Monday, 23 October 2017

Shocker alert: gut problems in autism impact on sleep

I don't mean to be sarcastic about the findings reported by Lena McCue and colleagues [1] talking about how gastrointestinal (GI) dysfunction might show an *association* with sleeping problems in the context of autism. There was however, an air of 'inevitability' about such findings that has been discussed previously in the peer-reviewed science literature (see here)...

Researchers drew upon data from the Autism Genetic Resource Exchange (AGRE) research program (something that they've done before) to identify over 600 children and young adults diagnosed with "idiopathic autism spectrum disorder, aged 2-18 years" (idiopathic = autism not secondary to a known genetic condition). They examined data on the presence of GI and sleep issues in order to gauge whether there was any relationship between the two.

Lo and behold: "The adjusted odds ratio for sleep disorder among those with gastrointestinal dysfunctions compared to those without was 1.74 (95% confidence interval: 1.22-2.48)." Results held even when various potentially confounding variables were taken into account. Ergo: "Early detection and treatment of gastrointestinal dysfunctions in autism spectrum disorder may be means to reduce prevalence and severity of sleep problems and improve quality of life and developmental outcomes in this population."

Gastrointestinal (GI) issues are very much over-represented when it comes to autism (see here). I'd say that the evidence is pretty overwhelming for that last statement both when it comes to functional bowel issues such as constipation and/or diarrhoea (see here) and also risk of more pathological conditions too (see here). Indeed, we've had peer-reviewed published guidance on screening and treating bowel issues in relation to autism [2] for some time now. Sleeping issues are also over-represented in relation to autism (see here). Alongside seemingly greater risk for specific sleep issues (see here for example) accompanying a diagnosis of autism, sleeping problems often feature as one of the more 'quality of life draining' aspects in relation to autism [3] (as they also affect significant others too [4]). It strikes me as a win-win situation that detecting and treating GI issues may also have positive implications for sleep issues in autism.

And finally, a small (peer-reviewed) contribution to this area from yours truly [5]...


[1] McCue LM. et al. Gastrointestinal dysfunctions as a risk factor for sleep disorders in children with idiopathic autism spectrum disorder: A retrospective cohort study. Autism. 2017 Nov;21(8):1010-1020.

[2] Buie T. et al. Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics. 2010 Jan;125 Suppl 1:S1-18.

[3] Kuhlthau KA. et al. Associations of quality of life with health-related characteristics among children with autism. Autism. 2017 Jul 1:1362361317704420.

[4] Tilford JM. et al. Treatment for Sleep Problems in Children with Autism and Caregiver Spillover Effects. J Autism Dev Disord. 2015 Nov;45(11):3613-23.

[5] Whiteley P. Food and the gut: relevance to some of the autisms. Proc Nutr Soc. 2017 Sep 26:1-6.


Saturday, 21 October 2017

"we found no association between maternal folic acid supplementation and offspring ASD" but...

The findings reported by Marit Strøm and colleagues [1] observing "no association between maternal folic acid supplementation and offspring ASD [autism spectrum disorder]" throw yet another research 'spanner in the works' when it comes to the [very generalised] idea that pregnancy folic acid supplementation might affect risk of offspring autism.

Don't get me wrong, I appreciate all the data suggesting that folic acid supplementation during pregnancy is a useful thing for helping to reduce the risks of neural tube defects (NTDs) for example. But when it comes to pregnancy folic acid (folate) potentially impacting on offspring risk of autism, I've always been a little cautious of the collected data so far and how its been interpreted/generalised in certain quarters (see here and see here for examples).

So, drawing on data from the "entire DNBC [Danish National Birth Cohort]" initially including nearly 100,000 singleton, live born children, researchers set out to find female "users" of folic acid supplements either just before conception or during the earliest stages of their pregnancy. Not just content with folic acid, they also looked at available data on "periconceptional vitamin B12" use too on the basis of some connection between the two vitamins. They then searched connected databases to find those offspring with a diagnosis of autism spectrum disorder (ASD): "identified by International Classification of Diseases (ICD)-10 diagnosis codes F840, F841, F845, F848, and F849; ‘childhood autism’ by diagnosis code F840." Analyses of these collected variables were undertaken, as well as adjusting for potentially confounding variables such as maternal age, parity, education level and the like.

Results: well, as per the title of this post, researchers reported finding very little when it came to pre-pregnancy or early pregnancy folate use: "There was no detectable association between maternal folic acid supplementation in the periconceptional period and offspring ASD" and: "Results from the analyses using midpregnancy exposure data were similar: there was no association with ASD/childhood autism neither for folic acid supplementation nor for dietary folate intake." Such results held when various 'corrections' were made for variables such as "sex specific effects" and cases where intellectual (learning) disability was present for example.

I have to say that the authors do seem genuinely surprised that their results did not tally with other large, population studies on this topic: "At present we are not able to present any viable explanation for these discrepant results." They do mention one particularly important point insofar as the usefulness of looking at small changes to something called the methylenetetrahydrofolate reductase (MTHFR) gene in the context of autism and folic acid as other authors have done [2]. This, on the basis that MTHFR plays an important role in folate metabolism (see here) and issues with this gene are no stranger to the autism research landscape (see here). I'm also minded to refer readers back to another potentially important issue identified in relation to some autism that might also affect folate metabolism: folate receptor autoantibodies (FRAAs) (see here).

I still think there is a place for further investigations on folic acid use during pregnancy and offspring autism risk. But like many things in the context of the plural 'autisms' (see here), it perhaps makes more sense to zoom in on potentially relevant sub-groups on the autism spectrum rather than treating all autism as being homogeneous in either aetiology or presentation. I might add that folic acid use as part of wider range of nutritional supplements potentially used during early pregnancy remains an important area of research attention in the context of offspring autism [3].

And also just to complicate things even further, the results from Wang and colleagues [4] add: "this comprehensive meta-analysis suggested that maternal use of folic acid supplements during pregnancy could significantly reduce the risk of ASD in children regardless of ethnicity, as compared to those women who did not supplement with folic acid." I don't think the debate is finished yet on this topic.

Music to close, and since my brood and I are competing again today, Sia (again) and some brilliant kata (hopefully our Heian Sandan will be as good).


[1] Strøm M. et al. Research Letter: Folic acid supplementation and intake of folate in pregnancy in relation to offspring risk of autism spectrum disorder. Psychol Med. 2017 Sep 26:1-7.

[2] Schmidt RJ. et al. Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study. Am J Clin Nutr. 2012 Jul;96(1):80-9.

[3] DeVilbiss EA. et al. Antenatal nutritional supplementation and autism spectrum disorders in the Stockholm youth cohort: population based cohort study. BMJ 2017; 359: j4273.

[4] Wang M. et al. The association between maternal use of folic acid supplements during pregnancy and risk of autism spectrum disorders in children: a meta-analysis. Molecular Autism. 2017; 8: 51.


Friday, 20 October 2017

Completing the set: features of ADHD in childhood epilepsy

'Completing the set' used in the title of this post refers to the idea that a diagnosis of epilepsy rarely(?) seems to exist in some sort of diagnostic vacuum as per previous discussions whereby features of autism (see here) and dyspraxia / developmental coordination disorder (DCD) (see here) seem to be over-represented in cases of epilepsy.

