Monday, 19 November 2018

"Hypovitaminosis D is frequent and associated with depressive symptoms and anxiety disorders in schizophrenia"

The paper published by Guillaume Fond and colleagues [1] concluding that: "Hypovitaminosis D is frequent and associated with depressive symptoms and anxiety disorders in schizophrenia" provides the blogging fodder today. Hypovitaminosis D is just another way of saying vitamin D deficiency (or perhaps insufficiency) and follows a number of previous research findings (see here) concluding that schizophrenia seems to be one of a number of conditions/diagnosis/labels where tested vitamin D levels show sub-optimality.

Fond report results based on their examination of the "national FondaMental Expert Center (FACE-SZ) Cohort", something that has been talked about on this blog before (see here). So: "A comprehensive 2 daylong clinical and neuropsychological battery was administered in 140 SZ subjects included between 2015 and 2017" including vitamin D testing and analyses looking for the signs and symptoms of depression and anxiety.

Results: about one in five of the study participants were in a state of hypovitaminosis D. Looking at the accumulated behavioural data - "Depressive symptoms were assessed by the Positive and Negative Syndrome Scale depressive subscore and current anxiety disorder by the Structured Clinical Interview for Mental Disorders" - I was particularly struck by the *link* between vitamin D deficiency and 'current anxiety disorder' ("aOR = 6.18 [2.15-17.75], p = 0.001"). Further: "Vitamin D supplementation has been administered during the previous 12 months in only 8.5% of the subjects but was associated with lower depressive symptoms... and lower rate of current anxiety disorder... compared to patients with hypovitaminosis D."

These are interesting results. They reiterate that a diagnosis of schizophrenia does not seem to be protective against the development of vitamin D deficiency/insufficiency. They also highlight that schizophrenia perhaps should not be considered as a stand-alone diagnosis; something that is beginning to be realised across various different behavioural labels (see here). The suggestion of an *association* between anxiety and/or depression in the context of vitamin D is also important (perhaps even relevant to other studies that have suggested a direct link between vitamin D and schizophrenia). And then there is the 'already supplemented' finding that seems to fly in the face of quite a lot of other evidence suggesting that correcting vitamin D deficiency in the context of something like depression might not be directly applicable to improvement in depressive symptoms (see here). Research questions remain but the Fond results look interesting...

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[1] Fond G. et al. Hypovitaminosis D is associated with depression and anxiety in schizophrenia: Results from the national FACE-SZ cohort. Psychiatry Res. 2018 Sep 13;270:104-110.

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Saturday, 17 November 2018

"Children are getting weaker, study finds"

The title of this post - "Children are getting weaker, study finds" - comes from one of the media headlines covering the study findings presented by Gavin Sandercock & Daniel Cohen [1]. In their study, the authors detail results derived from the Chelmsford Children's Fitness and Activity Survey, an initiative that has been monitoring the fitness of local children (local to Chelmsford) for about 20 years. Their results for the most recent cohort (2014) compared with previous study cohorts (2008, 1998) make for worrying reading: children are getting weaker alongside "a decrease in self-reported physical activity concurrent with the accelerated declines in fitness from 2008 to 2014."

So: "We measured; height, weight, standing broad-jump, handgrip, sit-ups and bent-arm hang in 10-year-old boys and girls from Chelmsford, England in: 2014 (n = 306), 2008 (n = 304) and 1998 (n = 310)." Researchers also asked about recent physical activity among their cohort using the Physical Activity Questionnaire for Children/Adolescents (PAQ-C), a self-report questionnaire. The collected results were analysed and among other analyses, authors "compared percentage change per year 1998–2008 with 2008–2014" across the variables being studied.

As per the headline, the results were worrying: "Pairwise comparisons showed muscular fitness of both sexes was significantly lower in 2014 than in 1998." They also observed that self-reported physical activity was lower in the later cohort. Obviously, I need to stress that this was self-reported physical activity information, so not exactly objective actigraphic data for example. Out of the several results reported relating to specific aspects of fitness across the cohorts, the issue of handgrip strength stuck out for me in light of some still emerging research suggesting that handgrip strength might have "prognostic value for mortality" according to some studies. Without wishing to make connection when none might exist, I do wonder whether such data might one day eventually tally with some other quite worrying statistics on longevity recently published?

Another detail discussed by Sandercock & Cohen is their finding that "Ten-year-olds in 2014 were taller and heavier than in 2008 and 1998 but there were no differences in BMI [body mass index]." They authors talk about this more in their media interviews: "As today's ten-year-olds are taller and heavier than the children measured six and 16 years ago we expect them to be stronger and more powerful, but this was not the case." Worrying. And it also appears that the declines in strength were increasing more rapidly in the later cohort than compared with the earlier ones, as the authors mention that from 1998 to 2008, strength (group strength) fell by just over half a percent per year, whereas from 2008 to 2014 this decline increased to 1.6% per year.

So what does this all mean for the health and well being of the next generation, and what can be done to reverse such trends? Well, health in childhood is often a good indicator of what health will look like in adulthood. I say this not only from a physiological point of view but also bearing in mind that habits bred in childhood tend to persist into adulthood. Low levels of physical activity probably also follow that pattern.

The possible reasons to account for the cohort disparities? Minus any sweeping generalisations I don't think it would be out of place to mention that things have changed quite a bit when it comes to hobbies and pastimes for at least some parts of the paediatric population. More time spent playing video games or on the Internet have perhaps replaced previous scenarios when kids would meet (in person), play out, run around, climb trees, play football and the like. I don't say that to demonise such digital pastimes (see here) but rather to point out a shifting pattern in activities that also have been noted in other relevant studies [2]. It's perhaps also worthwhile pointing out that opportunities for physical activity have also perhaps changed as a function of the environment we now live in. Why else would schools have had to implement strategies such as the daily mile for example?

Possible solutions? When I first tweeted about the publication of the Sandercock & Cohen article I added in the idea that physical activity specifically along the lines of strength and conditioning could perhaps be added to the learning curriculum. So, alongside maths and English (here in Blighty), there is also a focus on physical education too. Yes, I know physical ed(ucation) is part of the school agenda, but I actually meant something like getting kids into a gym and doing something akin to circuit training at least a few times a week. I know this is ambitious and I know that not every kid is going to be able to do this. But surely in these days of adaption and flexibility in teaching and learning, there are also ways to make such exercise open to all. And you never know, start children young with the mindset that exercise is fun and good for physical (and mental) health, and it might just serve them for a lifetime...

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[1] Sandercock GRH. & Cohen DD. Temporal trends in muscular fitness of English 10-year-olds 1998–2014: An allometric approach. Journal of Science and Medicine in Sport. 2018. Aug 1.

[2] Walsh JJ. et al. Associations between 24 hour movement behaviours and global cognition in US children: a cross-sectional observational study. The Lancet Child & Adolescent Health. 2018. Set 26.

