions (where one response needs to be selected or competition minimized) and the child’s brain is optimized for learning by not having frontal inhibition and control. An example they give is filtering noise form signal which the child are able to do, but adults can’t. for eg. if a new language has a phrase ‘et tu brute’ and 75 % of times it is in this form and 25% of times it is of the form ‘et tu vous Brute’, then adults will tend to probability match and select the utterance/ utter themselves phrase ‘et tu brute’ 75% of times and ‘et tu vous Brute’ 25 % of times. This is because when they want to utter the phrase their existing knowledge that sometimes the other phrase is also used, makes them sensitive to variations. In child’s brain on the other hand a competition between the two phrases takes place and as there is no moderating influence involved, the outcome hundred percent of the time is ‘et tu brute’. Thus, they are able to learn conventional meaning of a phrase/word etc more easily than an adult who gets bogged down by variations. Thus sometimes, less is more!
However the reason I got hooked to this study is the implications they draw for ADHD/Autism and creativity. I’ll quote them verbatim on the issue:
Central to our proposal is the claim that the timing of PFC development has been the target of selection and, therefore, that variations in timing are functionally meaningful. Recent neuroimaging studies have revealed potentially important differences in the timing of PFC development across typical and atypical individuals. Variations in the trajectory of PFC maturation (based on repeated measures of cortical thickness) have been associated with cognitive measures in typically developing children (Shaw et al., 2006). Children with attention-deficit hyperactivity disorder (ADHD) exhibit a delay in cortical maturation that is most prominent in the PFC (Shaw et al., 2007). In contrast, children with autism spectrum disorders (ASD) undergo early maturation of the PFC (Carper, Moses, Tigue, & Courchesne, 2002). A better understanding of the implications of these timing changes for both learning and performance may illuminate some of the behavioral and cognitive patterns associated with these diagnoses (e.g., impaired acquisition of social conventions in ASD), as well as offer a fertile ground for testing the validity of our hypothesis that typical PFC development involves a trade-off in favor of learning to the detriment of performance in infancy and early childhood.
This gels quite nicely with what I have been speculating for some time, that ADHD and Autism are opposed and that ADHD is childhood equivalent of psychosis. ADHD kids are bound to be good learners, more divergent creative and have better social and linguistic skills. Autistic kids on the other hand would be better performers (say child prodigies in memory etc) , more convergent thinkers, and have less social and linguistic skills- one mechanism of which may be lesser ability to learn social and linguistic conventions- like the usage of metaphorical terms.
On creativity this is what the authors say:
Creativity—the ability to approach an object or a situation from an alternative perspective—may benefit from the unsupervised competition that occurs in the absence of prefrontal control. Consider one common assessment of creative thinking, the Alternative Uses Task: When attempting to think of ways to use an object in some atypical way, adults struggle. In this case, an active PFC might, paradoxically, hinder flexible thinking, because the representation of the object is sculpted by prior experience and expectations. Interestingly, young children are immune to this kind of functional fixedness (German&Defeyter, 2000). Successful performance in similar tasks of ideational fluency has been associated with EEG changes in prefrontal regions (e.g., Mo¨lle, Marshall, Wolf, Fehm, & Born, 1999). Furthermore, patients with PFC damage solve insight-problemsolving tasks better than do their healthy counterparts (Reverberi, Toraldo, D’Agostini, & Skrap, 2005). This apparent flexibility of behavior can be interpreted as a stimulus-driven response: A mind that is at the mercy of its environment is not shaped by expectations or beliefs. This interpretation highlights a parallel between functional fixedness and probability matching, in that both of these ‘‘adult’’ phenomena involve biasing stimulus–response associations based on expectations. This proposal suggests new avenues of investigation into the processes that support creative thought and into putative relations between creativity and psychological disorders associated with hypometabolic prefrontal function (i.e., a state of lower energy consumption in the PFC, as in bipolar disorder, for example).