This time around the focus was on attention-deficit hyperactivity disorder (ADHD) and the findings reported by Isabell Brikell and colleagues [1] suggesting that: "Individuals with epilepsy had a statistically significant increased risk of ADHD." Researchers arrived at their conclusions on the basis of examining some of those wonderful Scandinavian population registries that are providing all-manner of interesting details on possible trends and patterns in various areas: "We identified 1,899,654 individuals born between 1987 and 2006 via national Swedish registers..." Said data were actually used to look at "the familial coaggregation of epilepsy and ADHD and to estimate the contribution of genetic and environmental risk factors to their co-occurrence" but also served the purpose of looking at ADHD prevalence alongside epilepsy. Indeed it was also interesting to note the authors' conclusions about familial liability to the "cross-disorder overlap": "The genetic correlation was 0.21 (95% CI = 0.02-0.40) and explained 40% of the phenotypic correlation between epilepsy and ADHD, with the remaining variance largely explained by nonshared environmental factors." Mmm...

Such research - although requiring quite a bit more independent investigation [2] - follows an important trend in recent times observing how stand-alone developmental and/or psychiatric diagnoses often 'clump together' in seemingly at-risk patient groups. I've for example, talked about the important concept of ESSENCE - Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations [3] on this blog and how "co-existence with other conditions was the rule" (see here) rather than the minority perspective in the area of childhood psychiatry. Now we seem to be able to add ADHD to the list of comorbidity potentially over-represented alongside a diagnosis of epilepsy (bearing in mind that epilepsy covers quite a lot of diagnostic ground).

Mechanisms? Well, far be it from me to speculate too much, but an important starting point is the nature of epilepsy and how it affects brain function. It's not inconceivable that particular alterations to the functioning of the brain as a result of epilepsy (or even during some prodromal phase) might be enough to *induce* other behaviours/symptoms to be pronounced. Equally, one might subscribe to the the idea that changes to brain function due to other events or factors that may be connected to conditions such as autism or ADHD or DCD could be enough to induce the onset of epilepsy (this hypothesis draws support from the onset patterns typically seen in cases of autism and epilepsy). I don't doubt that relationships are likely to be complicated.

Much more needs to be done on this topic, not least in ensuring appropriate screening services when cases of epilepsy are diagnosed, particularly in childhood. With no medical or clinical advice given or intended (don't mess with epilepsy), I do wonder whether some of the peer-reviewed data talking about dietary changes being used to manage certain types of epilepsy also potentially impacting on presented symptoms of *some* other labels (see here) might also provide some clues as to potential shared mechanisms between epilepsy and other developmental/psychiatric labels?


[1] Brikell I. et al. Familial Liability to Epilepsy and Attention-Deficit/Hyperactivity Disorder: A Nationwide Cohort Study. Biol Psychiatry. 2017 Aug 12. pii: S0006-3223(17)31858-9.

[2] Caplan R. ADHD in Pediatric Epilepsy: Fact or Fiction? Epilepsy Curr. 2017 Mar-Apr;17(2):93-95.

[3] Gillberg C. The ESSENCE in child psychiatry: Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations. Res Dev Disabil. 2010 Nov-Dec;31(6):1543-51.


Thursday, 19 October 2017

Weighing up genetics and environment in autism - reanalysed

Consider this post a sort of add-on to a previous entry (see here) published on this blog talking about the relative contributions of genetics and environment when it comes to autism. On that previous blogging occasion, the findings reported by Sven Sandin and colleagues [1] were the source material and the observation: "Heritability of ASD [autism spectrum disorder] and autistic disorder were estimated to be approximately 50%." The press release accompanying those results was titled: "Environment as important as genes in autism, study finds."

Now the same data has been though a bit of a re-analysis [2] and a slightly different conclusion and media headline - "Autism is mostly genetic, suggests study" - has been created. The reason for the quite different conclusions reached: "Instead of looking at just one time point when both members of a sibling pair had been diagnosed, they incorporated the fact that not all siblings would be diagnosed at the same time. They may start as being undiagnosed, then one would get diagnosed and, later, another might be determined to have autism" according to another media take on the findings (see here). I can't argue with the logic.

The data - 37 570 twin pairs, 2 642 064 full sibling pairs, 432 281 maternal and 445 531 paternal half sibling pairs - were now analysed in the context that diagnoses of autism/ASD among siblings are, for many reasons, not always uniform in timing. The influence of genetics or more specifically, heritability was subsequently boosted up to 83% (previously suggested to be 50%) and with it, 'nonshared environmental influence' relegated to an estimates 17%.

I've perhaps been a little unfair by using the word 'relegated' in the context of non shared environmental influence in relation to autism. There are plenty of examples out there whereby such influences might impact on autism risk: prenatal valproate exposure, congenital rubella syndrome, various types of encephalitis being linked to autistic symptoms onset (see here and see here for examples), etc and these are not to be downplayed. Environmental factors can be pretty important.

But it's critical to also mention that genetics do seem to play quite a significant role in many instances of autism too. Yes, the idea of an 'autism gene' is already a distant memory replaced by something altogether a lot more complicated, but when taking into account notions such as the broader autism phenotype (BAP) for example, one cannot discount that particularly in multiplex families, heritability is probably [mostly] driven by genetics and science still needs to continue looking at the specific hows-and-whys (see here for one example). I might add that looking at gene expression over just structural genetics is probably going to be useful in these days of epigenetics and the like.

And whilst the research of Sven Sandin is being discussed today, another recent paper where the name has appeared [3] has suggested that "little or no maternal genetics contribution" is the order of things when it comes to heritability and autism...


[1] Sandin S. et al. The Familial Risk of Autism. JAMA 2014; 311: 1770-1777.

[2] Sandin S. et al. The Heritability of Autism Spectrum Disorder. JAMA. 2017; 318(12): 1182-1184.

[3] Yip BHK. et al. Heritable variation, with little or no maternal genetics contribution, accounts for recurrence risk to autism spectrum disorder in Sweden. Biological Psychiatry. 2017. Sept 21.


Wednesday, 18 October 2017

Tobacco smoking and psychiatric illness

"The prevalence of smoking has remained alarmingly high among individuals with schizophrenia and bipolar disorder, and the disparity with those without psychiatric disorders and with the general population is increasing."

So said the findings reported by Faith Dickerson and colleagues [1] who surveyed nearly 2000 people "about their cigarette smoking at enrollment into a research study for which they were selected without regard to their smoking status." Their findings make for important reading in the context that tobacco smoking is not exactly a healthy activity (see here) and could potentially contribute to some of the health inequalities already recognised when it comes to serious mental illness (SMI) (see here).

The sorts of figures of smoking prevalence observed by Dickerson et al are not to be ignored: "62% of individuals with schizophrenia, 37% with bipolar disorder, and 17% of participants without a psychiatric disorder (control group) reported that they were current smokers." This set in the context of falls in the rates of smoking in the general population. It's also worthwhile noting that being a 'current smoker' with reference to a diagnosis of schizophrenia or bipolar disorder typically meant smoking "more cigarettes per day" than the control cohort.