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Friday, 16 November 2018

"Children with DDs [developmental disabilities] had higher chronic school absenteeism"

The findings reported by Lindsey Black & Benjamin Zablotsky [1] were not unexpected. Utilising data derived from the 2014–2016 National Health Interview Survey (NHIS) based in the United States, researchers concluded that: "In this nationally representative sample of children aged 5–17 years, children with ADHD [attention-deficit hyperactivity disorder], autism spectrum disorder, and intellectual disability were more likely to have had chronic school absenteeism compared with children who did not have these conditions even after controlling for demographic and selected physical health conditions." The reason I say that such findings were not unexpected is because such observations add to other independent literature on this topic (see here) suggesting that school isn't always a great environment for children with such diagnoses and attendance figures perhaps reflect that.

This isn't the first time that the NHIS has cropped up on this blog (see here and see here). On those previous occasions, the NHIS has provided important evidence that the rates of various developmental disabilities are continuing to increase (autism, developmental delay) whilst some diagnoses are a little more static (intellectual disability) in line with other data (see here). This time around, researchers looked at what role developmental disabilities (DDs) might play in the finding that "14% of all public school students are chronically absent from school, missing 15 or more days per year" in the United States.

Based on the NHIS methodology that involved sampling households with said households completing "a brief questionnaire to collect selected demographics and broad health measures", researchers first ascertained whether "the parent had ever been told by a doctor or health professional
that the child had attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, intellectual disability, or other developmental delay." They also asked about school absenteeism using the question: "During the past 12 months, about how many days did (sample child) miss school because of illness or injury?" Findings were collated and analysed.

Results: covering nearly 27,000 children, of which about 1 in 10 were diagnosed with ADHD and 2.5% reported to be diagnosed with an autism spectrum disorder (ASD), a few important results emerged. Those diagnosed with an intellectual disability (sometimes called a learning disability here in Blighty) "had the highest prevalence of chronic school absenteeism (14.0%)." Chronic school absenteeism by the way, was defined as 15 or more days missing from school throughout the school year. The percentage rates for school absenteeism for autism, developmental delay and ADHD were 9%, 7.2% and 5.2% respectively. Compared against data from children without any reported developmental disability diagnosis, those with DDs were quite a bit more likely to be chronically missing from school even when adjusted for various other co-occurring physical health conditions such as "asthma, allergies, and headaches" or for other demographic differences ("age, sex, race and ethnicity, poverty status, family structure (categorized as two parent, single parent, or other), and geographical region of residence").

Even taking into account possible research caveats such as the fact that "data are based on a parent or guardian report" the Black/Zablotsky findings represent some important data. 'Every school day counts' is an oft-heard about phrase in educational circles, drawing attention to the idea that not only is educational attendance a legal requirement in many countries, but also that as chronic absenteeism creeps in, so educational chances and opportunities start to slip by and where this can potentially lead (see here). This is bad for the kids, bad for the teachers (who often have to 'go over' missed work) and not particularly great for the rest of the class either.

Bearing in mind all that, the next question should really be 'why?' Why are children with DDs more prone to school absenteeism and what can be done to remedy the situation? Well I don't doubt that it's going to be complicated and so doesn't need any sweeping generalisations from me or anyone else. I'm first drawn to mention that whilst Black & Zablotsky controlled for various physical health conditions that might affect school attendance, they probably did not control for all of them (including bouts of illness due to infections for example) and so one needs to look more closely to see if these exerted any effect on their results (see here for another example). My second preference for further study would be to see whether education is actually meeting the child's individual requirements as another area associated with chronic absenteeism. Y'know, the idea that school can be a source of significant stress and strain for children (see here); even in those educational environments that have a more specialised ethos (see here). Finally, and again minus any sweeping generalisations, more research is needed on family circumstances and child's school absenteeism. I know it's a little uncomfortable to mention but irrespective of a child's diagnostic status or not, some parents are not always 'on message' when it comes to the 'every school day counts' idea. Coupled with a child who might not be particularly interested in school, and well, it's not difficult to see how this could play out with regards to the onset and perpetuation of chronic absenteeism. I would add that this is not a universal 'blame the parents' observation.

There are no easy fixes to this issue. But identifying potentially vulnerable groups, asking appropriate questions and providing targeted support, would seem to me to be a step in the right direction.

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[1] Black LI. &  Zablotsky B. Chronic School Absenteeism Among Children With Selected Developmental Disabilities: National Health Interview Survey, 2014–2016. National Health Statistics Reports. 2018; 118.

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Thursday, 15 November 2018

Big data does... the extreme male brain theory of autism and the Empathizing–Systemizing theory

"Two long-standing psychological theories – the empathising-systemising theory of sex differences and the extreme male brain theory of autism – have been confirmed by our new study, the largest of its kind to date."

That was the opening sentence to a write-up (see here) of a recent research paper published by David Greenberg and colleagues [1] which sought to "test 10 predictions from the Empathizing–Systemizing (E-S) theory of sex differences and the Extreme Male Brain (EMB) theory of autism." The 'big data' words included in the title of this post refer to the collection of data from hundreds of thousands of people as part of a TV documentary that aired here in Blighty called 'Are you autistic?' whose data were included for study. This follows a similar format from some of the co-authors on the Greenberg paper on previous research occasions (see here).

Minus any charges of plagiarism, a few descriptors might be useful. First: "The first theory, known as the empathising-systemising theory of typical sex differences, posits that, on average, females will score higher on tests of empathy than males, and that, on average, males will score higher on tests of systemising than females." Second: "The second theory, known as the extreme male brain theory of autism, extends the empathising-systemising theory. It posits that autistic people will, on average, show a shift towards “masculinised” scores on measures of empathy and systemising." Researchers also talked about something called a 'd score': "the difference between each person’s score on the systemising and empathy tests" in their research, alongside mention of the words 'brain type'.

As part of the interactivity of that TV documentary, some 670,000 people "who indicated they were males or females" completed various measures: "the Autism Spectrum Quotient-10 (AQ-10)... the Empathy Quotient (EQ)..., Systemizing Quotient-Revised (SQ-R)..., and the Sensory Perception Quotient (SPQ)" via an on-line questionnaire portal. About 36,000 people who took part "indicated that they had been diagnosed with an “Autism Spectrum Condition”." Data from responses to the questionnaires were crunched pertinent to those 10 predictions from both theories (said predictions concerned sex differences based on responses to the questionnaires, those various 'brain types' and how responses might look with reference to the presentation of autistic traits). For good measure, researchers also describe carrying out an 'independent replication' of their findings on a separate cohort of adults ("14,354 participants (226 autistic individuals, and 14,119 controls)"). Although there were some minor differences from the larger main trial, to all intents and purposes the same procedures were employed "for calculating brain types and performing statistical analysis."