The above analysis of creativity in terms of hypofunction of frontal cortex bodes well for my theories of creativity-ADHD relationships as well as creativity-psychosis (bipolar etc) relationship, both of which involve developmental or functional hypofucnction of frontal cortex.
Thompson-Schill, S., Ramscar, M., & Chrysikou, E. (2009). Cognition Without Control: When a Little Frontal Lobe Goes a Long Way Current Directions in Psychological Science, 18 (5), 259-263 DOI: 10.1111/j.1467-8721.2009.01648.x
ADHD has traditionally been conceptualized in terms of deficits- that of attention , impulse control or motor restraint; but the new neurodiversity paradigm forces us to take a more balanced look and acknowledge the strengths that the ADHD kid may have- divergent thinking, spontaneity and high energy and vitality.
That brings me to research by Cramform that shows that the symptoms that define ADHD/ADD- hyperactivity, impulsivity and distractability are just the negative connotation and spin put on some of the traits that define highly creative and gifted child– the traits of Vitality, spontaneity and daydreaming/wandering phenotype.
But first things first. ADHD , as many of the readers will know , is defined by three primary symptoms- hyperactivity or the restlessness and fidgety or squirming behavior of the kid; impulsiveness or the inability to control impulses manifest in overt behavior like getting up in class and interrupting; and distractibility where the kid ends up paying too much attention, even to stimuli that are extraneous and should be ignored, thus leading to fleeting attention! ADHD is a traditional classroom misfit and thus a traditional teachers nightmare. However, one should note that a traditional teacher is not too much impressed by the highly creative kid too, who proves to be a bit too much to placate and who doesn’t conform too easily.
Of course dopamine is not just involved in ADHD, but also in Psychosis and thus my theory of Autism and Psychosis as opposites would claim that ADHD is childhood form of psychosis and is opposed to Autism. There is already some support for that idea with autism and ADHD being discovered as opposites and with ADHD more common in bipolar probands.
The dual symptoms of ADHD as inattention and as hyperactivity/ implusivity are easy to conceptualize when one sees that one is trying to maximize predictive ability / minimize surprise and also maximize rewards by being flexible in one;s behavior and taking risks rather that persevering on the well trodden path. Both attention-allocation and action-selection are sensitive to dopamine and in one particular phenotype result in more leaning towards flexibility, distracatibility, hyper energy and arousal and more novelty and thrill seeking. The desire is to explore and not to exploit. The hunter rather than the farmer as per Hartman’s model. These same are characteristics of the creative phenotype- those touched with fire- and thus on the move literally or figuratively- always seeking new combination and ideas and exploring uncharted territory.
Perhaps its time we stopped negatively labellings the gifted, creative ADDers as difficult kids, but rather design and structure classrooms around them that bring their potential to the fullest and make them bloom fully. Lets not stifle the creativity. Lets not devalue the immense energy and joy these child exhibit and the creative potential they embody.
Cramond, B. (1995). The Coincidence of Attention Deficit Hyperactivity Disorder and Creativity University of Connecticut, The National Research Center on the Gifted and Talented. Other: ED388016
Autism is a hard disorder to nail down genetically- single nucleotide polymorphisms (SNPs) or even multiple locus genetic effects are not able to account for the large genetic component to the disorder. In recent times, Copy number variations (CNVs) has come to the forefront of Autism research , suggesting that microdeletions, duplications etc may account for some cases. Another new , till now unsuspected mechanism that has recently been implicated in autism is epigenetic mechanism of increased methylation in promoter regions that has the effect of silencing/reducing the expression of genes involved to a certain extent. The recent study by Gregory et al, is just such a step in the right direction, which will hopefully bring us closer to the truth.