There are other implications from this work. Without generalising (or stigmatising) if one draws on other work talking about a possible connection between prenatal nicotine exposure and offspring [heightened] risk of schizophrenia for example (see here), a complex pattern of *association* seems to emerge. No, I'm not saying that every woman with schizophrenia who is pregnant will smoke through their pregnancy (despite evidence of some increased risk [2]) but greater focus and education on the need to restrict tobacco smoking during that critical period is perhaps warranted. Such discussions may also have implications for the whole nature-nurture debate with regards to such psychiatric diagnoses too.

Although there are many (many!) good reasons for encouraging those with a SMI to quit smoking, I do feel it is important also to understand why so many are smokers. The findings reported by Li and colleagues [3] offer something of a perspective on this issue where for example: "Smokers had a higher mental QOL [quality of life] than non-smokers... in MDD [major depressive disorder]." Similarly, Mallet and colleagues [4] discussed results that suggested that "some therapeutics may improve daily smoking behavior in smokers" in the context of schizophrenia (as others seemed to be associated with 'not improving' smoking behaviours). In short, the roads that lead to, and perpetuate tobacco smoking in the context of SMI are likely as complex as the ones needed to lead people away from such habits...

And aside from the health reasons to quit smoking particularly among those diagnosed with a SMI, the grand review, meta-analysis and meta-regression paper by Cassidy and colleagues [5] lists tobacco smoking as one potentially important (and modifiable) correlate when it comes to risk factors for suicidality in schizophrenia...


[1] Dickerson F. et al. Cigarette Smoking by Patients With Serious Mental Illness, 1999-2016: An Increasing Disparity. Psychiatr Serv. 2017 Sep 15:appips201700118.

[2] Nilsson E. et al. Women with schizophrenia: pregnancy outcome and infant death among their offspring. Schizophr Res. 2002 Dec 1;58(2-3):221-9.

[3] Li XH. et al. Prevalence of smoking in patients with bipolar disorder, major depressive disorder and schizophrenia and their relationships with quality of life. Sci Rep. 2017 Aug 16;7(1):8430.

[4] Mallet J. et al. Cigarette smoking and schizophrenia: a specific clinical and therapeutic profile? Results from the FACE-Schizophrenia cohort. Prog Neuropsychopharmacol Biol Psychiatry. 2017 Oct 3;79(Pt B):332-339.

[5] Cassidy RM. et al. Risk Factors for Suicidality in Patients With Schizophrenia: A Systematic Review, Meta-analysis, and Meta-regression of 96 Studies. Schizophr Bull. 2017 Sep 23.


Tuesday, 17 October 2017

"What are the sex-specific recurrence rates of autism spectrum disorder among siblings?"

The paper by Nathan Palmer and colleagues [1] attempted to shed some light on the question posed in the title of this post: "What are the sex-specific recurrence rates of autism spectrum disorder among siblings?" The topic of sibling recurrence rates with regards to autism has been discussed for quite a few years (see here for example).

Already covered by Spectrum (see here), the Palmer data was derived from the records of a US health insurance organisation covering the period between 2008 and 2016 and some 3 million+ children. Researchers specifically looked at those in receipt of an autism diagnosis and onward to "estimate high-confidence sex-specific recurrence rates of ASD [autism spectrum disorder] among siblings." In other words, how many boy and girl younger siblings of children with autism were also diagnosed with autism or an ASD and whether the gender/sex of the older diagnosed sibling was an important variable in recurrence risk.

The answers: well, first it's worth noting that that prevalence of ASD came out at ~2%. This was based on administrative health insurance records remember, so is probably quite accurate given that such schemes have to 'pay out' for certain services/provisions as and when autism is diagnosed. Such a figure also adds to other data highlighting this upward trend in cases diagnosed (see here and see here).

Then: "When a male was associated with risk in the family, ASD was diagnosed in 4.2%... of female siblings and 12.9%... of male siblings. When a female was associated with risk in the family, ASD was diagnosed in 7.6%... of female siblings and 16.7%... of male siblings."

You can perhaps see that there were some subtle differences in the autism/ASD recurrence rate according to the sex/gender of the child first diagnosed with autism in a family. The Spectrum review of this paper quotes the lead author saying: "For a girl to emerge with [autism] in the first place indicates that that is a high-risk family" indicating that the appearance of females with autism might mean a greater genetic load is already present in relation to autism risk for example, which then affects subsequent recurrence risk for autism in later born siblings. That is, if one assumes that genes are the be-all-and-end-all of autism risk (see here)...

What else would I like to see in future investigations? Noting the name Isaac Kohane as part of the authorship group of this paper and acknowledging his past contributions to the autism research landscape with a focus on comorbidity and autism (see here) I do wonder if more could be done on that topic with autism recurrence in mind. Y'know, accepting that various psychiatric and somatic comorbidity are 'over-represented' following a diagnosis of autism (see here), a little more information on what else might be recurring alongside autism could provide some important clues about hows-and-whys, particularly bearing in mind that 'autism genes' aren't necessarily just genes for autism (see here)...


[1] Palmer N. et al. Association of Sex With Recurrence of Autism Spectrum Disorder Among Siblings. JAMA Pediatrics. 2017. Sept 25.


Monday, 16 October 2017

Vitamin A supplementation and autistic symptoms: hidden away but no significant effect...

I used the words 'hidden away' in the title of this post because I had a bit of a time deciphering the findings reported by Juan Liu and colleagues [1] (open-access) investigating "the role of VA [vitamin A] in the changes of gut microbiota and changes of autism functions in children with ASD [autism spectrum disorder]." Vitamin A by the way, is a fat soluble vitamin involved in various process such as immune function and vision health. There is a darker side to vitamin A however, as safe upper limits have been in place for quite a few years, particularly for pregnant women as a result of potential teratogenic effects.

Suffice to say that after 6 months of VA supplementation - "participants with an insufficient plasma retinol status (<1.05 μmol/L) received VAI [vitamin A intervention?] with a dose of 200,000 IU once orally" - the authors reported seeing no significant changes in autistic signs and symptoms as measured before and after using the Autism Behavior Checklist (ABC), Childhood Autism Rating Scale (CARS) and Social Responsiveness Scale (SRS). They did however report changes in retinol status (a marker for vitamin A availability) coinciding with supplementation: "The plasma retinol level increased from 0.59 ± 0.19 μmol/L to 0.72 ± 0.20 μmol/L in the group of 64 after 6 months of VA supplementation" and changes in the percentages of vitamin A levels (typical, marginal deficiency, deficient) across their group. I say this however, based on their use of high performance liquid chromatography (HPLC) with photodiode-array detection for assaying for retinol; state-of-the-art about 30 years ago and now superseded by better detection technology such as mass spectrometry...

No mind, Liu et al also looked at "CD38 and acid-related orphan receptor alpha (RORA) mRNA levels" as "autism-related biochemical indicators’ changes" following supplementation. RORA - retinoic acid-related orphan receptor-alpha - has some research history discussed before on this blog (see here). Authors reported that: "After 6 months of intervention, plasma retinol, CD38 and RORA mRNA levels significantly increased" despite the seeming lack of effect on presented autistic symptoms.