Results: well "all 10 predictions from the E-S and EMB theories" were confirmed. So for example, men taking part in the study "had a shift towards a high d score" suggestive of being more likely to be systemisers than empathisers, whilst "typical females had a shift towards a low d score" (i.e. more likely to empathetic than systemiser). The previous STEM (science, technology, engineering, and mathematics) findings [2] were also supported, in that: "STEM professionals on average scored significantly higher on the AQ" suggesting a link between the choice of STEM career and autistic traits. And for those reporting a diagnosis of autism or autism spectrum disorder (ASD): "autistic people, regardless of their sex, had a shift towards an even higher d score than typical males" (systemisers) but "were not more likely to work in STEM occupations, compared with controls."

There is a lot to take in from the Greenberg research and related commentary. The study has a number of things going for it insofar as the huge participant size and the use of an independent replication set to confirm findings. These factors should not be underestimated. The limitations? Well, self-report is still one of them, and the fact that at least one of the questionnaires used is probably picking up a lot more than just 'autistic traits' (see here). I'm also inclined to point out once again that the *correlation* between autistic traits and STEM career choice did not seemingly extend to those with autism being "more likely to work in STEM occupations, compared with controls." Going back to that 'what is being tested' issue, the AQ for example, might also be picking up something linked to "loneliness, social anxiety, depression, and anxiety" [3] or even something approaching the schizophrenia spectrum (see here) or personality disorder (see here). Indeed, one might have to entertain the idea that the definition 'autistic traits' may not tell the whole story in this study.

I have to admit to being still a little sceptical of big psychological theories such as the EMB or the E-S theory of sex differences. The reason? Whilst attractive in their compartmentalising nature, real life is often far from being so clear-cut and linear. The fact also that an important part of the evidence behind such theories remains a little 'fluffy' (see here for example) cannot be readily brushed under the scientific carpet. As for the use of the term 'brain types', well, I can see what the authors were getting at, but I'm not convinced such terminology is particularly useful. 'Brain types' kinda sits in the same category as 'neurotypical' (see here). I was also drawn to the fact that the authors have to explicitly say that their results don't mean that "autistic people lack empathy" and that "autistic people are not hyper-male in general." It kinda tells you how some of the history behind these theories shows that they have not exactly been received with open arms by many.

But even with all that, the Greenberg results cannot be just discounted, and more research on this topic is indicated.

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[1] Greenberg DM. et al. Testing the Empathizing-Systemizing theory of sex differences and the Extreme Male Brain theory of autism in half a million people. Proc Natl Acad Sci U S A. 2018 Nov 12. pii: 201811032.

[2] Ruzich E. et al. Sex and STEM Occupation Predict Autism-Spectrum Quotient (AQ) Scores in Half a Million People. PLoS One. 2015 Oct 21;10(10):e0141229.

[3] Reed P. et al. Loneliness and Social Anxiety Mediate the Relationship between Autism Quotient and Quality of Life in University Students. Journal of Developmental and Physical Disabilities. 2016; 28: 723-733.

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Wednesday, 14 November 2018

Vitamin D supplementation and autism: more work needed on the biochemistry of vitamin D metabolism

The findings reported by Conor Kerley and colleagues [1] provide the brief blogging fodder today. Researchers, who are no stranger to the research area that is vitamin D and autism (see here), decided to conduct a 'post-hoc analysis' of data from two controlled trials where vitamin D supplementation was experimentally tested for children with autism and children with asthma. They were specifically looking at the "serum response to vitamin D supplementation" rather that the amount of vitamin D supplemented as potentially being important to the clinical results obtained. They concluded that "children with ASD [autism spectrum disorder] had a lower increase in 25(OH)D levels with supplementation." Further: "Potential mechanisms include altered absorption/metabolism as well as well genetic factors."

Bearing in mind the relatively small participant group numbers used and comparisons between kids with autism and kids with asthma without any other 'asymptomatic' group involvement, I was really rather interested in the Kerley findings. This was a research group who previously concluded that vitamin D supplementation did little for their cohort of autistic children under experimental conditions [2]. Now they're perhaps suggesting that there may have been valid biological reasons behind such results with respect to the biochemistry/metabolism behind vitamin D with such issues potentially affecting how much vitamin D supplementation is required to suitably raise vitamin D levels.

Of course this is not necessarily a new finding. Science has already started to look at the genetics/biology of vitamin D metabolism in relation to autism (see here and see here) and continues to do so [3]. It also converges with the idea that a deficiency/insufficiency of vitamin D is an important clinical finding but does not necessarily mean that a universal dose of vitamin D supplementation will 'fix anything' (see here for another example in another label).

"Clinical and research work relating to vitamin D is ASD should measure 25(OHO)D response to supplementation to assess therapeutic doses." I can't argue with such sentiments on the basis of the results observed. Working back from sayings such as 'the dose makes the poison', it appears that for some on the autism spectrum, that dose may not be the same as everyone else...

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[1] Kerley CP. et al. Blunted serum 25(OH)D response to vitamin D3 supplementation in children with autism. Nutr Neurosci. 2018 Oct 10:1-6.

[2] Kerley CP. et al. Lack of effect of vitamin D3 supplementation in autism: a 20-week, placebo-controlled RCT. Arch Dis Child. 2017 Nov;102(11):1030-1036.

[3] Biswas S. et al. Fok-I, Bsm-I, and Taq-I Variants of Vitamin D Receptor Polymorphism in the Development of Autism Spectrum Disorder: A Literature Review. Cureus. 2018 Aug 29;10(8):e3228.

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Tuesday, 13 November 2018

SEED says... risk of overweight/obesity in autism is heightened

SEED - The Study to Explore Early Development - provides yet more discussion fodder today as I bring the findings reported by Susan Levy and colleagues [1] to the blogging table. This time around the focus was on the risk of being overweight and/or obese in relation to a diagnosis of autism and the conclusion that: "Prevention of excess weight gain in children with ASD [autism spectrum disorder], especially those with severe symptoms, and in children with developmental delays/disorders represents an important target for intervention" on the basis of results observed.

It's not exactly a new thing to observe that those diagnosed with autism are perhaps at a greater risk of being overweight and/or obese (see here). There are a multitude of possible reasons behind such statistics covering everything from research showing those on the autism spectrum to typically be more sedentary than peers (see here) (bearing in mind the idea that 'you can't outrun a bad diet'), to a heightened risk of receiving medicines that list weight issues as a side-effect (see here) to a possible role for over-represented comorbidity (see here) with regard to weight issues. The net results however is the same: being diagnosed with an autism spectrum disorder places someone at a heightened risk of being overweight or obese.

Levy et al compared three groups of young children - "2-5 years of age" - classified by a diagnosis of autism spectrum disorder (ASD) or developmental delay/disorder or classed as a general population controls (i.e. asymptomatic). Importantly they describe how height and weight were "measured during a clinical visit" thus removing the reliance on 'at home' or routine records measurements [2] and the risk of bias that they can sometimes bring. Researchers also gathered background information on various co-occurring conditions/diagnoses.

