Neurodiversity 2.0: Judy Singer setting the record straight

I know I've kinda let this blog slip a little in recent months but work is work and blogging is blogging. Anyhow, I'm back with a short post to bring to your attention a rather important 'revision' presented by Judy Singer on her blog titled: NeuroDiversity 2.0 (see here).
I'm not going to rehash everything that Judy talks about in her post because it's all done exceptionally well in her blogpost. Neurodiversity is the term that has kinda turned into a movement (even a political movement) which has found something of a voice particularly on social media. As a critical voice to neurodiversity (see here) I would say that the concept of neurodiversity has been pushed way beyond it's original meaning and intention and well outside the scientific remit of the description (no, no-one is 'neurotypical' or NT). In her blogpost, Judy aims to clarify some important points about her description of neurodiversity and, as with all good ideas, adapts and modifies them as knowledge has increased. 

Some important things are mentioned by Judy which are worthy of note:

• "Neurodiversity is NOT a Psycho-Medical diagnosis for individuals." She goes on to say that "if Worker A has identified themselves with a specific syndrome, e.g. Autism, in which case call them "autistic". But they are no more neurodiverse than anyone else on the planet." In other words, neurodiverse or neurodivergent are not replacements for autism or autism spectrum disorder (ASD) and they don't magically bestow some differing neurological feature(s) or advantage(s). And just before you ask, "undiagnosed neurodiversity issues" (see here) is basically psychobabble BS and a good example of how neurodiversity has gone well beyond it's remit.
• "Neurodiversity is a term that refers to an obvious and indisputable feature of Earth's biosphere." Basically, everyone is neurodiverse. With all the millions of differing biological processes that everyone encounters and undergoes, every second of every day, neurodiversity is the property of populations not individuals.
• "It is not a synonym for "Neurological Disorder"." I might be repeating myself here but whether diagnosed or 'self-diagnosed' (another inherently problematic issue) with anything remotely related to behaviour and/or the brain, identifying as 'neurodiverse' says nothing about a person and their presentation. 
• "Neurodiversity is a positive principle, but it is NOT a moral principle." As the property of a population, neurodiversity says just that: everyone is different, and we should be proud of our individual differences. I know sometimes people don't like to be seen as different (group membership is a powerful thing), but everyone has strengths and everyone has weaknesses at an individual level. Yes, there are things that society can do to ensure that more strengths are seen as strengths, but that's a different topic altogether.

I'm not expecting Judy's revisions to be immediately and universally accepted by everyone. There are some really ingrained views and opinions about neurodiversity out there, and to some degree, people have already adapted the term to fit their experience and/or agenda. I am hopeful however that we can move on from identity politics (of which neurodiversity has certainly been a focal point) and start to move forward on this. Moving forward means reclaiming labels like autism and ADHD and various other labels that have often got missed from the whole neurodiversity thing (e.g. schizophrenia and psychosis) and moving away from the idea that there is something universally and inherently 'different' about the minds of those with such labels. Science has yet to pinpoint anything that universally distinguishes those diagnosed with autism from those not diagnosed with autism outside of the diagnostic features (similar to every other diagnostic label with a behavioural element to it). If and when it does, then we can start talking about possible neurodivergence, but until then it's all hot air and bluster. 

Bravo Judy for the revision and clarification.

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Roger Moore's eyebrows, ADHD and coeliac disease part 2

Consider this post an extension of some previous blogging chatter (see here) about how behaviourally defined diagnostic labels such as attention-deficit hyperactivity disorder (ADHD) seem to rarely exist in some sort of clinical vacuum. Part of that vacuum also potentially encompasses a range of somatic symptoms and/or diagnostic labels.

The findings reported by Vendel Kristensen and colleagues [1] set out to "assess self-reported symptoms of impaired concentration in coeliac disease before and after treatment with gluten-free diet, compared with healthy controls and patient controls." Coeliac (celiac) disease, in case you didn't know, refers to the archetypal 'gluten can affect biology' condition, where a certain genetic predisposition (or two) adds to gluten exposure to start a whole cascade of biological actions that impact on physical health and well being. Alongside things like bowel symptoms, there is an increasing recognition that coeliac disease (CD) also potentially brings with it certain psychological symptoms, particularly when it is not properly treated/managed (see here).

Kristensen et al asked some 30 people - "newly diagnosed coeliac patients" - to complete various questionnaires pertinent to the presentation of ADHD type symptoms, depression and anxiety and gut issues. These were compared with responses from those diagnosed with an inflammatory bowel disease (IBD) and controls (healthcare professionals).

They reported that those diagnosed with CD before implementation of a gluten-free diet had "significantly higher scores than healthy controls" in relation to the presence of self-reported ADHD and depression/anxiety symptoms. Further: "After a gluten-free diet, their scores improved and were not significantly different from healthy controls." That gluten-free diet by the way, was in place for a minimum of 12 months.

One has to be careful not to make too many sweeping generalisations from the Kristensen data. The data do not, for example, mean that all cases of ADHD are somehow the product of undiagnosed coeliac disease. Not even close. What do they do (cautiously) suggest, is that preferential screening for something like coeliac disease *might* be a good idea as and when ADHD is diagnosed or significant ADHD-like symptoms present. Such findings also resonate with the idea that certain dietary interventions to manage *some* ADHD could be a research area to consider (see here) and bring into play an interesting concept: the gut-brain axis.

Oh, and in case you were wondering about the 'Roger Moore's eyebrows' bit, well, he was the best James Bond wasn't he?

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[1] Kristensen VA. et al. Attention deficit and hyperactivity disorder symptoms respond to gluten-free diet in patients with coeliac disease. Scand J Gastroenterol. 2019 May 3:1-6.

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Nighttime body movements and autism

I was rather interested in the findings reported by Nobushige Naito and colleagues [1] talking about how atypical body movements during the night seemed to be more frequently observed in children diagnosed with an autism spectrum disorder (ASD) compared to not-autism controls. Interested because, sleep is a long-running 'issue' in relation to autism (see here) and because, researchers relied on the use of actigraphy in their study: "a movement-based index measured by an accelerometer" rather than just second-hand observational questioning.

So: "Seventeen TD [typically developing] children and 17 children with ASD participated in this study (5 to 8 years old)." Importantly (see here) we are told that: "Considering the frequent co-occurrence of ASD and ADHD [attention-deficit hyperactivity disorder] symptoms, we did not exclude ASD patients with ADHD symptoms." Authors relied on data from a waistband accelerometer worn by participants over at least 3 nights. Using a waistband was seen as preferable to the more typical wristband. Data was collected and analysed. It included something called a movement index (MI): "the ratio of the body movement period in 20 minutes was calculated continuously for 9 hours using the sliding window method."

Results: "a higher rate of body movement 2 to 3 hours after the first onset of body stillness was more prominent in children with ASD than in TD children." Importantly authors also mention how the objective data provided by the waistband accelerometer showed a different "time course of body movements during night in young children with ASD" despite parents/carers reporting no "apparent" problems with sleeping. They also talk some of the differences in body movements seen in those children with ASD potentially *related* to some awake behaviours - "a lower social ability and more frequent maladaptive behaviour."