Further: "Fresh stool samples were collected from participants who did not receive supplemental probiotics or prebiotics and who were not treated with antibiotics for the previous 1 month." Said poo(p) samples - pre and post-vitamin A supplementation - were analysed alongside food diaries and food frequency behaviours. Authors observed that bacterial species showed changes between the baseline and post-intervention samples; specifically settling on "significant increases in the proportion of Bacteroidetes/Bacteroidales and decreases in Bifidobacterium after the VAI, accompanying significant increases in autism biomarkers, while no significant changes were observed in autism symptoms."

What can we make of these collected findings? Well, whilst vitamin A deficiency is something to look out for among children with autism [2] (see here too) and previous research has indicated "an empirical basis for the development of a pharmacological ASD treatment strategy based on retinoids" [3] the lack of a significant behavioural effect from vitamin A supplementation in this case cannot be just glossed over. Yes, this was an open-trial - "we aimed to conduct a placebo-controlled intervention study, but all the participants showed an insufficient VA status and were thus enrolled into the VAI group" - and so has shortcomings but the findings of a lack of significant change across any and all of the autism-related behaviour schedules used is notable. The biological results are a little more interesting; particularly the bacterial findings. But again it wouldn't be difficult to say 'so what?' to such bacterial results given that no corresponding changes in autistic behaviour(s) were noted...


[1] Liu J. et al. Effect of vitamin A supplementation on gut microbiota in children with autism spectrum disorders - a pilot study. BMC Microbiology. 2017; 17: 204.

[2] Chiu M. & Watson S. Xerophthalmia and vitamin A deficiency in an autistic child with a restricted diet. BMJ Case Rep. 2015 Oct 5;2015. pii: bcr2015209413.

[3] Riebold M. et al. All-trans retinoic acid upregulates reduced CD38 transcription in lymphoblastoid cell lines from Autism spectrum disorder. Mol Med. 2011;17(7-8):799-806.


Saturday, 14 October 2017

Bullying and autism: stating the bleedin' obvious...

A short post today to reiterate the 'bleedin' obvious': children diagnosed as being on the autism spectrum are far more likely to be the victim of bullying than perpetrator (see here for a previous blog post on this topic).

This conclusion comes from the paper by Hwang and colleagues [1] based on responses to the Behavior Assessment System for Children: Second Edition (BASC-2) (parental report version). The authors initially reported that "children with ASD [autism spectrum disorder] showed significantly increased risk for bullying involvement compared to community children" potentially indicating that a diagnosis of autism does not somehow shield someone from either being bullied or indeed, participating in bullying behaviour (perpetrator). But... "after controlling for comorbid psychopathology and other demographic factors, increased risks for being perpetrators or victim-perpetrators disappeared while risk for being bullied/teased continued to be significantly elevated." Said 'comorbid psychopathology' included aggression and conduct problems as well as the signs and symptoms of depression potentially accompanying a diagnosis of autism. Indeed, aggression was pretty much linked to every type of bullying behaviour in both autism and control groups...

What's more to say on this topic? Well, further recognition that school in particular, can be a significant source of stress and anxiety for children on the autism spectrum is one thing (and potentially contributory to the stats on school refusal in the context of autism). Indeed, without trying to armchair diagnose nor artificially inflating the seriousness of bullying, I wonder whether quite a few more children on the autism spectrum need to be screened for possible post-traumatic stress disorder (PTSD) in the context of how traumatic bullying can be for a person (see here). In relation also to the point made about aggression being a common variable predicting bullying across the Hwang cohort, I wonder whether more needs to be done more generally in relation to reducing aggression in places like school and thus potentially reducing bullying behaviour more generally?

And whilst on the topic of bullying, it appears that some of the longer term effects of bullying for some might be countered by some kind of resilience (whatever 'resilience' might mean)...


[1] Hwang S. et al. Autism Spectrum Disorder and School Bullying: Who is the Victim? Who is the Perpetrator? J Autism Dev Disord. 2017 Sep 21.


Friday, 13 October 2017

Quarter of kids with autism with iron deficiency but...

Iron (Fe) is something that I've always been a little bit interested in on this blog with specific regards to autism (see here). Outside of the typical 'helping to produce red blood cells' bit, I've always been intrigued by the potential behavioural and cognitive effects following issues with suitable iron supplies. My particular interest in an enzyme that relies on iron as a co-factor (see here) is also worthwhile noting...

A new paper by Serkan Gunes and colleagues [1] (open-access) continues the important theme of iron and autism suggesting that various iron-related parameters might be sub-optimal in relation to the autism spectrum but also with a possible confounding effect of comorbidity in relation to the presence of iron deficiency anemia (IDA) and autism.

Looking at 100 children and young adults diagnosed with an autism spectrum disorder (ASD) and 100 not-autism (I hate the term "healthy controls") controls, researchers surveyed both blood samples and behaviour using a variety of measures. Alongside just having a diagnosis, participants with autism were also subject to various measures covering autistic behaviours, "intellectual evaluation" and various behavioural schedules in-between. Various iron-related parameters were studied: serum ferritin ("as an indicator for ID [iron deficiency] since it is a precursor for ID and represents iron levels in body tissues including brain") and then hemoglobin, hematocrit, iron, ferritin, MCV (mean corpuscular volume), and RDW (red blood cell distribution width).

Results: as per the title of this blog post, 25% of participants fell into the range of iron deficiency (ID). Perhaps a little more seriously, some 13% also presented with iron deficiency anaemia (IDA). This compared with 15% and 6% of the control group respectively. The 'but...' in the title of this post reflects the fact that saying a quarter of children with autism might have ID sounds dramatic but perhaps not so dramatic when it compares with that 15% of controls; hence the lack of significant difference between the groups. Having said that, it is worthwhile noting that controls in this study were not necessarily children and young adults just plucked at random: "For the control group, 100 children (an equal number with patients), who referred to the department [child and adolescent psychiatry department] for counseling about child development, school adjustment and performance, teenage problems, family and friend relations, were recruited."

Then: "Hemoglobin, hematocrit, iron, and MCV (p < 0.05) levels were found to be lower in children with ASD."

Finally, taking into account age (comparing those with autism under 6 years (n=46) with those over 6 years (n=54)) and the presence of learning (intellectual) disability (n=58) vs. those with none (n=42) and autism severity (mild-moderate ASD (n=50) vs. severe ASD (n=50)), some other interesting trends were observed. "Hemoglobin, hematocrit, and MCV (p < 0.05) levels were found to be significantly lower in preschool ASD patients" and "Hemoglobin and hematocrit (p < 0.05) levels were significantly lower in ASD patients with intellectual disability."

What can we conclude from the Gunes paper? Well, I don't want to belittle the various issues with iron detected in either group included for study. If ID or more seriously IDA is detected, remedial measures need to be adopted to correct such issues irrespective of a diagnosis of autism or anything else. Insofar as the relationship(s) between iron parameters and autism, the Gunes papers reiterates that this is likely to be complex and not necessarily just exclusive to autism. Perhaps the most accurate thing I can say is that yet again, a diagnosis of autism or ASD is seemingly protective against nothing when it comes to comorbidity and [preferential] screening is once again implied. Oh, and when it comes to trying to predict those people on the autism spectrum who might be at greatest risk of iron deficiency et al, the findings published by Sidrak and colleagues [2] offer some possible variables: "problems sucking, swallowing or chewing...; poor eating behaviour...; and inadequate amounts of meat, chicken, eggs or fish."