Results: "The odds of overweight/obesity were 1.57 times... higher in children with ASD than general population controls and 1.38 times... higher in children with developmental delays/disorders than general population controls." One needs to be bear in mind the quite young age of participants when putting that last sentence into some context. Also: "Among children with ASD, those with severe ASD symptoms were 1.7 times... more likely to be classified as overweight/obese compared with children with mild ASD symptoms."

There's little more to say about such findings other than autism or autistic traits, yet again, seems to place someone as a quite significant disadvantage when it comes to their physical health and wellbeing. Now, the important question: what can be done about it?

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[1] Levy SE. et al. Relationship of Weight Outcomes, Co-Occurring Conditions, and Severity of Autism Spectrum Disorder in the Study to Explore Early Development. The Journal of Pediatrics. 2018. 9 Oct.

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Monday, 12 November 2018

Quality of life and autism continued

"In this study it was found that psychiatric comorbidity, sleeping difficulty, intellectual disability, maladaptive behavior, adaptive functioning, autism symptomatology, main daytime activity and residence were associated with QoL [quality of life], independent of respondent type."

So concluded the findings reported by Ane Knüppel and colleagues [1] continuing an important research theme looking at quality of life with autism in mind (see here and see here and see here). There's nothing specifically novel about the factors reported on as affecting quality of life (QoL) where a diagnosis of autism is mentioned (mental health issues, autism severity, comorbidity, activities, social inclusion) but the fact that authors drew on data from both self-reports and proxy-reports is important and perhaps provides an important dual perspective. Indeed as the authors noted: "Proxy-reported QoL is different from self-reported QoL and should be considered as an alternative source of information." Similar sentiments have been expressed recently (see here).

Having previously talked [2] about the properties of the specific instrument used to gauge QoL with autism in mind, the authors relied on responses on the INICO-FEAPS scale in their investigation. More than 1700 participants with autism completed the scale where: "For 165 individuals with ASD [autism spectrum disorder], self-reports only were available, and for 863 individuals with ASD, only parental proxy-reports were available." The scale itself is pretty comprehensive, consisting of "72 items divided into the following eight subdomains: self-determination, rights, emotional wellbeing, social inclusion, personal development, interpersonal relationships, material wellbeing, and physical wellbeing." A higher score on the INICO-FEAPS scale denotes a higher QoL 'level'. Various other measures were also included for study; some of them based on the setting of the study in Denmark and the fact that Scandinavian countries are particularly 'geared up' for collecting all-manner of details on the basis of various national registries held on the population.

Alongside the results suggesting that various factors seemed to be important to QoL, there were some details to consider. So: "Across all respondent groups, the lowest rated QoL domains were emotional wellbeing (range of means = 71.10–74.05) and interpersonal relationships (range of means = 65.07–71.88), and the highest rated QoL domains were rights (range of means = 83.79–86.21) and material wellbeing." Further, researchers also observed that being employed or in education also correlated with a higher QoL score "compared to individuals without any regular daytime activity" and "significant associations were found for all respondent groups, with lower levels of QoL among individuals living with their parents... and among individuals with ASD living outside the family home with support... compared to individuals living independently without support."

I was also interested in the idea discussed by the authors that: "treating psychiatric comorbidity, reducing maladaptive behavior, raising the level of independence, and offering individuals with ASD an opportunity to be involved in any job-related occupation or to receive education may raise the level of QoL." 'Treating psychiatric comorbidity' is already a research and clinical priority when it comes to autism (see here and see here). Yes, science needs to do a lot better in terms of establishing the 'hows-and-whys' of such comorbidity being over-represented alongside autism but there are some important themes starting to emerge (see here) including that looking at core autism symptoms as being potential risk factors for the appearance of such issues. And once again we can look to an important group of people for further clues as to how such psychiatric issues are indeed perhaps more 'core' than comorbidity (see here).

Although 'reducing maladaptive behaviour' potentially covers a lot of 'challenging' ground - "Behavior classified as self-destructive, breaking belongings, defiant, disruptive, hurtful to others and/or socially offensive" - I don't think anyone would seriously argue against the idea that such behaviours are neither good for the individual nor good for those around them. I'm minded to suggest that the reason(s) for such behaviour are likely to be complex (see here and see here), but one thing that could be useful would be to look at some of the research on particular 'profiles' being present and connected to autism and beyond (see here) as a starting point.

And then there is also the suggestion of a possible effect for society more generally, as in ensuring that education and employment opportunities are available to all and making 'an inclusive society' a priority...

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[1] Knüppel A. et al. Quality of life in adolescents and adults with autism spectrum disorder: Results from a nationwide Danish survey using self-reports and parental proxy-reports. Research in Developmental Disabilities. 2018; 83: 247-259.

[2] Knüppel A. et al. Psychometric properties of the INICO-FEAPS scale in a Danish sample with autism spectrum disorders. Research in Developmental Disabilities. 2018; 75: 11-21.

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Saturday, 10 November 2018

"an association between maternal experience of childhood abuse and risk for ADHD in offspring"

As per the title of this post - "an association between maternal experience of childhood abuse and risk for ADHD [attention-deficit hyperactivity disorder] in offspring" - this is another entry about some uncomfortable but potentially important research [1]. Indeed, the findings reported by Andrea Roberts and colleagues continue a theme from this research group (see here and see here) on how maternal exposure to various forms of abuse both in childhood and adulthood *might* have some important repercussions for offspring psychological and developmental health and well being.

The authors begin with the premise that: "Children whose mothers experienced childhood abuse are more likely to suffer various neurodevelopmental deficits" based on quite a lot of their own previous findings [2]. Such abuse - which comes in many different forms - is, they observe, likely to impact various psychological and biological functions; some of those functions *could* also have an inter-generational effect.

So: "We examined the association of maternal experience of childhood abuse with ADHD in offspring, assessed by maternal report of diagnosis and validated with the ADHD Rating Scale-IV in a subsample, in the Nurses' Health Study II (n = 49,497 mothers, N offspring cases = 7,607, N offspring controls = 102,151)." The Nurses' Health Study II seems to be a favourite resource for these researchers, and continues to contribute to many areas of health science and research (see here). Alongside looking at maternal experience of abuse and ADHD diagnosis in offspring, researchers also looked for the presence of various other 'adverse circumstances' that might be important to any enhanced risk of offspring ADHD being diagnosed. This included exposure to tobacco smoking (see here) which has some pretty strong 'observational' evidence on a possible effect.

Results: "Exposure to abuse was associated with greater prevalence of ADHD in offspring." Although important, the nature of the relationship between abuse exposure and offspring ADHD was not exclusive, i.e. ADHD was present in both offspring of mums exposed to abuse and those not exposed to abuse. The percentage difference between abuse exposure vs. no exposure was statistically significant however, and importantly, remained significant even after adjustment for those other adverse circumstances mentioned previously. Ergo, maternal exposure to childhood abuse *might* have an important impact on offspring enhanced risk of a diagnosis of ADHD.