In a nutshell, the study authors used CNV determining methods to discover that a deletion of OXTR (oxytocin receptor) gene was presnet in an autistic subject and was not de novo , but the deletion was inherited from his mother. One of the affected siblings of the autistic subject, who too was autistic, on the other hand did not have a deletion, but had increased methylation of the OXTR. this led the study authors to revisit their genomics data and look at adta across all autistic subjects and controls and discover that indeed, in other autistics too the OXTR had increased methylation. Then they looked for expression of OXTR in peripheral blood cells and temporal cortex and found that indedd in autistics, as compared to controls, there was reduced expression of OXTR. This strongly suggest that the epigentic changes that lead to autism (the efffect of OXTR suppression) happen quite early in the devlopmenet and might happen in utero.
Before I elaborate on my take home from the study, there are some excerpts (as I know you didn’t read the originals)
Classic autism comprises a spectrum of behavioral and cognitive disturbances of childhood development. The core autism phenotype includes deficits in social interaction, language development and patterns of repetitive behaviors and/or restricted interests. The population prevalence of the spectrum of autism disorders is estimated to range between 1/300  to 1/100 (http://www.nschdata.org/), with a male: female ratio of 4:1 [2,3]. The disorder has been shown to be highly heritable with the relative risk for siblings being approximately 2% to 8%, much higher than that of the general population . To date, only a small percentage of autism cases (<10%) have been ascribed to single gene disorders such as fragile X syndrome, tuberous sclerosis  and Rett syndrome . Numerous approaches including genetic linkage, genome-wide association, candidate gene association and gene expression analysis have been used to identify the additional genes
implicated in the development of autism [7,8]. However, the heterogeneous nature of autism and autism spectrum disorders has limited their success.
An additional approach to identify genes involved in autism is to characterize copy number variants (CNVs), that is, chromosomal deletions and duplications, that are known to be present within at least 5% of individuals with idiopathic autism . Autism CNVs have been shown to involve almost all chromosomes [10,11], with the most frequently observed alteration localizing to chromosome 15q11-13 [12-23]. A number of different methods have been used to characterize autism related CNVs, including but not limited to, cytogenetic Gbanding [14,23,24], metaphase fluorescence in situ hybridization (FISH) , Southern blotting , loss of heterozygosity (LOH) analysis [15-17,19], quantitative polymerase chain reaction (PCR)  and, more recently, genotyping and representational oligonucleotide microarray analysis (ROMA) .
Here we describe the use of genome-wide tilepath microarrays and array comparative genomic hybridization (CGH) to identify CNVs in a dataset of 119 unrelated probands from multiplex autism families . The genomic profiles of our autism dataset were compared to the array CGH profiles of 54 phenotypically normal individuals, to previously published CNVs present within the database of genomic variants  and to the Autism Chromosome Rearrangement Database (http://projects.tcag.ca/autism/). The most significant finding thus far from our analysis is a heterozygous deletion of the oxytocin receptor gene (OXTR) (MIM accession no.: 167055) in an individual with autism and his mother with putative obsessive-compulsive disorder (OCD). We further investigated the relationship between OXTR and autism by carrying out epigenetic analysis of the promoter region of OXTR. We show that the gene is hypermethylated in independent cohorts with autism as compared to controls, in both peripheral blood mononuclear cells (PBMCs) and the temporal cortex. Additionally, our analysis of expression levels of OXTR in the temporal cortex shows decreased levels of expression in individuals with autism as compared to controls matched for age and sex.
These data suggest that OXTR and the oxytocin signaling pathway play an important role in the etiology of autism and autism spectrum disorders and implicate epigenetic misregulation of OXTR in this complex disease.
Epigenetic control of autism susceptibility is a recent concept and most certainly a topic of great interest in the field. Over the past decade, researchers have uncovered suggestive links between epigenetics and autism, for example, autism is associated with duplications of 15q11-13 (especially maternally inherited), an imprinted region in the genome where DNA methylation status has been linked to Prader-Willi syndrome (PWS) and Angelman syndrome (AS) ; mutation within a gene that encodes a methyl-DNA-binding protein (MECP2, (MIM accession no.: 300005)) is the causative agent of Rett syndrome ; and mutation of this same gene has been associated with both autism and AS populations . Nagarajan et al. have shown that 79% of autism cases have a decrease in MECP2 expression in the frontal cortex and that an increase in aberrant DNA methylation correlates with this decrease in MECP2 expression . These data implicate epigenetic dysregulation as a mechanism for the development of autism and justify the examination of DNA methylation of autism candidate genes, such as OXTR identified in this study.