The Naito results represent a good start at looking at these important behaviours. I'm a little bit hesitant to go all-in with the suggestion from the authors that "atypical nocturnal body movement could be an ASD state and trait marker in young children with ASD" but can see the importance of further investigations in this area.

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[1] Naito N. et al. Atypical body movements during night in young children with autism spectrum disorder: a pilot study. Sci Rep. 2019 May 6;9(1):6999.

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Constipation and autism is not an uncommon combination

For those who know (or think they know) anything about autism, the title of this post - "Constipation and autism is not an uncommon combination" - is unlikely to be new or novel. Indeed, I've talked again and again and again about how functional gastrointestinal (GI) symptoms are very well over-represented when it comes to a diagnosis of autism (see here for example).

Enter then two further recent articles - one from Bradley Ferguson and colleagues [1] and one from María José Penzol and colleagues [2] - which further add to the evidence base in this area. Both papers are open-access, so please peruse at your leisure. The long-and-short of them can be quickly summarised:

• The Ferguson paper set out to examine the "relationships among GI [gastrointestinal] problems, problem behaviors, and internalizing symptoms in a sample of 340 children and adolescents with ASD [autism spectrum disorder]." Caregivers/parents reported on their child's GI issues. Bottom line: "The majority of the sample experienced constipation (65%)." Various other functional GI issues were also reported.
• The Penzol paper "reviewed the medical records of all patients admitted to the Comprehensive Medical Program for ASD (AMITEA) at Gregorio Marañón University General Hospital from January 2012 to December 2015." They analysed records for nearly 850 patients diagnosed with ASD. Their data were collected and transcribed by physicians including the "presence of fGID [functional gastrointestinal disorders] (gastrointestinal reflux, aerophagia, functional diarrhea, functional constipation, functional abdominal pain, cyclic vomiting)." Bottom line: "At least one fGID was present in 30.5% of patients, constipation being the most prevalent (47.4% of fGID patients)." They also observed that GI issues *seemed* to be related to the presence of intellectual (learning) disability, sleep issues and behavioural problems. These are not novel associations (see here and see here).

Of course there are strengths and weaknesses to those studies. No-one would dispute the fact that these are not perfect data. But, set within the context of a mountain of peer-reviewed science suggesting that something like constipation is over-represented when it comes to a diagnosis of autism, the collected results add a further layer of evidence. They also ask the question 'why', why oh why have we not got a greater handle on how to successfully treat/manage such symptoms?

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[1] Ferguson BJ. et al. The Relationship Among Gastrointestinal Symptoms, Problem Behaviors, and Internalizing Symptoms in Children and Adolescents With Autism Spectrum Disorder. Front Psychiatry. 2019 Apr 9;10:194.

[2] Penzol MJ. et al. Functional Gastrointestinal Disease in Autism Spectrum Disorder: A Retrospective Descriptive Study in a Clinical Sample. Front Psychiatry. 2019 Apr 10;10:179.

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That 'gut bacteria transplant provokes autistic signs in mice' paper is not perfect but...

The paper by Gil Sharon and colleagues [1] has certainly created headlines and discussion in equal measure (see here and see here and see here and see here). Concluding that: "Mice harboring human ASD [autism spectrum disorder], but not TD [typically developing], microbiomes exhibit ASD-like behaviors", the idea of a gut-brain connection in relation to autism (see here) potentially gains some research traction.

The Sharon study involved transplanting gut bacteria - the gut microbiome - from a small number of participants - "from 5 control volunteers and 11 patients diagnosed with autism spectrum disorder" - into mice lacking a microbiome and breeding said mice. They then analysed the behaviour and other biological parameters of those offspring mice according to whether their mother mice had received a transplant from controls or participants with various 'degrees' of autism. They also looked at 'metabolite profiles' based on "analyses of colon contents from oTD [offspring typically developing] and oASD [offspring autism spectrum disorder] mice."

Results: "colonization with ASD microbiota is sufficient to induce hallmark autistic behaviors." By 'hallmark autistic behaviors' researchers observed that said mice showed "increased repetitive behavior, decreased locomotion, and decreased communication... compared to mice colonized with samples from TD controls (oTD), as tested by marble burying (MB), open-field testing (OFT), and ultrasonic vocalization (USV), respectively." Researchers also observed specific differences across the mouse group gut microbiomes, some of which were consistent with that noted in other independent studies.

Also: "Twenty-seven out of 313 detected metabolites were significantly different in the colon contents of oASD mice, compared to oTD mice." They specifically focused in on two metabolites - taurine and 5-aminovaleric acid (5-AV) - both of which were reported in lower levels in the oASD mice, and how these compounds show a *connection* to GABA, a compound potentially important to autism (see here). Further they showed that supplementation of 5-AV and taurine to another strain of mouse that serves as a 'mouse model of autism' (BTBR T+ tf/J (BTBR) mouse model) resulted in "improved repetitive and social behaviors." I should add the word 'mouse' into the sentence "improved repetitive and social behaviors."

Insofar as the limitations of the Sharon studies and paper, various people have been keen to point out that the results should be viewed cautiously and as preliminary. This on the basis of the number of animals included for study, the reliance on mouse models of autism (and the logical fallacies that can sometimes follow) and some of the generalisations made in the study write-up by the authors. I wouldn't disagree with such cautions, bearing in mind that some mouse models of autism - the valproic acid autism mouse model for example - actually seem to be pretty good at mimicking some facets of (induced) autism. I'd also point out that the metabolomics work undertaken by Sharon and colleagues looks to be pretty wide-ranging (GC-MS and NMR are discussed) and findings related to taurine have also been noted in other independent study (see here). I also observed that there was a research tie-up with Arizona State University in the Sharon study, as the name Dae-Wook Kang is mentioned and 'poo transplants for [some] autism' makes yet another appearance (see here and see here).

"While ours is a limited study, with 16 donor samples from a pediatric cohort, the results support a hypothesis that the human gut microbiota contributes to ASD phenotypes." I'd agree that the Sharon results add a further layer to the idea that the new triad - intestinal permeability, mucosal immunology and intestinal microbiota - could be important to at least some autism. The results offer a road map for further investigation in this area and perhaps eventually, yet another avenue for screening and intervention to complement other recent initiatives (see here); all set with the view of the (plural) 'autisms'.

Finally, I note that another study [2] mentioning the words 'mouse' and 'autism' has been published recently. With some media attention mentioning how: "Exercise reversed autistic behaviors in an animal model of the condition" there didn't seem to be the same 'keenness' to point out the flaws of the Andoh study, despite once again a reliance on 'mouse autism' and all which that entails. It makes me wonder whether the focus on the second brain (gut) and autism detailed in the Sharon study might still have the ability to raise hackles in some quarters?

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[1] Sharon G. et al. Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice. Cell. 2019 May 30;177(6):1600-1618.e17.