Although requiring further study, these are important findings. A case is made for further inspection of how such a relationship comes about covering important areas such as the effects of childhood abuse on maternal state and behaviour(s) [3] and indeed, whether adverse pregnancy factors such as tobacco smoking may also actually be related to such previous experiences of abuse [4]. I daresay that things are going to be complicated and not straight-forward when it comes to any relationship(s) and so no sweeping generalisations are required from me or anyone else.

The possibility of an 'inter-generational' aspect to the experience of childhood abuse and subsequent offspring ADHD risk is important. It provides evidence that the expression of some childhood developmental disorders may not necessarily be 'hard-wired' in a genetic sense (assuming that is, that exposure to childhood abuse is not able to 'modify' the structure/functioning of the genome [5] for example). It provides evidence for the idea that adverse life experiences may be able to manifest as physical issues (being careful how I use the term 'biopsychosocial' for example). It also might suggest that alongside the continuously important stress on preventing any form of childhood abuse, there may interventions that could eventually be put in place to 'undo' any biological effects that it causes to offspring... Eventually.

I do want to end by reiterating that whilst the experience of childhood abuse may be *associated* with a heightened risk of offspring ADHD, such a relationship does need to be treated with some caution. I'm particularly keen to 'nip in the bud' any idea that every diagnosis of ADHD is somehow an intergenerational product of abuse: it's not.

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[1] Roberts AL. et al. Association of Maternal Exposure to Childhood Abuse With Elevated Risk for Attention Deficit Hyperactivity Disorder in Offspring. Am J Epidemiol. 2018 May 14.

[2] Roberts AL. et al. Maternal exposure to intimate partner abuse before birth is associated with autism spectrum disorder in offspring. Autism. 2016 Jan;20(1):26-36.

[3] Chronis AM. et al. Maternal depression and early positive parenting predict future conduct problems in young children with attention-deficit/hyperactivity disorder. Dev Psychol. 2007 Jan;43(1):70-82.

[4] Pear VA. et al. The Role of Maternal Adverse Childhood Experiences and Race in Intergenerational High-Risk Smoking Behaviors. Nicotine Tob Res. 2017 May 1;19(5):623-630.

[5] Cecil CA. et al. Epigenetic signatures of childhood abuse and neglect: Implications for psychiatric vulnerability. J Psychiatr Res. 2016 Dec;83:184-194.

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Friday, 9 November 2018

Relative age and ADHD: more data and a meta-analysis

So, relative age and ADHD. The observation that in amongst the various pathways that might lead someone to a diagnosis of attention-deficit hyperactivity disorder (ADHD), "the youngest children within a school class are at a disadvantage in many aspects compared with their older classmates" including increasing "the probability of having ADHD-related symptoms... or other psychopathology..., of receiving a diagnosis of ADHD... or being treated with stimulant medications."

I've talked about this issue a few times on this blog (see here and see here) and am blogging today about a couple of other studies that add to the literature in this area. The first investigation was undertaken by Janine Wendt and colleagues [1] and concluded that: "Using a prospective study design and comprehensive adjustment for confounding and baseline symptoms, we confirmed prior evidence of the association between young ASE [age at school entry] and teacher-reported ADHD symptoms in primary school." The second study was published by Josephine Holland & Kapil Sayal [2] who, following a systematic review of the peer-reviewed science literature on this topic, concluded that "the majority of studies show evidence of a relative age effect influencing both the diagnosis of and receipt of medication for ADHD."

Both studies are open-access so really don't require too much explanation from me. The Wendt study relied on data collected from over 120 "Rudolf Steiner Schools (Waldorf Schools) located within Germany" (Waldorf schools are based on the philosophy of producing "free, morally responsible, and integrated individuals equipped with a high degree of social competence") covering over 3000 children. We are told that this prospective study gathered data via parent- and teacher- reports: "ADHD-related symptoms were assessed at school entry and second and fourth grades by parent-reported and teacher-reported versions of the Strengths and Difficulties Questionnaire (Hyperactivity-Inattention Subscale)." Their results found a possible *association* between age and school entry (ASE) and teacher-reported ADHD symptoms using the SDQ: "ASE was negatively associated with ADHD-related symptoms in the second grade... and fourth grade. Associations remained after adjusting for potential confounders and pre-existing symptoms at baseline." Those 'potential confounders' included "gender, time of observation and source of information." I'm also inclined to point out that the prevalence of possible ADHD overall in the Wendt study was pretty high in some scenarios: "The frequency of ADHD indications ranged from 3.7% (girls, second grade, parent reports) to 25.0% (boys, second grade, teacher reports)."

Then to the Holland-Sayal study. This was a systematic review of the existing research literature pertinent to the questions: "Is there an association between younger relative age, defined as being in the second half of the academic year, and: (1) the presence of high levels of ADHD symptoms, (2) receiving a clinical diagnosis of ADHD and (3) receiving medication for ADHD?" Based on an examination of the literature "published from the 1st of January 2000 to the search date of the 7th September 2017" and including 20 papers for review, the answer: yes, generally-speaking, there is more evidence for a relative age effect in relation to ADHD symptoms, diagnosis or receipt of medication for ADHD than against it.

Holland & Sayal do caution that their findings were not totally unambiguous. They discuss how differences across the various studies included for analysis might be important to the final outcome determined. So: "studies differed by sample size, years studied, ages studied and methods of reporting and recording ADHD diagnosis and medication." They also noted that: "The culture of diagnostic practice within a country’s health system may have an influence on the relative age effects found" implying that the willingness to diagnose ADHD in a particular country or region could very well have had an effect on the main findings.

Overall however, these studies add to the existing research-based message observing that age and maturation may be important 'influencers' of reported ADHD symptoms, diagnosis and/or receipt of ADHD medicines.

The big question now is 'what is science and clinical practice going to do about it? bearing in mind that there may be 'redshirting' models to follow [3]...

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[1] Wendt J. et al. Young age at school entry and attention-deficit hyperactivity disorder-related symptoms during primary school: results of a prospective cohort study conducted at German Rudolf Steiner Schools. BMJ Open. 2018;8:e020820.

[2] Holland J. & Sayal K. Relative age and ADHD symptoms, diagnosis and medication: a systematic review. European Child & Adolescent Psychiatry. 2018. Oct 6.

[3] Whitely M. et al. Attention deficit hyperactivity disorder late birthdate effect common in both high and low prescribing international jurisdictions: systematic review. J Child Psychol Psychiatry. 2018 Oct 14.

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Thursday, 8 November 2018

"a 256-peptide immunosignature with the ability to separate ME/CFS cases from controls"

The findings reported by Oliver Günther and colleagues [1] (open-access available here) really interested me. They interested me because they talked about the "hit and run" hypothesis being pertinent to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), where "a pathogen or other immunological insult experienced by a subject may be gone, but leaves behind physiological disequilibrium." They interested me because researchers turned to "an immunosignature assay (ISA) that employs a microarray of thousands of random-sequence peptides to interrogate antibodies in a broad and unbiased fashion" to try and pick out the biological effects of the 'hit and run' hypothesis in relation to ME/CFS. And they interested me because researchers reported that they were able to identify "a 256-peptide signature that separates ME/CFS samples from healthy controls, suggesting that the hit-and-run hypothesis of immune dysfunction merits further investigation." Lots of interesting things (honest!).