[1] Gunes S. et al. Iron deficiency parameters in autism spectrum disorder: clinical correlates and associated factors. Italian Journal of Pediatrics. 2017; 43: 86.

[2] Sidrak S. et al. Iron deficiency in children with global developmental delay and autism spectrum disorder. J Paediatr Child Health. 2014 May;50(5):356-61.


Thursday, 12 October 2017

Severe mental illness translates into "more sedentary behavior and significantly less physical activity"

The title of this post reflects the findings reported by Davy Vancampfort and colleagues [1] (open-access) who concluded that various diagnoses - "schizophrenia, bipolar disorder or major depressive disorder" - under the label of severe mental illness were associated with decreased physical activity and increased sedentary behaviour(s).

Under the auspice of a "global systematic review and meta-analysis", authors settled on some 70-odd studies that met their search criteria comprising over 35,000 people diagnosed with one of the conditions described and nearly 3000 asymptomatic (asymptomatic for severe mental illness) controls. Vancampfort et al describe assessing for "co-primary outcomes" that "were the mean time (min) per day that people with severe mental illness and healthy controls (in case-control studies) engaged in physical activity, or were sedentary." They found "23 study estimates of physical activity were based on objective measures, three utilized objective and subjective measures and 57 were based on self-report questionnaires"; something important in the context of the technology available to measure activity these days.

Results: Those diagnosed with a severe mental illness (SMI) were "more sedentary than age- and gender-matched controls from the general population, spending a mean of 476 min per day (or almost 8 hours) during waking hours in sedentary behavior." Further: "people with severe mental illness are significantly less physically active and spend only an average of 38.4 min per day in moderate or vigorous physical activity." When tweeting about this article, one of the authors - Brendon Stubbs - also linked to another important paper [2] published on the same day as their own, observing that: "Increasing physical activity is a simple, widely applicable, low cost global strategy that could reduce deaths and CVD [cardiovascular diseasein middle age." It's not difficult to see the connection(s) between the two findings.

"Our data documented that higher body mass index, lower cardiorespiratory fitness, and antidepressant or antipsychotic prescription might constitute barriers for engaging in physical activity." One of the value-added bits to the Vancampfort data were the discussions on some of the barriers to engaging in physical activity in those with SMI. Combined with observations such as: "Those who are single or unemployed, those with a low educational level and men are less physically active" it's not too difficult to see what areas might need to be 'tackled' if physical activity levels are to be improved. Indeed, other data (see here) has even talked about what types of exercise might be best suited to what labels (minus any sweeping generalisations).

And since I've mentioned the topic of depression in this post, I might also draw your attention to another paper recently published by Joseph Firth and colleagues [3] - one of the authors on the Vancampfort paper - talking about how technology might provide a useful backdrop to intervention for depressive symptoms. Specifically how the delivery of smartphone apps might be something useful to consider in the context of depression. Indeed, if one assumes that physical activity levels might also be lower in relation to something like depression, one could forsee a time when one or more smartphone apps might either prompt the need for more physical activity or even potentially offer a tailor-made physical activity schedule complementary to other intervention options...

Music to close and Sammy singing Mr Bojangles...


[1] Vancampfort D. et al. Sedentary behavior and physical activity levels in people with schizophrenia, bipolar disorder and major depressive disorder: a global systematic review and meta-analysis. World Psychiatry. 2017. Sept 21.

[2] Lear SA. et al. The effect of physical activity on mortality and cardiovascular disease in 130 000 people from 17 high-income, middle-income, and low-income countries: the PURE study. Lancet. 2017. Sept 21.

[3] Firth J. et al. The efficacy of smartphone-based mental health interventions for depressive symptoms: a meta-analysis of randomized controlled trials. World Psychiatry. 2017 Oct;16(3):287-298.


Wednesday, 11 October 2017

On the "co-occurrence of autism and delinquency": no association for the majority

"The extant research shows that for most people with ASD [autism spectrum disorder] there is no association between ASD and delinquent behavior."

That was one of the primary conclusions reached in the literature review published by Alexa Rutten and colleagues [1] (open-access) looking at the collected peer-reviewed science from 1990 to 2015 on this topic. Boiling down the literature to 12 papers "five of which report the prevalence of delinquency in patients with ASD and seven the prevalence of ASD in a forensic population", authors reported on quite a lot of variability when it came to delinquency and offending behaviours but overall, offending behaviour was "lower in people with ASD than in the general population."

This is welcomed research. It reiterates what many people have already known/suspected, in that the label 'autism' for many is not typically associated with intentional delinquency or offending behaviour. As Rutten et al note: "many people with ASD have an overactive sense of right and wrong and are usually conscientious and unwilling to break the law." I should also point out that a diagnosis of autism is not however necessarily some kind of 'shield' when it comes to offending behaviour (see here and see here for a more recent example) or indeed, potential 'vulnerability' to becoming involved in specific offences (see here). But serious 'intentional' delinquency is not the norm; even that is, in the context of something like greater likelihood of contact with law enforcement agencies (see here).

There are still lessons to learn in this area of research and practice. Certain 'over-represented' comorbidity appearing alongside autism is still something to potentially consider [2] as per other findings (see here and see here). I say that without 'trying to pass the [diagnostic] buck'. Bearing in mind also how wide the autism spectrum is, specific diagnoses on the spectrum might also require further study as per the authors comments: "The prevalence of ASD diagnoses, particularly Asperger’s syndrome, in forensic settings is remarkable because it is much higher than the prevalence of ASD diagnoses in the general population." At this point I'll also refer you once again to the comprehensive review paper by Tom Berney [3] that mentions some of the potential how-and-whys of offending in the specific context of Asperger syndrome, again minus any sweeping generalisations. Recent media attention on previously undiagnosed Asperger syndrome in a prison context also makes for important and relevant reading too (see here) particularly where substance abuse is prominently mentioned (see here).

I would however question one rather sweeping statement made by Rutten and colleagues: "It is important to diagnose ASD carefully and to differentiate autism symptoms such as a lack of empathy from psychopathic traits". Lack of empathy and autism? Hmm, sounds a bit old hat to me...

I will again close with the point made that for the majority of people on the autism spectrum, the label is much more likely to be associated with law abiding rather than law breaking.


[1] Rutten AX. et al. Autism in adult and juvenile delinquents: a literature review. Child and Adolescent Psychiatry and Mental Health. 2017; 11: 45.

[2] Newman SS. & Ghaziuddin M. Violent crime in Asperger syndrome: the role of psychiatric comorbidity. J Autism Dev Disord. 2008 Nov;38(10):1848-52.

[3] Berney T. Asperger syndrome from childhood into adulthood. Advances in Psychiatric Treatment. 2004. 10; 341-351.


Tuesday, 10 October 2017

Psychiatric disorders accompanying "immune-mediated inflammatory disease"

I wasn't actually that surprised at the results published by Ruth Ann Marrie and colleagues [1] (open-access available here) observing that: "Individuals with IMID [immune-mediated inflammatory diseases], including IBD [inflammatory bowel disease], MS [multiple sclerosis] and RA [rheumatoid arthritis] are at increased risk of psychiatric comorbidity."

On more than one occasion on this blog I've talked about how the psychiatric and the somatic are seemingly intertwined (see here and see here for examples) for whatever reason(s). The current results from Marrie et al however add further weight to calls to study "a common underlying biology that may be best elucidated by studying different psychiatric disorders and different IMID together."