[2] Andoh M. et al. Exercise Reverses Behavioral and Synaptic Abnormalities after Maternal Inflammation. Cell Reports. 2019; 27: 10. June 4.

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Lactobacillus plantarum PS128 "ameliorated opposition/defiance behaviors" in boys with autism?

There was something potentially rather special about the results published by Yen-Wenn Liu and colleagues [1] suggesting that use of a probiotic - Lactobacillus plantarum PS128 - might, under "randomized, double-blind, placebo-controlled" conditions, have some important effects with some young people diagnosed with an autism spectrum disorder. Special because, if such results are eventually replicated and borne out, some of the more 'disruptive' behaviours that can sometimes be observed alongside a diagnosis of autism - "opposition/defiance behaviors" - might be amenable to quite a simple intervention. That could be important for many, many different reasons.

The basics: PS128 containing "3 × 1010 CFU/capsule of PS128 with microcrystalline cellulose as the carrier" was the compound under investigation, pitted against a placebo that "only contained microcrystalline cellulose." Eighty participants, all boys diagnosed with an autism spectrum disorder (ASD) were recruited for study; 39 were assigned to receive PS128 and 41 receiving the placebo for a period of 4 weeks. Various different schedules and questionnaires were used to measure behaviour at baseline and week 4 between the groups. With a fairly small attrition rate - data for 36 participants in the PS128 and 35 in the placebo group were analysed - the results were pretty interesting.

Results: first and foremost we are told that no adverse events were reported during the study. That's important. Next, for the vast majority of measures used when straight comparing of PS128 and placebo, no significant difference was noted. The authors even mention how a clinician rated scale, the CGI-I, basically said that "both groups were equivalent to "minimally improved""  between baseline and study end. It was only when results were stratified for age that things started to 'happen' as various behaviours around anxiety, rule-breaking, inattention and opposition/defiance showed something like a 'nominal' reduction in the PS128 group compared with placebo, particularly for those aged between 7-12 years. As per the use of the word 'nominal' to denote a small 'change' the results were not spectacular.

Caveats? Well, this was a 4-week study of boys on the autism spectrum. Not a long time in anyone's book but longer than other studies on other interventions that did show a statistically significant effect (see here for example). The Liu study was also a study that exclusively relied on behavioural observation measures, so we can't say anything about how something like PS128 might have impacted on gut bacteria for example. Other, less methodologically sound studies have been more comprehensive (see here).

But there are strengths to the Liu study; strengths around the design and use of a placebo condition. And if there is a chance that something like Lactobacillus plantarum PS128 or other preparations (see here and see here) or related techniques (see here) *might* help improve quality of life for young and old people on the autism spectrum minus any significant side-effects, they should be explored an awful lot more...

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[1] Liu Y-W. et al. Effects of Lactobacillus plantarum PS128 on Children with Autism Spectrum Disorder in Taiwan: A Randomized, Double-Blind, Placebo-Controlled Trial. Nutrients. 2019; 11: 820.

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"support the hypothesis that early life gut microbiota are associated with neurodevelopmental outcomes in childhood"

Question: "Is the gut microbiome in infancy associated with neurodevelopment in children at preschool age?" Answer: "findings appear to support the hypothesis that early life gut microbiota are associated with neurodevelopmental outcomes in childhood."

That was the about the sum of the findings reported by Joanne Sordillo and colleagues [1] and their analyses of "Ages and Stages Questionnaire, third edition (ASQ-3)" data and "microbiome analysis using 16S rRNA gene sequencing" of stool samples from over 300 infants who were taking part in something called the "Vitamin D Antenatal Asthma Reduction Trial (VDAART)."

The Sordillo paper is open-access so doesn't require any rehashing from me. A few details do however stick out. So: "findings suggest that the infant gut microbiome may be associated with subsequent development of communication, personal and social, and fine motor skills in typical developing 3-year-old children and with odds of possible developmental delays." The authors were specifically drawn to "Clostridiales (Lachnospiraceae genera and other, unclassified Clostridiales taxa)" as being important when it came to their stool analyses. Said bacteria seemed to be *associated* with various ASQ-3 data covering "poorer ASQ-3 communication... and personal and social... scores and with increased odds of potential delay for communication... and personal and social skills."

The word 'autism' is also mentioned in the Sordillo paper, alongside the idea that (1) "poor performance of children on the ASQ-3 (particularly on communication skills) at 16 to 30 months of age has been shown to be sensitive (but not specific) for diagnosis of ASDs [autism spectrum disorders]", and (2) "A number of cross-sectional studies comparing the gut microbiome of neurotypical children with that in children with ASDs have reported increased levels of Clostridiales in the gut microbiome of individuals with ASDs, including higher levels of Clostridium,... Clostridium histolyticum,... and Ruminococcus." Indeed, there's also mention of the Luna study [2] covered on this blog previously (see here).

Obviously there are caveats to the Sordillo findings; not least that this all about looking at two variables (ASQ-3 scores and stool bacterial content) and marrying them together at some quite specific time points. I'd for example, be interested to see whether further follow-up studies saw a continuation of the trends described in this paper perhaps covering examination of multiple stool samples taken over different testing occasions. Also going back to the 'autism' suggestion, the authors note that they "did not have data on clinical diagnoses of ASDs for our analysis" so one has to be a little bit careful with any suggestions there too.

Still, such work is important and further contributes to the idea that the brain probably isn't the only place to look when considering things like cognitive and behavioural development (see here). Indeed, as mentioned previously on this blog (see here), a possible role for inflammation 'impairing' social cognitive processes might not be a million miles away from the Sordillo findings on the basis that the new triad - gut bacteria, intestinal permeability, gut immune function - might be really quite important for lots of processes. And then there is another question to consider: if one is able to 'alter' the gut bacterial make-up at an early age, can one potentially affect behavioural and/or developmental outcomes? I say that in the context that something similar has been talked about before (see here).

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[1] Sordillo JE. et al. Association of the Infant Gut Microbiome With Early Childhood Neurodevelopmental Outcomes. JAMA Netw Open. 2019; 2: e190905.

[2] Luna RA. et al. Distinct Microbiome-Neuroimmune Signatures Correlate With Functional Abdominal Pain in Children With Autism Spectrum Disorder. Cellular and Molecular Gastroenterology and Hepatology. 2017; 3: 218-230.

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Saffron for ADHD?

I'm very partial to a bit of 'left field' research on this blog. By 'left field' I mean research that is slightly unusual or atypical. I'd place the study findings by Sara Baziar and colleagues [1] in that 'left field' category because they reported results - randomised double-blind study results - suggesting that: "Short-term therapy with saffron capsule showed the same efficacy compared with methylphenidate" when it came to managing some of the symptoms of attention-deficit hyperactivity disorder (ADHD).

Saffron a.k.a Crocus sativus L is a herb commonly cultivated in places like India and Greece. As with many herbs/spices, cooking represents but one potential use of saffron. It contains a myriad of different chemical compounds, some of which seem to have a variety of potential medicinal uses. Real pharmacognosy in action.