The Günther paper is open-access so doesn't really need too grand an explanation from me. The long-and-short of it was that following the adoption of a discovery and validation methodology (an increasingly favoured option in ME/CFS research circles), authors came up with a sort of 'biological fingerprint' "optimally separating ME/CFS cases and controls" based on the examination of serum samples. They also noted that in amongst their 256-peptide signature, one particular peptide - "LRVVWLSGVASG" - was also mentioned in another independent study with similar aims [2] perhaps therefore requiring further research focus. For those who might not be totally au fait with peptide designation, that string of letters is not meant to be pronounced, but rather each letter corresponds to an amino acid making up that particular peptide.

Whilst this is great work and indeed, represents some really quite detailed analysis, the authors caution that the science is not quite there yet when it comes to a 'biological test' for ME/CFS. So: "the heterogenous nature of ME/CFS clinical presentation and the variance natural present amongst control samples means that group labels in the Discovery and Validation Sets are not based on any gold standard." Diagnosis of ME/CFS still remains a point of real contention in various circles (see here) given the variety of diagnostic criteria available. Indeed, some commentators have suggested that the combination of 'ME/CFS' as a unified diagnostic label simply cannot ever exist (see here). The authors further note that: "Even the best research case definitions are often subjective and—in the absence of clear biomarkers—any group of ME/CFS cases likely comprise a heterogeneous set of pathologies."

I'm also minded to suggest that as per the lessons being learned in connection to autism biomarker research for example (see here), one needs to perhaps think about getting different research groups together who are looking at ME/CFS from different angles (see here). Y'know, sort of combining various different biomarker studies looking at various different biological 'angles' and sorta meta-analysing all the collected data to see if a larger, grander, range of variables might provide a more accurate biomarker picture of the condition(s)...

Still, the Günther study represents some good science and good value-for-research-money. It stresses how, by utilising the pretty sophisticated analytical equipment available these days, one can start creeping ever closer to some of the possible biochemistry that underpins ME/CFS (or at least some ME/CFS) and perhaps then also start some conversations centred on what can be done to alleviate symptoms and cure such a devastating illness.

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[1] Günther OP. et al. Immunosignature Analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Mol Neurobiol. 2018 Oct 8.

[2] Singh S. et al. Humoral Immunity Profiling of Subjects with Myalgic Encephalomyelitis Using a Random Peptide Microarray Differentiates Cases from Controls with High Specificity and Sensitivity. Mol Neurobiol. 2018 Jan;55(1):633-641.

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Wednesday, 7 November 2018

"Has Daniel always been autistic?"

"Has Daniel always been autistic?"

That was the question that led to Twitter uproar and newspaper headlines calling a TV presenter an 'idiot' and "embarrassing" and "ignorant" these past few days. Some have even called for veteran daytime TV presenter Richard Madeley to be sacked, as one of the premier national autism charities here in Blighty authoritatively announced "autism is a lifelong condition, people are born autistic, it’s not something a child grows out of" following the reporting of an interview between Madeley and Daniel Wakeford, one of the stars of the not particularly well titled TV series called The Undateables. Personally, I would have liked to have seen said charity comment on how the term 'undateable' really shouldn't be used in this day and age with any diagnosis/label in mind...

Emotions ran high following the interview, as many parents of children with autism and autistic people voiced their opinions about their own personal experiences of autism. These are all valid opinions. The problem however, is that within the wide - very wide - heterogeneity that is autism, some of the peer-reviewed science on the topic of autism actually supports the line of questioning from Madeley. Some of the peer-reviewed science highlights the sweeping error in saying that autism is (a) lifelong for everyone and (b) that everyone, past, present and future is 'born autistic'.

OK, first things first, autism is a label ripe for sweeping generalisations. We've seen it numerous times as psychological theories for example, have swept through proclaiming that everyone with autism is lacking a theory of mind or empathy or some other related construct. Likewise, I've seen people quite vehemently opine that autism is the product of this or that 'environmental factor' insinuating that simple changes to drink, food or medicines use for example, will 'stop autism'. The reality however is that autism is a label used to describe vast heterogeneity. It's also a label that says nothing about how a person came to be autistic and nothing about the prognosis of their presentation or their life in general.

So what is the cold, objective peer-reviewed scientific evidence to say that autism is not present from birth for everyone? Well, it's multi-fold. It comes from a number of studies that have followed children from early infancy into later childhood to see whether autism *always* manifest from the very earliest days. Take the recent findings from Sally Ozonoff and colleagues [1] (see here for my take) that concluded among late diagnosed children in their cohort: "Seven showed very little evidence of ASD [autism spectrum disorder] in preschool, whereas 7 demonstrated subtle, subthreshold symptomatology." Add it to other independent data [2] that "validate parents' reports that ASD may appear after a period of nonautistic development" (also that "such reports should not be attributed to recall bias") and then throw in the idea that 'regression', as in a regression of previously acquired skills, is perhaps no stranger to many instances of autism (see here). Then to top it all add in other data highlighting specific cases of 'acquired autism' following exposure to particular post-natal infections for example (see here), and the old 'autistic from birth' mantra does not universally hold for everyone diagnosed as being on the autism spectrum. The evidence against the sweeping 'autism is a lifelong condition' statement made following the interview? I'll direct you to some of the numerous occasions that I've talked about such an idea on this blog (see here and see here and see here) based again on the available peer-reviewed science. Cold. Objective. Science.

Minus making any sweeping generalisations of my own, there is scientific evidence out there that 'born autistic' is not something that can be universally applied to everyone on the autism spectrum no matter how many people would like it to be so. In that respect, the question from Richard Madeley was not ignorant nor disrespectful but rather quite sensible and easily discernible from the available science. The fact also that Daniel's mother Carol talked about a 'loss of his language abilities' in her reply to the question (something I'm sure must have been mentioned before the interview took place and was aired) kinda adds to the sound reasoning for Madeley to ask. It also implies that science should keep studying such an important phenomenon.

It seems that when Carol Wakeford responded with the words 'yes, well there's controversy about that' as the first part of her answer to Madeley's question about Daniel, she certainly wasn't wrong...

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[1] Ozonoff S. et al. Diagnosis of Autism Spectrum Disorder After Age 5 in Children Evaluated Longitudinally Since Infancy. J Am Acad Child Adolesc Psychiatry. 2018 Nov;57(11):849-857.e2.

[2] Landa RJ. et al. Social and communication development in toddlers with early and later diagnosis of autism spectrum disorders. Arch Gen Psychiatry. 2007 Jul;64(7):853-64.