Now from the accompanying (more accessible) commentary:
The article by Gregory et al. published this month in BMC Medicine, reports on genomic and epigenetic alterations of OXTR, the gene encoding the receptor for oxytocin. The involvement of this gene was suggested by its deletion in an autistic patient. The subsequent analysis of a group of unrelated autistic subjects did not show an OXTR deletion, but rather hypermethylation of the gene promoter, with a reduced mRNA expression.
These findings address two major points of the current debate on the etiology and pathogenesis of autism: the role of oxytocin, known to be involved in modeling human behavior, and the possible involvement of epigenetic mechanisms. The nature of this epigenetic dysregulation is unknown but, if proved to be true, might explain the failure to identify sequence alterations in a host of candidate genes. Practical implications of these findings may be forthcoming, however not before extension and validation on a larger scale have confirmed their value.
The second issue raised by Gregory et al. deals with the epigenetic inhibition of OXTR expression in ASD. Such epigenetic modification, at least as reported so far, does not seem to be sequence based but rather of a different, as yet unknown nature. This might explain why researchers have been looking for decades for genetic mutations in ASD and yet have found almost none. An epigenetic mechanism would justify the ‘unusual’, non-Mendelian familial aggregations of ASD. In this respect, even the family with OXTR deficiency reported by Gregory et al. shows an unusual genotype-phenotype correlation, in that the same phenotype is caused by alterations of the same gene but due to different molecular defects (deletion versus hypermethylation).
Also, the possibility that in most ASD patients there might be an epigenomic instability is of interest in consideration of the fact that it has been shown that the epigenetic status in early fetal development can be reprogrammed by maternal behavior in a reversible way . Therefore, other environmental factors, yet to be discovered, might also be able to reprogram the epigenotype of the embryo.
I hope the fact that epigenetic changes may happen during pregnancy line of reasoning does not lead to the harmful and without-any-basis vaccination is cause of autism arguments. On the other hand I had covered earlier how Autism is more likely if mother was exposed to valproate during pregnancy or the child soon after birth. What if valproate is instrumental in an epigenetic fashion in leading to more or less methylation and gene expression. It is well known that valproate and valporic acid is given as treatment for psychosis/bipolar. In a similar vein, I am inclined to stick my neck out and claim that in schizophrenics/psychotics , the OXTR should be more expressed : perhaps more methylation, duplications etc . However I am checked in my musings by these studies that claim that negative symptoms of schizophrneia may be associated with reduced oxytocin activity in the brain. Yet, all said and done I would like to see a study that analyzes for epigenetic mechanisms in schizophrneia especially at the OXTR locus. Although the negative symptoms like social withdrawal of schizophrenia may lead to the opposite hypothesis regarding schizophrenia and oxytocin correlation, I am inclined to believe that schizophrenics (at least those suffering from positive symptoms predominantly) are too much oxytocin guided , trusting and socially too much involved in others type of people.
Gregory, S., Connelly, J., Towers, A., Johnson, J., Biscocho, D., Markunas, C., Lintas, C., Abramson, R., Wright, H., Ellis, P., Langford, C., Worley, G., Delong, G., Murphy, S., Cuccaro, M., Persico, A., & Pericak-Vance, M. (2009). Genomic and epigenetic evidence for oxytocin receptor deficiency in autism BMC Medicine, 7 (1) DOI: 10.1186/1741-7015-7-62 Gurrieri, F., & Neri, G. (2009). Defective oxytocin function: a clue to understanding the cause of autism? BMC Medicine, 7 (1) DOI: 10.1186/1741-7015-7-63
Hat tip to @Boraz for tweeting about this study.
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