The starting point for the Baziar study was that although methlyphenidate (ritalin) is indicated for treating / managing many cases of ADHD, not everyone is suited to such a medicine or the side-effects that it can sometimes produce. So "alternative medication, like herbal medicine, should be considered." Enter then saffron, and some evidence that it might be a useful herb for various psychiatric complaints [2], to be pitted against methylphenidate in a sort of scientific head-to-head contest with ADHD symptoms in mind.

For 6 weeks, fifty or so children and young adults with "a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of ADHD" were randomly allocated to receive methylphenidate (MPH) "20-30 mg/d (20 mg/d for <30 kg and 30 mg/d for >30 kg)" or saffron capsules "20-30 mg/d saffron capsules depending on weight (20 mg/d for <30 kg and 30 mg/d for >30 kg)." At baseline, 3 weeks and 6 weeks researchers measured ADHD-related symptoms.

The results were unsurprisingly surprising. By that, I mean that there were no statistically significant differences between the two groups, bearing in mind the clinical effectiveness profile that methylphenidate use for ADHD has already established (see here). So: "General linear model repeated measures showed no significant difference between the two groups on Parent and Teacher Rating Scale scores." Importantly too we are told that: "The frequency of adverse effects was similar between saffron and MPH groups."

The Baziar results don't immediately open the floodgates to saffron being used to 'manage ADHD' instead of a clinically-proven molecule like methylphenidate. It doesn't work like that. As far as I can see this seems to be the first time that saffron has been put under the scientific spotlight with ADHD mind (taking into account other 'herbal medicines' have been explored with ADHD in mind). We therefore need more data and some all-important replication. We need more data comparing saffron against methylphenidate and other intervention options for ADHD. And we also need more data on why? Why might saffron be a useful therapeutic option for some ADHD? What are the pertinent biological mechanisms at work?

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[1] Baziar S. et al. Crocus sativus L. Versus Methylphenidate in Treatment of Children with Attention-Deficit/Hyperactivity Disorder: A Randomized, Double-Blind Pilot Study. J Child Adolesc Psychopharmacol. 2019 Feb 11.

[2] Shafiee M. et al. Saffron in the treatment of depression, anxiety and other mental disorders: Current evidence and potential mechanisms of action. J Affect Disord. 2018 Feb;227:330-337.

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A poo(p) transplant for [some] autism? 2 years on with caveats...

The results published by Dae-Wook Kang and colleagues [1] provide some important follow-up work to a study already discussed on this blog (see here) which suggested that: "MTT is safe and well-tolerated in children with ASD ages 7–16 years" and also "led to significant improvements in both GI- and ASD [autism spectrum disorder] -related symptoms" [2]. MTT by the way, refers to Microbiota Transfer Therapy, or in other words a poo(p) transplant. A press release accompanying the recent Kang paper is also available (see here).

The original Kang study included quite a bit more than just a poo(p) transplant as per their use of a 4-stage protocol: "(1) oral vancomycin, (2) MoviPrep, (3) SHGM [Standardized Human Gut Microbiota], and (4) Prilosec" with 18 participants diagnosed with an autism spectrum disorder (ASD). The results on that last occasion were promising insofar as (a) adverse effects being small and fairly limited and (b) some improvements noted in relation to behaviour and gastrointestinal (GI) symptoms. That all being said, one needs to remember that the previous study was an open trial and results were therefore preliminary.

On this latest research occasion, Kang et al followed up their 18 participants "two years after treatment was completed." The follow-up involved "the same GI and behavior tests that we employed previously" which involved the use of various parent- and professional-report questionnaires on behaviour, questionnaire analysis of GI issues and analysis of poo(p) samples: "16 out of 18 original ASD participants provided an additional fecal sample two years after the open-label trial."

Researchers reported that "most improvements in GI symptoms were maintained, and autism-related symptoms improved even more after the end of treatment." They observed something of a possible *relationship* between bowel and behavioural signs and symptoms whereby "GI relief provided by MTT may ameliorate behavioral severity in children with ASD, or vice versa, or that both may be similarly impacted by another factor" which is interesting (see here). They also noted that the bacterial composition of stools analysed at follow-up showed evidence of sustained change "including significant increases in bacterial diversity and relative abundances of Bifidobacteria and Prevotella." In short, things were still looking pretty good after 2 years.

"Despite steady and continuous improvement in behaviors over two years, we must underscore that the original clinical trial and current follow-up study are open-label trials without a control for placebo effect." The authors are frank about the limitations of their studies, and how behavioural and GI symptoms in particular can potentially be influenced by all-manner of different variables. Indeed, they noted that "12 of 18 participants made some changes to their medication, diet, or nutritional supplements" which allied to the waxing and waning of symptoms typically associated with autism (see here), means that one has to be careful about making too many sweeping statements about cause-and-effect.

But in the context that for these 18 participants, a poo(p) transplant was seemingly not associated with too many adverse side-effects and that their behavioural and GI data typically followed a course of improvement, one cannot easily discount the Kang results. The call for further research "with a placebo-control arm" made by the authors should echo throughout the autism research landscape. And with it, further focus on how gut bacterial make-up and the all-important metabolites that specific bacterial species produce seem to be something quite important to at least some autism (see here)...

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[1] Kang D-W. et al. Long-term benefit of Microbiota Transfer Therapy on autism symptoms and gut microbiota. Scientific Reports. 2019; 9: 5821.

[2] Kang D-W. et al. Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome. 2017; 5: 10.

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ADHD and a link with zinc?

"The present results indicated that there were alterations in blood levels of zinc, which was associated with the symptom scores of ADHD [attention-deficit hyperactivity disorder]."

So concluded the paper published by Rongwang Yang and colleagues [1] looking at blood levels of various trace elements including "zinc (Zn), copper (Cu), iron (Fe), magnesium (Mg), and lead (Pb)" in a group of children diagnosed with ADHD compared to a group of non-ADHD controls.

Based on their analysis of blood samples using atomic absorption spectrometry, researchers observed that many of the metals (trace elements) analysed were not greatly different between their groups. Lower levels of zinc however, and "the number out of normal ranges" in relation to zinc were noted. Further: "Zinc levels were negatively correlated with parent-rated scores of inattentive subscale of SNAP-IV (r = − 0.40) as well as with total score of SNAP-IV (r = − 0.24)" where the SNAP-IV refers to the Swanson, Nolan, and Pelham – IV questionnaire, a tool used to screen/assess for possible ADHD.

The Yang results have to be treated with some caution as the old 'correlation is not necessarily the same as causation' rule is observed. It's not beyond the realms of possibility that any suggested *association* between zinc and ADHD is purely epiphenomenal. But...

This is not the first time that zinc and ADHD have been talked about in the same breath (see here). Outside of linking levels of zinc to ADHD - or diagnostic facets of ADHD - one is also presented with other research suggestive that supplementation 'for ADHD' including zinc *might* show some effect (see here). There is the other question of whether zinc alone or in conjunction with other elements and/or biological factors might be important to the presentation of ADHD [2] but this is perhaps another reason why this area is deserving of further investigation. Indeed, further study of the possible processes through which zinc might influence the presentation of ADHD is also required.