So, based on the use of "population-based administrative (health) data" based in a region of Canada, authors identified nearly 20,000 participant records of people diagnosed with IMID. They compared this IMID group with almost 100,000 not-IMID "age-, sex- and geographically-matched controls" with regards to "the incidence of depression, anxiety disorder, bipolar disorder and schizophrenia in each of the study cohorts." The authors noted that: "To estimate incidence of psychiatric disorders after the diagnosis of the IMID of interest, the first claim for the psychiatric disorder had to occur after the index date for the IMID, and be preceded by a five-year period with no claims for that psychiatric disorder."

Results: The incidence of CMD (comorbid mental disorder) was increased in the IMID group compared with the non-IMID control group. This observation survived adjustment for other potential variables of interest such as region of residence and socioeconomic status (although authors did note that: "Female sex, urban residence, and lower SES were associated with increased incidence of psychiatric disorders.") Looking at the individual IMID, authors reported that: "Depression and anxiety affected the MS population more often than the IBD and RA populations."

What's more to say? Well, aside from more research being required to look at the connection(s) between immune function and psychiatric presentations there is an argument for enhanced screening for psychopathology as and when IMID are diagnosed. Perhaps intriguingly, there is also the idea that where the two systems coincide, new intervention and treatment regimes *might* show some promise as the per the idea for example, that some kinds of depression might be sensitive to certain anti-inflammatory compounds (see here).

To close, what else but more insight into the potential Last Jedi?


[1] Marrie RA. et al. Increased incidence of psychiatric disorders in immune-mediated inflammatory disease. J Psychosom Res. 2017 Aug 1;101:17-23.


Monday, 9 October 2017

Extended release melatonin for sleep issues in autism

"PedPRM was efficacious and safe for treatment of insomnia in children with ASD [autism spectrum disorder] with/without ADHD [attention-deficit hyperactivity disorder] and NGD [neurogenetic disorders]."

So said the results published by Paul Gringras and colleagues [1] (open-access) covering a topic that is bound to create some excitement/interest given that the diagnosis of autism is no stranger to the issue of sleep problems (see here). Indeed, some have talked about sleep issues/problems in the context of autism as being an important influencing variable on parental well-being too [2].

From a starting population of over 250 children diagnosed with an ASD who were reported to have sleeping issues "(minimum 3 months of impaired sleep defined as ≤6 hours of continuous sleep and/or ≥0.5-hour SL from lights-off on 3 of 5 nights based on parent reports and patient medical history)" but not necessarily a sleep disorder, some 95 children / young adults completed the randomized, double-blind, placebo-controlled element of the trial. PedPRM - Paediatric Prolonged-Release Melatonin - was the active treatment option, compared against a placebo given over 13 weeks. "The a priori primary endpoint was SND [Sleep and Nap Diary]-reported total sleep time (TST) after 13 weeks of treatment." Melatonin, by the way, is one of the treatment options of choice when it comes to sleeping issues across various different clinical scenarios.

"The study met the primary endpoint demonstrating statistically significant effects of PedPRM vs. placebo on change from baseline in mean SND-assessed TST after 13 weeks of double-blind treatment." In other words, it worked. Indeed, when researchers set a standard of 45 minutes or more extra total sleep time as an indication of clinical response to PedPRM, almost 40% of their cohort taking the drug fitted that category compared with only 16% of those taking the placebo. "The 21.5% difference in percentage between groups equals NNT [number needed to treat]=4.7 for any additional responder above placebo."

When first looking at the study design presented by Gringras et al I was about to comment on a potential weakness based on the [subjective] use of caregiver report when it came to total sleep time. I'm not saying that this may not have provided a good rough-and-ready measure of TST but rather that it cannot provide actual physiological data on something like sleep duration and 'intensity' for example. As it happens however: "Actigraphy monitors (Actiwatch) were included in the study as a secondary objective measurement tool for the primary (TST) and first secondary (SL) sleep parameters." They weren't used throughout the whole study duration and were subject to some consumer resistance - "Despite major efforts to ensure adherence, actigraphy monitoring was challenging in this population, and a majority of participants (75% in the PedPRM and 77% in the placebo group) refused to wear the device during one or both periods and/or took it off some time during the night" - but did appear to show some effect in favour of PedPRM on TST and sleep latency (the time taken to fall asleep) for those who wore them during the study period. I guess the challenge for future studies is to make research actigraphy more 'autism-friendly'...

On the important issue of side-effects, the authors also report some observations. Treatment-emergent adverse events (TEAEs) were reported in not-insignificant numbers in both active (PedPRM) and placebo groups: "TEAEs judged by the clinician as treatment-related occurred in 12 (20.0%) participants in the PedPRM and 11 (16.9%) in the placebo group (28 and 20 events respectively)." Somnolence defined as sleepiness and drowsiness was one of them(?) but on the whole, the cost-benefit balance of the intervention seemed to favour use over non-use of PedPRM. There are a few other details included in the Gringras findings but I'm satisfied that the trial showed quite a good profile for the preparation in terms of efficacy and safety. Given also that melatonin is one of the more widely used medicines when it comes to autism, such results are perhaps not unexpected.

I do think more needs to be done in this area, not least on the hows-and-whys of melatonin working on sleep and other physiological functions. Yes, I know the whole biological pathway of melatonin (I've blogged about it before) but like many other medicines, melatonin has other many effects too, not least potentially affecting something else potentially important to some autism - intestinal barrier integrity a.k.a the leaky gut (see here). I wonder therefore if, when it comes to looking at potential responders and non-responders to such melatonin use, researchers might consider measuring gut permeability and perhaps other related compounds (see here) as part of their clinical research scheduling?

And whilst talking about sleep issues in the context of autism, I'll be coming to the findings reported by Len McCue and colleagues [3] on gut and sleep issues potentially intersecting in autism quite soon...


[1] Gringras P. et al. Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children With Autism Spectrum Disorder. Journal of the American Academy of Child & Adolescent Psychiatry. 2017. Sept 19.

[2] Bourke-Taylor H. et al. Relationships between sleep disruptions, health and care responsibilities among mothers of school-aged children with disabilities. J Paediatr Child Health. 2013 Sep;49(9):775-82.

[3] McCue LM. et al. Gastrointestinal dysfunctions as a risk factor for sleep disorders in children with idiopathic autism spectrum disorder: A retrospective cohort study. Autism. 2017 Nov;21(8):1010-1020.


Saturday, 7 October 2017

"mitochondrial dysfunction is involved in the pathobiology of GWI [Gulf War Illness]"

Among the various research distractions that I take on this blog away from the core material of autism science, one condition/diagnosis/state continues to particularly intrigue me: Gulf war syndrome or Gulf war illness (GWI).

I've covered this topic a few times on this blog (see here and see here and see here for examples); specifically how the hostile environment of the Persian Gulf during the 1990-1991 Gulf War perhaps aligns with this conflict being labelled as 'one of the most toxic wars in human history' (see here). If you think I'm overplaying that last sentence have a look at what was housed at one facility in Iraq under Saddam Hussain and then understand the nature of some of the compounds to which combatants were potentially exposed to.