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Tuesday, 6 November 2018

Autistic traits assessed between 5 and 8 years old are 'primarily stable'

The findings reported by Hideyuki Haraguchi and colleagues [1] (open-access available here) provide the [brief] blogging fodder today and their conclusion that: "total and two subdomain-related autistic trait scores remained primarily stable in males and females" in the general population. Further that "assessing autistic traits before school entrance may aid in predicting later autistic traits as well as other co-occurring social and emotional problems."

Autistic traits were measured "by a mother-reported quantitative measure, the Social Responsiveness Scale, at age 5 and 8 years." The Social Responsiveness Scale or SRS has some good history with autism in mind both from a research and clinical perspective. In this case the Japanese version of the SRS was used, and data from total scores and "Social Communication and Interaction (SCI)" and "restricted and repetitive behaviors (RRBs)" domains also reported on in approaching 170 "Japanese community-based children."

Results: "We found that although autistic traits assessed by the SRS decreased slightly from age 5 to 8, the extent of this change did not reach statistical significance in this sample, indicating that autistic traits are primarily stable during this transition period at the group level."

This is an important finding. Whilst one has to be careful of any sweeping generalisations that for example, the expression of autistic traits by individual children or smaller subgroups might not be as stable as you think (see here and see here), the results do have implications for various areas. Not least those areas connected to the idea that autistic traits might have some subsequent important 'influence' on later psychopathology (or indeed, a subsequent diagnosis of autism). I say this in several important contexts covering the presence of depression and anxiety (see here) and also in relation to other 'overlapping' spectrums (see here and see here) and what this *could* mean for some potentially life-threatening risks (see here and see here).

The next stage of such research? Look beyond the late childhood years and into adulthood with autistic traits in mind.


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[1] Haraguchi H. et al. Stability of Autistic Traits from 5 to 8 Years of Age Among Children in the General Population. J Autism Dev Disord. 2018 Oct 5.

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Monday, 5 November 2018

"Starting this week, the first blood test for autism will be available to the public"

I have to say that of all the news outlets that I peruse now and again, the resource known as Disability Scoop is typically one of the best. They just always seem to be 'on the ball'. The headline titling this post - "Starting this week, the first blood test for autism will be available to the public" - comes from that resource and well, 'whoa' is a word that springs to mind.

The report details that a company called NeuroPointDX is "launching its NPDX AA test, a blood plasma test that screens for certain metabolic markers that the company has linked to autism spectrum disorder." Said test is based on some peer-reviewed science by Alan Smith [1] which concluded that the: "Identification and utilization of metabotypes of ASD [autism spectrum disorder] can lead to actionable metabolic tests that support early diagnosis and stratification for targeted therapeutic interventions." And before you ask, yes, I have covered the Smith paper before on this blog (see here).

Specific details of what is included in the NPDX AA test are, at the time of writing, not seemingly readily available. The 'AA' mention in the test name implies amino acids are going to be central to the analysis. Indeed, the Smith paper [1] talked about a few specific amino acids as potentially being important: "The combination of glutamine, glycine, and ornithine AADMs [Amino Acid Dysregulation Metabotypes] identified a dysregulation in AA/BCAA [branch chain amino acids] metabolism that is present in 16.7% of the CAMP [Children’s Autism Metabolome Project] ASD subjects and is detectable with a specificity of 96.3% and a PPV [positive predictive value] of 93.5%." What this translates into is that for at least one part of the very heterogeneous autism spectrum (maybe one or more of the autisms?), this test might be able to identify some metabolic issues that could be considered both diagnostic (for that particular 'type of autism') and also therapeutic, insofar as specific interventions aimed at specific amino acid 'issues' when identified (see here for one possible example).

Of course we've kinda been here before with the talk about a biological test for autism (see here for example) and history teaches us to be quite cautious when it comes to such discussions. We'll just have to see how well the NPDX AA test does 'in the field' before any further claims are made and even bigger 'shifts' in our knowledge of autism reported and accepted. But hey, at least give it a chance...

To close, your customary 'chat' from V to remember the date today...

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[1] Smith AM. et al. Amino acid dysregulation metabotypes: potential biomarkers for diagnosis and individualized treatment for subtypes of autism spectrum disorder. Biological Psychiatry. 2018. Sept 6

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Saturday, 3 November 2018

Colliding spectrums again: autism and schizophrenia meta-analysed (again)

"The systematic review and meta-analysis showed a significant association between schizophrenia and ASD [autism spectrum disorder]."

That was the conclusion made by Zhen Zheng and colleagues [1] following their trawl through the peer-reviewed science literature with a view to examining "the association between schizophrenia and ASD."

This is not the first time that Zheng et al have featured in the autism meta-analysis arena (see here and see here and see here) so one could perhaps see them as seasoned professionals when it comes to this type of science. It's also not the first time that the relationship between autism and schizophrenia has been subjected to such analyses either (see here) continuing quite a long relationship between the labels and/or spectrums [2] (see here also).

So: "The meta-analysis of the prevalence of schizophrenia in individuals with ASD encompassed 1,950,113 participants and 14,945 individuals with ASD." From such numbers/data, authors were quite confidently able to determine that schizophrenia was more frequent in cases of autism than in control participants. Indeed, this was described as a 'robust' finding and the magnitude of the risk was not to be sniffed at: "odds ratio = 3.55, 95% confidence interval: 2.08-6.05, P < .001."

In relation to the "prevalence of ASD in individuals with schizophrenia", the authors relied on a smaller number of participants but concluded that: "The prevalence of ASD in individuals with schizophrenia ranged from 3.4 to 52%." Ergo, schizophrenia occurring alongside autism and autism occurring alongside schizophrenia both show over-representation.

As I mentioned on a previous blogging occasion when these labels were discussed in an overlapping sense, there are many implications from such findings. There are implications related to the preferential screening for schizophrenia and/or autism (also including other related issues too) when one or other label is diagnosed and for timely and appropriate intervention for such issues when detected (see here). There are implications for the idea that, biologically-speaking, there may be some shared mechanisms at work covering both (heterogeneous) labels (see here and see here for examples). There are also implications in relation to the social impact of such an association; bearing in mind the often very negative image portrayed of schizophrenia in certain quarters of the media and the rise and rise of 'autistic identity' in other circles. There is lots to think about.

And finally and quite timely, the paper from Giacomo Deste and colleagues [3] talking about the PANSS Autism Severity Score (PAUSS) as a "simple, fast and reliable tool for the identification of autistic features in adult patients with schizophrenia" looks rather interesting...

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[1] Zheng Z. et al. Association Between Schizophrenia and Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. Autism Res. 2018 Oct 3.

[2] Evans B. How autism became autism: The radical transformation of a central concept of child development in Britain. History of the human sciences. 2013;26(3):3-31.

[3] Deste G. et al. Looking through autistic features in schizophrenia using the PANSS autism severity score (PAUSS). Psychiatry Research. 2018. Oct 29.