And given that ADHD is something not exactly under-represented when it comes to other labels (see here), one has to question what role this fact might play in a more complicated clinical picture with zinc in mind (see here)?

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[1] Yang R. et al. Blood Levels of Trace Elements in Children with Attention-Deficit Hyperactivity Disorder: Results from a Case-Control Study. Biological Trace Element Research. 2019; 187: 376-382.

[2] Villagomez A. & Ramtekkar U. Iron, Magnesium, Vitamin D, and Zinc Deficiencies in Children Presenting with Symptoms of Attention-Deficit/Hyperactivity Disorder. Children (Basel). 2014 Sep 29;1(3):261-79.

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NMDAR encephalitis presenting with "behavioral changes and some autistic features"

Anti N-methyl-D-aspartate (anti-NMDA) receptor encephalitis is yet again (see here) the blogging topic today, as I bring the case report published by Yasmin Khundakji and colleagues [1] to your attention. It's an important case report because, in keeping with the primary focus of this blog, the words 'autistic features' also appear in the Khundakji account. This follows quite a bit of other independent research where autism or autistic features has been mentioned in the context of NMDA receptor encephalitis (see here and see here).

The details? "The patient was a healthy girl" ('was' being the operative word). Some time before she was 2 years of age, she experienced some really quite sudden and stark behavioural changes "manifesting as bouts of irritability, aggression, inconsolable crying, and self-mutilatory behavior (self-biting)." A fever brought about various other somatic symptoms, as eye contact was lost and insomnia set in. "In addition, she developed a progressive regression in gross and fine motor skills and an inability to swallow" with seizures following. Things were getting really serious.

Various tests were carried out which in the most part came up within typical reference ranges (including a "brain MRI"). Someone had their suspicions that NMDA receptor encephalitis *might* fit with the presented profile. Lo and behold, following testing a positive result was received albeit "one month later" (samples had to be sent out of country for analysis). Interventions were put in place ("intravenous immunoglobulin (IVIg) and intravenous methylprednisolone... plasma exchange... rituximab") with some being more successful than others. Of particular note: "A dramatic improvement in her social skills and irritability appeared within hours following plasma exchange." Interesting. Things did eventually improve for the young girl at the centre of the Khundakji paper as we are told that: "Apart from mild speech delay, her neurological exam and developmental milestones are normal."

What lessons can be learned from such case reports? How about starting with the idea that rapid onset childhood regression that includes 'autistic features' should always be investigated as a sign of unmet medical need such as a response to infection (see here)? Perhaps also acknowledge that the presentation of autism or autistic features is not a life-long, immutable, set-in-stone scenario for some people (see here and see here and see here)? And as for the effects of plasmapheresis (plasma exchange) on this particular young child linked to a "dramatic improvement in her social skills and irritability", I'm wondering whether there is a research study or two to be designed and conducted on this topic (with due care)?

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[1] Khundakji Y. et al. Anti-NMDA receptor encephalitis in a toddler: A diagnostic challenge. International Journal of Pediatrics and Adolescent Medicine. 2018; 5: 75-77.

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Carnitine supplementation and autism: "side-effects and behavioral outcomes"

'Favourable outcomes' is a term mentioned in amongst the various findings reported by Robin Goin-Kochel and colleagues [1] following their examination of "dose compliance, attrition, and potential side effects of short-term, high-dose carnitine supplementation" in a small group of boys diagnosed with an autism spectrum disorder (ASD). Understanding that the Goin-Kochel study was primarily directed at looking at safety, on the basis of 'high-dose' carnitine supplementation, it appears that an elevation of plasma carnitine and related metabolites was not the only effect noted in their small cohort (N=10).

Tracking back slightly, carnitine is an important compound. Not quite an amino acid, carnitine plays an important role in energy production; as per use of the word 'mitochondria' and it's transporting duties of long-chain fatty acids to the cell powerhouse for energy conversion. You probably won't be surprised to hear that carnitine has a *connection* to some autism (see here and see here). Indeed, Goin-Kochel et al mention the findings reported by Patrician Celestino-Soper and colleagues [2] and their identification of a genetic issue that impacts on 'carnitine biosynthesis' in some people diagnosed with ASD. At least one of the authors on the Goin-Kochel paper has some pretty important knowledge about that finding of trimethyllysine hydroxylase epsilon (TMLHE) gene issues in the context of autism...

Alongside looking for reports of any side-effects from the use of carnitine - "oral suspension or tablets of levocarnitine in 3 divided doses, starting at 200 mg/kg/day and increasing to 400 mg/kg/day, with a maximum daily dose of 6 g" - various behavioural schedules were included in the study protocol. Some were objective measures of autism symptomatology; others were parent-report measures. The use of the Clinical Global Impression Scale (CGIS) also provided a helpful 'clinicians' overview' of before and after supplementation in this open-trial.

Results: a few side-effects coinciding with carnitine use were reported. These included: "heavy odor (4 parents), diarrhea (4 parents), and sporadic vomiting (1 parent)." Such reported side-effects meant that three children remained at the lower dose of carnitine over the experimental period (8 weeks).

Alongside, a few other 'favourable outcomes' were also reported: "calmer behavior (2 parents), more energy (2 parents), increased prosocial behaviors (4 parents), greater awareness (2 parents), better eye contact (2 parents), and improved language skills (2 parents)." These parental reports were accompanied by some 'changes' noted on the various schedules included in the study protocol, including those CGIS ratings. The authors used the study results produced by Geier and colleagues [3] as their comparator; highlighting how both studies had picked up "improvements in overall ASD symptoms... and some language ratings." Importantly too, Goin-Kochel et al talk about how none of their cohort were rated as "worse at post treatment."

Where next? More research please. Bigger participant numbers, more methodologically sound study designs and perhaps also, investigation of the potential pros-and-cons of carnitine supplementation over a longer period of time. By all means keep an eye on those side-effects and perhaps look to the biochemistry as to why such side-effects might appear; indeed look to the biochemistry for potential best-responders to this type of intervention too ("One child had documented TMLHE deficiency and 3 had low carnitine levels" in the Goin-Kochel cohort). But more study is definitely indicated...

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[1] Goin-Kochel RP. et al. Side Effects and Behavioral Outcomes Following High-Dose Carnitine Supplementation Among Young Males With Autism Spectrum Disorder: A Pilot Study. Global Pediatric Health. 2019; 6: 1-8.

[2] Celestino-Soper PB. et al. A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism. Proc Natl Acad Sci U S A. 2012 May 22;109(21):7974-81.

[3] Geier DA. et al. A prospective double-blind, randomized clinical trial of levocarnitine to treat autism spectrum disorders. Med Sci Monit. 2011 Jun;17(6):PI15-23.