The [small scale] findings reported by Yang Chen and colleagues [1] (open-access) adds to the still-growing research base suggesting that for the 25%+ soldiers who returned from theatre in ill-health, the biological nature of their symptoms is both wide-ranging and complex. The authors concluded that: "veterans with GWI exhibit greater mtDNA [mitochondrial DNAdamage which is consistent with mitochondrial dysfunction."

Looking at "21 cases of GWI (CDC and Kansas criteria) and 7 controls" (I told you it was 'small scale') researchers looked in blood samples in order to "quantify mitochondrial and nuclear DNA lesion frequency and mitochondrial DNA (mtDNA) copy number (mtDNAcn)" as well as to provide some information on "mitochondrial complex I and IV enzyme activities." In effect, covering both genetic and biological presentation in relation to any possible mitochondrial dysfunction (mitochondria being the 'powerhouse' of the cell).

"This study provides the first direct biological evidence of mtDNA damage in the blood of veterans with GWI." I'm always a little cautious when a study claims to provide 'first evidence' of anything but a quick search of PubMed seems to confirm that mitochondrial DNA (mtDNA) has not been discussed in the research literature before. Although not an expert on mtDNA or anything, the details being discussed by Chen et al point to an excess of mitochondrial and nuclear DNA damage in the GWI group compared with the small control group. This is however, not the first time that mitochondrial dysfunction has been discussed in the context of the GWI as per other peer-reviewed research outings [2].

"Mitochondrial dysfunction among veterans with GWI may help explain, in part, the persistence of this illness for over 25 years." This is an important observation made by the authors. Drawing on data from another area of [overlapping] research - chronic fatigue syndrome (CFS) - it's worthwhile noting that some fatigue-related conditions do have a mitochondrial element to them (see here) even if not universally linked to mtDNA (see here). The fact that this group with GWI did show some evidence of mtDNA damage begs the questions: how and why?

Minus any sweeping statements or the like, I would draw your attention to one particular 'toxic exposure' seen in the Gulf War - depleted uranium tipped munitions - and some research suggesting that particular radioactive particles emitted from something like depleted uranium might very well be able to impact on mitochondrial DNA [3]. I'm not saying this is 'truth', just a testable hypothesis in the context of GWI.

Of course, further investigations are required in this area, both larger in scale and also carried out by other, independent groups. There is also the possibility that certain mitochondrial and interconnected issues, if detected, could be treatable as per again, what has been talked about in CFS circles (see here). Our troops deserve the most thorough and best care we can possibly provide...


[1] Chen Y. et al. Role of mitochondrial DNA damage and dysfunction in veterans with Gulf War Illness. PLoS ONE. 2017; 12(9): e0184832.

[2] Koslik HJ. et al. Mitochondrial dysfunction in Gulf War illness revealed by 31Phosphorus Magnetic Resonance Spectroscopy: a case-control study. PLoS One. 2014 Mar 27;9(3):e92887.

[3] Zhang S. et al. Mitochondrial alteration in malignantly transformed human small airway epithelial cells induced by a-particles. International Journal of Cancer. 2012; 132: 19-28.


Friday, 6 October 2017

Managing childhood ADHD with exercise: a systematic review

"Physical activity, in particular moderate-to-intense aerobic exercise, is a beneficial and well-tolerated intervention for children and adolescents with ADHD [attention-deficit hyperactivity disorder]."

Another day, another systematic review and with it, another step closer to determining what intervention(s) might be effective in ameliorating (or at least managing) some of the more 'life-changing' aspects to ADHD.

This time around it was the findings reported by Qin Xiang Ng and colleagues [1] whose analyses seemingly support the use of both short-term and long-term exercise regimes when it comes to managing ADHD. I hasten to add, this is not the first time that this topic has been discussed on this blog (see here) and perhaps links into other non-pharmacological interventions being promulgated with ADHD in mind (see here).

Thirty studies were included in their review and various dimensions of ADHD were found to be [mostly] positively affected by the use of exercise regimes.

Another important detail of the Ng review was the observation that: "No adverse effects arising from physical exercise were reported in any of the studies, suggesting that exercise is a well-tolerated intervention." I guess that might depend on the type of exercise undertaken, but given the startling array of exercise options open to all - including those diagnosed with ADHD - I don't doubt that there is something for everyone. Indeed, if one is to extrapolate from other research, there may be no 'non-responders' to this type of intervention [2] and one might even expect there to be other potential positive effects from regular exercising (see here)...

The take-home message: get (and keep) moving whether diagnosed with ADHD or not.


[1] Ng QX. et al. Managing childhood and adolescent attention-deficit/hyperactivity disorder (ADHD) with exercise: A systematic review. Complement Ther Med. 2017 Oct;34:123-128.

[2] de Siqueira Mendes Barbalho M. et al. There are no no-responders to low or high resistance training volumes among older women. Exp Gerontol. 2017 Sep 13. pii: S0531-5565(17)30487-4.


Thursday, 5 October 2017

Obesity and overweight in autism meta-analysed

So: "The meta-analysis showed a significant association between obesity and ASD [autism spectrum disorder]. However, no significant association was identified between overweight and ASD."

Those were the conclusions reached by Zhen Zheng and colleagues [1] (open-access) who surveyed the pertinent peer-reviewed science literature up to November 2016 on the topic of the prevalence of overweight and obesity in relation to the autism spectrum (see here).

Including some 15 studies in their meta-analysis mix "encompassing 49,937,078 participants and 1,045,538 individuals with ASD" authors observed a connection between obesity and autism (a body mass index - BMI - between 30 and 39 for obesity and 40 and over for severely obese) but not being overweight. Among the many analyses undertaken by the authors, we are told that "the sensitivity analysis showed that removing any study did not change the final results, suggesting that our findings were robust."

Zheng et al have covered many bases when it comes to the interpretation of their findings. Feeding and eating issues potentially making "healthy dietary interventions less effective"... check (see here). Physical activity levels and 'sedentary activities'... check (see here). Potential side-effects of medication - antipsychotic medication in particular - check (see here). Also: "some individuals with ASD have been reported to have 16p11.2 or 11p14.1 microdeletions, which encompass genes related to obesity susceptibility." Yup, some genetic conditions that manifest autism also place that person at a greater risk for weight issues, either directly or peripherally.

Minus any sweeping generalisations, there are some obvious implications from such results. Obesity places a person at some heightened risk for various adverse health outcomes and potentially, early mortality outside of other, more socially-defined adversities. Prevention and treatment are key. Yes, facets of autism may make intervention slightly more complicated than perhaps noted in not-autism populations but that does not mean that one should not try to impact on the variables that lead someone down a pathway to obesity. And such intervention should be multi-faceted and perhaps also take into account a role for comorbidity that seemingly follows autism (see here)...

Oh, and probably relevant to today's posting, the scientific support for the old "healthy at every size" notion is dwindling...


[1] Zheng Z. et al. Association among obesity, overweight and autism spectrum disorder: a systematic review and meta-analysis. Sci Rep. 2017 Sep 15;7(1):11697.


Wednesday, 4 October 2017

Can a 'disturbed gut microbiota' explain a cognitive performance dip in those born by C-section?