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Friday, 2 November 2018

"no evidence of any beneficial effect of monthly vitamin D3 supplementation on mood-related outcomes"

The quote titling this post - "no evidence of any beneficial effect of monthly vitamin D3 supplementation on mood-related outcomes" - comes from the paper published by Maria Choukri and colleagues [1] (open-access available here). Their study represents an important continuation of research looking at whether supplementing with vitamin D (the sunshine vitamin/hormone) may affect depression or depressive symptoms (see here). The authors in this case observed that their study "did not provide evidence for the benefit of single monthly dose of vitamin D3 supplementation over autumn and winter on depression and other mood outcomes in healthy pre-menopausal women."

Just before heading further into the Choukri findings, it's worthwhile mentioning some of the history in this area. So, vitamin D is an essential part of maintaining good bone integrity as per the connection between deficiency of the stuff and conditions like rickets (see here). More recently, scientific and clinical eyes have turned to other possible roles for vitamin D in light, for example, of 'deficiency' connections to various developmental and/or behaviourally-defined labels such as autism, schizophrenia and depression (see here and see here and see here respectively). When deficiency (or insufficiency) is detected, people supplement with vitamin D to correct the deficiency, following Government guidance (see here). Speculation then turned to whether supplementation might also 'impact' on the presentation of some of those developmental/clinical labels as well as just correcting any biological deficiency. The results have tended to be mixed so far (see here and see here) with some important biological caveats (see here)...

"This study was a double-blind, placebo-controlled, randomised clinical trial conducted from February 2013 to October 2013 in Dunedin, New Zealand (45° 52′0 S, similar to the latitude of Montreal, Canada; or Lyon, France in the northern hemisphere)." The latitude information is important to various studies mentioning vitamin D because geography influences sun exposure which then influences vitamin D production (see here). Importantly too, the Choukri study was focused on 'healthy' women who were not currently diagnosed with a variety of exclusionary conditions/labels. "A total of 152 healthy women (18–40 years) in Dunedin, New Zealand were randomly assigned to receive 50 000 IU [international units] (1·25 mg) of oral vitamin D3 or placebo once per month for 6 months" we are told, and measures covering anxiety, depression, 'flourishing' and positive and negative mood were utilised before and after.

Results: first and foremost measured vitamin D levels did what they were expected to do as a function of vitamin D or placebo receipt. There was for example, no significant baseline difference in vitamin D levels between the groups (vitamin D vs placebo). At the end of the study, those in the placebo group showed "the expected seasonal pattern in terms of a decline in absolute level and change over the seasonal periods" in vitamin D levels, whilst the supplemented group did not.

But alongside... "There were no statistically significant differences between the vitamin D and placebo groups in any of the outcome measures – depression, anxiety, flourishing, or positive and negative mood, controlling for the baseline measures and the covariates." Indeed, across the various measures, there wasn't even anything close to a statistically significant difference reported between the groups. Ergo, in healthy women "over the winter period", vitamin D supplementation did not seemingly impact on mood-related outcomes despite altering biological vitamin D levels.

I could mention about some possible caveats attached to this study such as the fact that this was a study carried out on an already healthy population "with no vitamin D deficiency or high depressive symptoms." But this is not the first time that vitamin supplementation has 'failed' to show a demonstrable connection to improving mood and probably won't be the last either...

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[1] Choukri MA. et al. Effect of vitamin D supplementation on depressive symptoms and psychological wellbeing in healthy adult women: a double-blind randomised controlled clinical trial. J Nutr Sci. 2018 Aug 23;7:e23.

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Thursday, 1 November 2018

"abnormally high extra-axial cerebrospinal fluid (CSF) volume" and autism

"Increased extra-axial CSF [cerebrospinal fluidvolume is a reliable brain anomaly that has now been found in three independent cohorts, comprising both high-risk and normal-risk children with autism spectrum disorder."

So concluded the findings reported by Mark Shen and colleagues [1] following their study results - "case-control MRI study" results - enquiring whether "increased extra-axial CSF volume is found in a large, independent sample of children diagnosed with autism spectrum disorder, whether extra-axial CSF remains abnormally increased beyond infancy, and whether it is present in both normal-risk and high-risk children with autism."

This latest study from Shen et al follows a research theme [2], a quite long running research theme [3] by all accounts, observing that extra-axial CSF volume might be important to at least some autism. Increased extra-axial CSF volume is described as a brain anomaly insofar as representing a larger than expected volume of cerebrospinal fluid 'coating' the brain, or at least filling the extra-axial space sitting on top and around the brain. It's perhaps not surprising that this work has also included the words 'brain enlargement' in discussions given the physical effect that such increased volume might have.

This latest chapter in the extra-axial CSF volume research comes from a familiar research initiative - the UC Davis MIND Institute Autism Phenome Project - "a longitudinal analysis of children diagnosed with autism spectrum disorder and age-matched typically developing children." The Autism Phenome Project (APP) has already been discussed a few times on this blog for various research reasons (see here and see here). The APP also has something of an interest in brain enlargement appearing alongside regression too (see here). This time around "159 children with autism spectrum disorder (132 male, 27 female) and 77 with typical development (49 male, 28 female) underwent MRI scans." Researchers were looking at extra-axial CSF volume as well as things like brain volume and head circumference. Alongside, various other behavioural measures and questionnaires on things like sleep were included.

"The autism spectrum disorder group had an average of 15·1% more extra-axial CSF than controls after accounting for differences in brain volume, weight, age, and sex." Further: "Both extra-axial CSF volume... and brain volume... uniquely contributed to enlarged head circumference in the autism spectrum disorder group." Authors also reported that: "Increased extra-axial CSF volume was associated with greater sleep disturbances... and lower non-verbal ability."

As per the opening quote to this post, this is not the first time that some of those findings have been reported in the science arena and I very much doubt that it will be the last time either. The authors also talk about such MRI findings in light of "normal risk (ie, from simplex families) or high risk (ie, from multiplex families)" for autism and applying "a previously validated machine learning algorithm based on extra-axial CSF volume, brain volume, age, and sex" but I'd like to see a lot more data before venturing further into these aspects. Not least, data covering the question of 'why?'. From the previous studies in this area, some hypotheses have been put forward, for example: "[as] CSF circulates through the developing brain, it removes inflammatory cytokines and proteins secreted by neurons that can otherwise accumulate and have a pathological effect on brain development." Such a hypothesis needs further research but is perhaps complementary to other discussions about 'neuroinflammation' in the context of autism (see here).

We await further investigations.

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[1] Shen MD. et al. Extra-axial cerebrospinal fluid in high-risk and normal-risk children with autism aged 2-4 years: a case-control study. Lancet Psychiatry. 2018 Sep 27. pii: S2215-0366(18)30294-3.

[2] Shen MD. et al. Increased Extra-axial Cerebrospinal Fluid in High-Risk Infants Who Later Develop Autism. Biol Psychiatry. 2017 Aug 1;82(3):186-193.

[3] Shen MD. et al. Early brain enlargement and elevated extra-axial fluid in infants who develop autism spectrum disorder. Brain. 2013;136(9):2825-2835.

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