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"two in five young people scoring above thresholds for emotional problems, conduct problems or hyperactivity"

The quote titling this post - "two in five young people scoring above thresholds for emotional problems, conduct problems or hyperactivity" - comes from the eye-opening findings published by Jessica Deighton and colleagues [1] (open-access available here).

It's based on a study of over 28,000 adolescents here in Blighty: "51.2% of whom were in Year 7 (age 11–12) and 48.8% of whom were in Year 9 (age 13–14) in 97 state-maintained secondary schools across six geographical locations in England."

Said young people were given the "child self-report Strengths and Difficulties Questionnaire (SDQ)" to complete, and the received data were analysed alongside other information collected by the authors "from the National Pupil Database: SEN status; FSM eligibility; child in need status (CIN, this is a child who either (a) is unlikely to achieve/maintain a reasonable standard of health and development without local authority provision; (b) is likely to be impaired without local authority provision; or (c) is disabled); and ethnicity (Asian, Black, Chinese, Mixed, White or any other ethnic group)."

In more detail: "18.4% scored above the abnormal threshold for emotional symptoms, 18.5% for conduct problems, 25.3% for inattention/hyperactivity and 7.3% for peer-relationship problems." Going back to the title of this post, researchers mention how "around two in five young people scoring above ‘abnormal’ thresholds for three of the four problem areas measured (emotional problems, conduct problems and hyperactivity)." They also observed that:

• SEN - special educational needs - status played a role in those figures (those with SEN were consistently more likely to provide an above-threshold response to all the areas measured, particularly peer-relationship problems). 
• Entitlement to free school meals (FSM), a potential marker of deprivation, was also associated with an above-threshold response to all areas.
• "Being male significantly increased the odds of scoring above threshold for behavioural problems and inattention/hyperactivity, whereas being female significantly increased the odds of experiencing emotional symptoms."

There are caveats attached to the Deighton findings; not least the sole reliance on "child self-report data from a very brief assessment tool" without any accompanying further analysis on the presence (or not) of diagnosable psychopathology. But, in the context of the large participant number included for study and that most adolescents aren't likely to 'lie' about their positive responses to items such as "I get very angry and often lose my temper" or "I take things that are not mine from home, school or elsewhere" I'd be inclined to view the Deighton findings as a pretty accurate representation of their 'in the thousands' cohort.

So where next? Well, if we're talking about findings observing that "42.5% scored above threshold for any one of the first three problem scales (emotional symptoms, conduct problems or inattention/hyperactivity)" we have to talk about what services are in place (and should be in place) to support this large group. This, on the basis that, such 'problems' can potentially lead to various other 'adverse' outcomes both in later childhood and beyond. And when I talk about 'support', I mean both support and intervention to help those young adults to manage such issues. All of this set in the context of a continually squeezed financial and resource position (at least here in Blighty).

The other question has to be 'why'? Why have so many young people reported as they have? Deighton et al talk about various factors as potentially being important: "the impact of austerity, increasing experience of academic pressures, reduced rates of sleep and increased use of social media", to a large extent talking about the social environment as playing a significant role. I don't doubt that these external factors and other related variables will play a role in how young people are reporting, but I'm not convinced that the social environment is the only important factor to consider. It's not, for example, beyond the realms of possibility that other genetic and non-genetic variables (i.e. in the physical environment) could also play a role; something I say in the context of a 'growth' in the number of children and young adults being diagnosed with all-manner of different behavioural and/or psychiatric labels (see here and see here for examples).

Something important seems to be going on with our young people (see here and see here). We have to assume that such an issue is not going to resolve itself and may even increase in terms of numbers as time goes on. We really need to find out what factors are behind this and start taking action... like now.

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[1] Deighton J. et al. Prevalence of mental health problems in schools: poverty and other risk factors among 28 000 adolescents in England. Br J Psychiatry. 2019 Jan 30:1-3.

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Autism, school exclusion and the criminal justice system: a complicated association

This is a difficult post to write. It's difficult because it covers several topics which are increasingly being *linked* together: autism, the school experience, behavioural problems and aggression, school exclusion and onward 'engaging' with the criminal justice system. Such topics aren't exactly great PR for autism as a diagnosis or label, but do need to be more openly talked about and researched. Useful and productive lives are potentially being wasted (and already vulnerable lives at that).

I was brought to write this post by an opinion piece published in The Conversation titled: "Too many children with autism are let down by schools and end up in prison" [1] by Chrissie Rogers. The author details her research talking to mothers with sons diagnosed with autism or autism spectrum disorder (ASD) who have been and/or are involved with the criminal justice system. Looking at her biography at the University of Bradford, this research looks like its been (partly) published (see here). Having said that, comments left following publication of the Conversation piece, hint that there might be more to come from the author too.

"Mothers in my research talked to me about how their sons were “different”. They were violent to other children and teachers as well as their own families." Reiterating that discussions on this topic don't make for great PR when it comes to autism, such words complement something that has recently been legally enshrined in English law: "aggressive behaviour is not a choice for children with autism." That ruling (see here), based on the case of the unlawful exclusion from school of an autistic boy "after he hit a teaching assistant with a ruler, punched her and pulled her hair" has some potentially far-reaching consequences. It tells us that (a) such behaviour is "akin to a spasmodic reflex" and also that (b) such behaviour should be always be investigated as a 'sign of unmet need'. By saying all that, please don't assume that I condone such behaviour or am trying to pass/move on any blame; I merely suggest that there are often complicated processes behind such actions (see here and see here) which one needs to fully analyse and take into account.

"All the mothers told me they felt something was “not quite right” with their child. And because the support was not forthcoming at school, this negative behaviour escalated and then as these boys got older, they ended up in prison." I think we have to be a little bit careful with some of the things that Rogers discusses here. Yes, it's perfectly sensible to imply that schools 'just excluding pupils' does little to nothing to help efforts to address such 'negative behaviour'; indeed, such actions probably add to a downward spiral, including impacting on the self-esteem of the child concerned. But I'm not altogether convinced that schools that exclude should shoulder such blame alone. Although school exclusion is quite a prominent historical feature of the prison population for example (see here), there are lots of other variables to potentially consider as exerting an important effect on offending behaviour too. And bear also in mind the concept of 'vulnerability' when it comes to autism (see here and see here), and what this can sometimes/often mean in relation to specific types of offending behaviour. What I'm trying to say is that simple correlations or connections are often not entirely correct correlations.

"If more support and intervention in the education system was to occur before the police got involved, then these young people would be less likely to end up incarcerated and at the bottom of a human hierarchy." Again I'm slightly cautious about such sweeping statements being made despite supporting the idea that the educational sector should be the more influential factor over the criminal justice system. 'Support and intervention' is quite a nebulous term and could cover a lot of ground. Although provisions like an EHCP (education, health and care plan) make it (financially) easier for schools and the like to provide additional support, the idea that there is a quantitative correlation between more support and intervention and better outcomes needs to be treated quite cautiously. Indeed, going back to that legal ruling about aggressive behaviour not being a choice for children with autism, the focus really needs to be dual-purpose, examining questions like 'what are the biological and social reason(s) and circumstance(s) for aggression?', and 'what mechanisms can be put in place to minimise such aggressive acts and/or their effects?' I also noted that puberty is mentioned as being part of the behavioural 'mix' in the Rogers article. It strikes me that this is a good place to start when examining the impact that biology in particular can have in relation to the presentation of aggression in the context of autism (see here).