In answer to the question posed in the title of this post - Can a 'disturbed gut microbiota' explain a cognitive performance dip in those born by C-section? - I have to say that I don't know. I was however, rather intrigued by the findings reported by Cain Polidano and colleagues [1] (open-access) who observed that "cesarean-born children perform significantly below vaginally-born children, by up to a tenth of a standard deviation in national numeracy test scores at age 8–9" when allowing for "a large range of confounders."

Based on data derived from the Longitudinal Study of Australian Children (LSAC), a sort of Aussie equivalent to ALSPAC here in Blighty, researchers set about examining whether the growth in Caesarean sections might have some long-term implications for child cognitive development. The question of whether those trillions of wee beasties (bacteria and the like) that call our gastrointestinal (GI) tract home might be implicated in the cognitive findings stems from previous research talking about how, theoretically, said bacteria might be doing so much more than just helping us to digest our food or producing the odd nutrient here and there (see here for example). This also bearing in mind that those born by C-section have been suggested to show a different gut bacteria profile from those not. I say all that acknowledging that gut bacteria doing this, that and t'other is going through something of a period of reflection at the moment (see here).

It is the size of the Polidano participant sample (N=3,666) and the "internationally recognized and widely-used longitudinal" nature of the LSAC that interested me in these findings. The authors provide quite a bit of detail on how the initiative works and what measures have been put in place to potentially rule out mediating and/or confounding variables. Even missing data has been discussed and accounted for: "non-random attrition does not appear to be seriously biasing our results."

What is unfortunately missing from the Polidano paper is any measure of 'gut bacteria' to substantiate the possibility of a connection between C-section birth, gut bacteria and academic outcome(s). I say this bearing in mind that whilst there is extensive literature talking about *associations* between C-section birth and a variety of cognitive and developmental outcomes, the details are still a little scarce insofar as whether any association is tied to a specific family of bacteria or indeed, something like overall bacterial diversity. One also has to bear in mind that other factors also affect newborn gut bacterial make-up such as breastfeeding and seemingly specific components of breastfeeding [2]. I note that other authors are also not sold on the ideas generated from the Polidano paper (see here) and caution that C-sections are not somehow demonised as a result (not everyone is 'too posh to push').

"While the magnitude of our estimated difference in outcomes is not large, up to a tenth of a standard deviation in national test scores in numeracy, they are large enough to warrant action." The authors note that their observations might not seem to show a particularly large contribution to cognitive development, they are nonetheless still potentially important. Indeed: "A tenth of a standard deviation in national test scores is comparable in size to differences related to gender, class size and teacher quality that are the focus of policy effort." In other words, don't discount this potentially important area of investigation just yet...


[1] Polidano C. et al. The relation between cesarean birth and child cognitive development. Scientific Reports. 2017; 7: 11483.

[2] Toscano M. et al. Impact of delivery mode on the colostrum microbiota composition. BMC Microbiology. 2017; 17: 205.


Tuesday, 3 October 2017

SHANK3 and intestinal barrier function might have implications for some autism...

According to the Spectrum Wiki, SHANK3 - SH3 and multiple ankyrin repeat domains 3 - is described as "a leading autism candidate gene, with mutations occurring in between 1 and 2 percent of individuals with autism spectrum disorder."

Providing instructions for making the SHANK3 protein, alterations to the structure or function of the SHANK3 gene can have some quite far-reaching consequences, notably including disrupting communication between neurons in the brain.

A recent paper published by Shu-Chen Wei and colleagues [1] provides some further discussion on how issues with SHANK3 may very well extend beyond just 'brain function' and indeed, may overlap with reports of an over-representation of bowel disease in the context of autism (see here). In effect, a *possible* genetic association between autism and inflammatory bowel disease. Possibly...

Wei et al initially relied on a mouse model of SHANK3 disruption, something that has also reached autism research [2]. Said mouse model was artificially exposed to dextran sulfate sodium, a compound that creates experimental colitis mimicking human inflammatory bowel conditions such as ulcerative colitis. Various measures were employed to explore the interaction between colitis in the SHANK3 knockout mice pertinent to the expression of intestinal permeability, hyperpermeability of which is also known as 'leaky gut' in some quarters. Gut permeability issues are 'on the radar' when it comes to at least some autism (see here). Researchers also looked at SHANK3 expression in a cohort of human participants diagnosed with an inflammatory bowel disease called Crohn's disease.

Results: "SHANK3 knockout resulted in a leaky epithelial barrier phenotype, as demonstrated by decreased transepithelial electrical resistance, increased paracellular permeability, and increased Salmonella invasion." Going back to the idea that genetic issues identified as being potentially pertinent to some autism might extend beyond just 'effects on the brain' this is an important finding. Much like in other identified genetic conditions manifesting autism or autistic traits, the indications are that intestinal issues might be part and parcel of some autism where SHANK3 issues have been identified (see here and see here for other examples under other genetic conditions).

Further: "Overexpression of SHANK3 enhanced ZO-1 expression, and knockdown of SHANK3 resulted in decreased expression of ZO-1." ZO-1 refers to zonula occludens-1, something called a tight junction protein which serves an important function in intestinal barrier biochemistry. In effect, ZO-1 and other tight junction proteins seal the space - paracellular space - that is part of the intestinal barrier. The implication being that under expression of SHANK3 seems to have a detrimental effect on metabolites involved in intestinal barrier integrity; something also noted when it came to Wei and colleagues looking at "colonic tissue of patients with Crohn's disease" with ZO-1 in mind.

I used the words 'might have implications for some autism' in the title of this post but hasten to add that much more investigation is still required. Yes, SHANK3 seems to have a place in the aetiology and pathology of 'some autism' but further confirmatory research is required. Not least that, as far as I am aware, no-one has actually looked at intestinal barrier function directly in cases of Phelan-McDermid syndrome a primary outcome of SHANK3 genetic issues, despite some chatter about gastrointestinal issues potentially being no stranger to such a diagnosis [3]. I would also like to see a little more done on the measurement of something like zonulin where SHANK3 is mentioned in the context that zonulin seems to have a connection to intestinal barrier integrity. Whether, similar to other preliminary work looking at autism and zonulin (see here), there may be merit in testing when SHANK3 issues are likewise identified.

And while we're on the topic of mouse models and possible connections to autism, it's worth noting the findings reported by Groves and colleagues [4] talking about what vitamin D deficiency might do to certain mouse behaviours in the context that vitamin D has some autism research history too...

Music to close, and not to make light of SHANK3 but it does conjure up the sound of quite a famous song...


[1] Wei SC. et al. SHANK3 Regulates Intestinal Barrier Function Through Modulating ZO-1 Expression Through the PKCε-dependent Pathway. Inflamm Bowel Dis. 2017 Oct;23(10):1730-1740.

[2] Yoo J. et al. Shank mutant mice as an animal model of autism. Philosophical Transactions of the Royal Society B: Biological Sciences. 2014;369(1633):20130143.

[3] Kolevzon A. et al. Phelan-McDermid syndrome: a review of the literature and practice parameters for medical assessment and monitoring. Journal of Neurodevelopmental Disorders. 2014;6(1):39.

[4] Groves NJ. et al. Adult vitamin D deficiency exacerbates impairments caused by social stress in BALB/c and C57BL/6 mice. Psychoneuroendocrinology. 2017 Sep 6;86:53-63.