I know lots of people talk about how our one-size-fits-all education system is not necessarily fit for purpose for every child. I wouldn't disagree with such sentiments. Rogers also points out that the drive towards 'inclusive education' whereby education in mainstream schools is becoming the default option for anyone and everyone is also not seemingly serving many children very well. Again, I wouldn't disagree (see here). What I would however say is that focusing in on schools and their actions as 'being the problem' strikes me as being too broad and sweeping a generalisation to make. Indeed it's revealing that Rogers mentions how the mums she interviewed talked about "a lack of support, lack of access to professional help and an overwhelming lack of understanding about their son’s disability, and the impact this had on their lives." Such words speak volumes about how school is but one piece of a larger puzzle that needs a lot more investigation and resources to be directed towards it when it comes to autism, aggression, school exclusion and any subsequent heightened risk of contact with the criminal justice system.

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[1] Rogers C. Too many children with autism are let down by schools and end up in prison. The Conversation. 2019. Jan 24.

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A puppet portrays the character of Laurence, who is described as “autistic, non-verbal and occasionally violent”

The title heading this non-sciencey post - "A puppet portrays the character of Laurence, who is described as “autistic, non-verbal and occasionally violent”" - comes from a news report discussing a play opening soon at a London theatre. The play is called 'All In A Row' and I believe centres on a family struggling to care for their son who is autistic. I believe the play specifically focuses on "the night before social services finally intervenes"...

That news item centres on the use of a puppet to depict Laurence and how writers arrived at such a decision on the reported basis that "We don’t think we could get informed consent from a non-verbal autistic actor aged 11 to play the role." Needless to say that the old tenet about not pleasing all of the people all of the time came into play, as "a backlash online" developed. Despite some initial input from the National Autistic Society (NAS) around "accuracy" and "representation" of autism in the play, they eventually decided that they couldn't support the play "particularly the use of a puppet to depict the autistic character alone."

I was a little surprised by the NAS stance on this. Surprised because when another puppet character came into being depicting autism, the NAS was a little more 'positive' on its introduction. That character was Julia "a little girl who also has autism" who appears on Sesame Street. And at the time of her introduction, the head of the NAS was reported as saying "his organisation hopes it will "inspire" other creators to include characters with autism in their work." Well it might have done, but what's the difference between Laurence and Julia, and why the different response?

I don't have any divine insight as to why the different response, but let's have a look at a few 'possibilities'.

Both puppets appear in productions that also include real-life actors, so this is not about the setting in a character-sense. The look of the puppets? Well, Julia has the typical muppet features: warm skin tone, big eyes, mouth inclined to a smile. A typical 'Anything Muppet'. Laurence is quite a bit different. More human in features, a much less warm skin tone, and eyes that can only be described as piercing. There's quite a physical difference between them. So could this be about that physical difference between the puppets?

Depiction is another factor to potentially consider. Outside of the 'autistic, non-verbal and occasionally violent' description, we are also told that "Laurence likes pizza. Laurence is about to go to school. Laurence thinks it’s okay to wee on mummy’s pillow." Allowing for the age difference in intended audiences between Sesame Street and All In A Row, I think you can see some potential differences between how autism is being depicted by Julia and Laurence. Indeed this perhaps ties into another part of the the NAS response about the use of Laurence: "we could not support the play overall due to its portrayal of autism." The question therefore is whether the depiction of autism including physical violence for example (something that has recently been enshrined in English educational law with autism in mind) is a reason for the 'backlash'? Is this more about PR than anything else?

I think what many people forget (or don't want to remember!) is that autism is a very, very heterogeneous spectrum. It describes so much human experience under one banner. There are no doubt many children who fit the Julia description of autism. Fairly quiet, wouldn't hurt a fly, thriving in some areas yet struggling in others. On the other hand, there are also children who probably better fit the Laurence description of autism: 99% of the time like Julia but also prone to aggressive outbursts (against themselves and also others) and sometimes challenging in their behaviour. The trend to show the world the Julia children over the Laurence children is quite pronounced in some quarter these days. It's also accompanied by online 'abuse' of parents and guardians who dare to show / talk about their 'challenging' children and their reality (see here). Indeed, social media is full of parents showing the good and not-so-good side of their kids, but if your child has autism / is autistic it seems some people think you're not entitled to do the same? Sounds like discrimination to me. Such sentiments have also probably partly contributed to the formation of a society that focuses on "the burgeoning population of children and adults affected by severe forms of autism or related disorders." Even that society attracted criticism (see here) despite, as far as I can see, some noble goals around healthcare and vocational options which may well benefit everyone on the autism spectrum. Like I said "not pleasing all of the people all of the time."

Finally, the word 'dehumanising' is used quite a bit in that news report: "a negative narrative of dehumanising" and "literally dehumanised the identity you sought to represent." My question: does Julia, as a puppet, also dehumanise autism? Because surely if the charge is levied against Laurence as a puppet, then Julia as a puppet also fits the bill too? And if so, perhaps the media need to come up with other ways and means of getting more characters with autism on the screen (see here) to depict the wide range of behaviour covered under the [currently] singular term of autism...

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Maternal prenatal acetaminophen use and the risk of ADHD in offspring (again)

By discussing the findings - meta-analysis findings - published by Xiaoyun Gou and colleagues [1] I once again approach the topic of whether some medicines use during pregnancy might have some important implications for offspring development. And yet again we're talking about the use of acetaminophen a.k.a paracetamol, during pregnancy and how it *might* have some important implications when it comes to offspring development (see here and see here and see here for other blogging examples on this subject).

The Gou study focused on the risk of an offspring diagnosis of attention-deficit hyperactivity disorder (ADHD) following maternal exposure to paracetamol during pregnancy. And whether timing of said exposure and/or duration of exposure showed any *association* to risk of offspring ADHD.

As per the opening sentence to this post, the Gou study was a meta-analysis, meaning that it was a synthesis of the available peer-reviewed research literature. Indeed, authors identified 8 studies published up to November 2018 that included data on nearly a quarter of a million participants in total.

Given the quite consistent consensus already seen in the science on this topic (see here for example) it's probably not unexpected that that authors concluded that: "Maternal exposure to acetaminophen during pregnancy increased the risk of attention deficit/hyperactivity disorder in offspring with a pooled adjusted risk ratio of 1.25." Further: "Children exposed prenatally to acetaminophen in the third trimester seemed to have the greatest risk of developing attention deficit/hyperactivity disorder" and "a longer duration of maternal acetaminophen use during pregnancy was correlated with a higher risk ratio."

Of course such findings, even such meta-analysis findings, come with cautions about correlation not necessarily being the same as causation given the observational nature of the studies included for review. There are also a myriad of other potential factors that seemingly impact on offspring risk for ADHD (see here and see here for some other possible examples) which perhaps require consideration at the same time.

But... this is a topic that requires a lot more investigation. Investigations into whether (a) the association is indeed a real one and not just epiphenomenal, (b) the reasons leading to paracetamol use during pregnancy which may also exert an effect on offspring risk, and (c) which biological mechanisms may be pertinent to any connection (see here and see here), are all indicated. As for where medical opinion stands on this topic at the moment, well, minus any medical or clinical advice from me, I go with the research literature on this topic [2] and would suggest that if you're in doubt, talk to your medical professional...

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[1] Gou X. et al. Association of maternal prenatal acetaminophen use with the risk of attention deficit/hyperactivity disorder in offspring: A meta-analysis. Aust N Z J Psychiatry. 2019 Jan 17:4867418823276.

[2] Andrade C. et al. Use of acetaminophen (paracetamol) during pregnancy and the risk of attention-deficit/hyperactivity disorder in the offspring. J Clin Psychiatry. 2016 Mar;77(3):e312-4.

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"a probiotic (Bifidobacterium infantis) in combination with a bovine colostrum product (BCP)" for autism?

The study findings reported by Megan Sanctuary and colleagues [1] caught my eye recently, and their aim to "assess tolerability of a probiotic (Bifidobacterium infantis) in combination with a bovine colostrum product (BCP) as a source of prebiotic oligosaccharides and to evaluate GI [gastrointestinal], microbiome and immune factors in children with ASD [autism spectrum disorder] and GI co-morbidities."

I appreciate that such a study is probably not going to be everyone's cup of tea given, for example, the rather *interesting* history of colostrum and autism (including the words 'transfer factor' [2]). The Sanctuary study however, should be taken on its own merit regarding "concurrent supplementation with both the probiotic B. infantis and bovine colostrum product (BCP) as a source of immune factors and prebiotic glycans could alter the microbiota to a more beneficial composition in order to improve gut health in children with ASD and GI symptoms." The rationale behind such work is that (a) what goes on the in the deepest, darkest recesses of the GI tract in a microbial sense could impact on the functional gut symptoms, and (b) said functional gut symptoms seem to be 'over-represented' in relation to autism (see here) and *could* in some cases, be linked to behavioural presentation (see here). Ergo, try and impact on functional gut symptoms and one *might* be able to impact on behaviour...

Sanctuary et al report preliminary findings designed to "assess tolerability" and "to evaluate GI, microbiome and immune factors in children with ASD and GI co-morbidities." This work represented a first step towards a bigger research trial to ascertain whether such a supplemental combination *might* be useful for some people on the autism spectrum in a 'clinically relevant' sense. Despite being a pilot study, researchers did conduct what is considered a gold-standard study insofar as it being a "double-blind, crossover, randomized clinical trial (RCT)." The study protocol was also research registered (see here), so quite a few methodological boxes were ticked.

Given that this study was carried out at the MIND Institute, an institution that has quite a lot of experience in all-manner of different autism research areas (see here and see here), researchers were pretty precise when it came to diagnosing autism/ASD and ascertaining the presence or not of GI symptoms in their small cohort (N=11). The authors also provide quite a bit of information about the supplements used including "the bovine colostrum product (Imucon)" and details of its safety: "The product was tested and found to be negative for Escherichia coli, Salmonella, Listeria, coagulase positive Staphylococcus and antibiotic residue." Insofar as dosages, we are told that: "The colostrum powder dose administered in this study was 0.15 g/lb body weight per day" and "The probiotic dose administered in this study was 20 billion CFU [colony forming units] per day." A couple of supplemental combinations were examined during the study including BCP on its own and BCP+probiotic.

Results: there were quite a few different types of results reported on for 8 of the original 11 participants. Importantly: "Bovine colostrum product appears to be well-tolerated in these children [diagnosed with autism] as its own treatment as well as when combined with the probiotic B. infantis." 'Well-tolerated' means that there were "no participants needing to withdraw due to adverse events" despite a small number of reports of things like gassiness. A couple of kids were also reported to find the taste of the products not too great.

Also: "Some participants on both treatments saw a reduction in the frequency of certain GI symptoms, as well as reduced occurrence of particular aberrant behaviors." Being really careful here because of the small participant number included for study for example, researchers reported that "87.5% (7/8) of participants exhibited some improvement in GI symptoms while on the BCP only arm and 100% (8/8) of participants exhibited some improvement in GI symptoms while on the combination treatment arm." The sorts of GI effects mentioned included reductions in "pain with stooling, frequency of diarrhea, and consistency." Researchers also reported that appetite seemed to be improved for some kids too, particularly the consumption of fruit and meat.

A few other changes were noted in the study, but on the basis of the small participant size and the aims of the study I'm gonna leave them for now. As the authors mention: "the lack of a clear control group receiving a placebo" means that this was a "cross-over study where each participant was his own control" and therefore one needs to be cautious for now. What is needed next is a larger trial and more focus on the behavioural presentation side of autism...

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[1] Sanctuary MR. et al. (2019) Pilot study of probiotic/colostrum supplementation on gut function in children with autism and gastrointestinal symptoms. PLoS ONE 14(1): e0210064.

[2] Fudenberg HH. Dialysable lymphocyte extract (DLyE) in infantile onset autism: a pilot study. Biotherapy. 1996;9(1-3):143-7.

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Sex differences in autism presentation continued

The paper by Ligia Antezana and colleagues [1] provides the brief blogging fodder today and some further focus on potential sex/gender differences when it comes to the presentation of autism (see here).

The aim of the study was a relatively simple one: "to identify whether specific RRBI [restricted and repetitive behaviors and interests] (i.e., stereotyped, self-injurious, compulsive, insistence on sameness, ritualistic, and restricted), as measured by item-level data on the Repetitive Behavior Scale-Revised (RBS-R), can distinguish girls from boys with ASD [autism spectrum disorder]." The sample was a pretty good size - "615 individuals with ASD (507 boys; 82.4%)" - and the findings were rather interesting...

So: "Items that best-discriminated gender were heightened stereotyped behaviors and restricted interests items in boys and compulsive, sameness, restricted, and self-injurious behavior items in girls." The authors add that: "This study is the first to find that girls with ASD may have increased compulsive, sameness, and restricted RRBI compared to boys."

Bearing in mind the care required when talking about sweeping generalisations about 'boy autism' and 'girl autism', the Antezana results do point to a need for further study in this area. Not least because the authors rightly mention how: "Future research should disentangle whether elevated rates of RRBI in girls are central to the presentation of ASD in girls or an epiphenomenon of the high rates of co-occurring disorders (e.g., anxiety) noted in girls." This based on the idea that autism rarely exists in some sort of diagnostic vacuum (see here) and some of that *comorbidity* (if that is the right word to use) could very well be part and parcel of such clinical observations.

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[1] Antezana L. et al. Gender differences in restricted and repetitive behaviors and interests in youth with autism. Autism Res. 2018 Dec 17.

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