Breastfeeding and autism continued

"We found that the percentage of mothers who started breastfeeding was similar between the two groups, but mothers of children with ASD [autism spectrum disorder] breastfed for a shorter amount of time compared to mothers of children without ASD."

So said the findings reported by Gnakub Soke and colleagues [1] continuing a research theme that I've had some professional interest in down the years (see here) on whether breastfeeding (use, duration, etc) *might* have some important *links* to risk of offspring autism and/or related conditions (see here). The same caveats mention in some of my other musings on this topic come into effect when talking (briefly) about the Soke findings (i.e. no-one is saying that a lack of breastfeeding 'causes' autism). That being said, there might still however be some important science to do on how breastfeeding and/or the constituents of breast milk might have some important biological effects for the developing child (minus any psychobabble explanations).

The Study to Explore Early Development or SEED was the starting point for the Soke study (continuing an autism research theme), and specifically investigation into the: "associations between ASD and breastfeeding initiation (yes/no) and duration (months categorized in tertiles)." The findings suggested that (a) breastfeeding rates (initiation rates) were high in mums of children with ASD compared to not-autism controls (85% vs. 90%), and (b) "mothers of children with ASD were less likely to report duration of breastfeeding in the high (≥12 months) versus low tertile (<6 months)... or the middle (6-<12 months) versus low tertile."

I don't want to dwell too much on the whys-and-wherefores of the Soke findings but there are some important questions that need answering. Not least the question of why breastfeeding seems to end quicker for those mums of children who were subsequently diagnosed as having an ASD. Were these infants more difficult to feed (something which Kanner might have picked up on in his seminal paper describing autism)? What role does the presentation of the 'broader autism phenotype' (BAP) in mothers mentioned by Soke et al play in such findings? That last point in particular, draws on the need for lots more research into the experience of pregnancy and motherhood with the BAP (see here) and/or autism in mind (see here).

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[1] Soke GN. et al. Association Between Breastfeeding Initiation and Duration and Autism Spectrum Disorder in Preschool Children Enrolled in the Study to Explore Early Development. Autism Res. 2019 Mar 9.

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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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"To examine associations between early developmental exposure to ambient pesticides and autism spectrum disorder"

The quote heading this post - "To examine associations between early developmental exposure to ambient pesticides and autism spectrum disorder" - reflects the aim of the study published by Ondine von Ehrenstein and colleagues [1]. Said aim was accomplished by examining data from "California’s main agricultural region, Central Valley, using 1998-2010 birth data from the Office of Vital Statistics" with regards to autism diagnoses (see here) and pesticide use and exposure. The results: "Findings suggest that an offspring’s risk of autism spectrum disorder increases following prenatal exposure to ambient pesticides within 2000 m of their mother’s residence during pregnancy, compared with offspring of women from the same agricultural region without such exposure." Also: "Infant exposure could further increase risks for autism spectrum disorder with comorbid intellectual disability."

The von Ehrenstein findings also come with an accompanying editorial [2] both published in the British Medical Journal (BMJ). That editorial provides a good overview of the findings and, importantly, some of their limitations. The editorial notes for example, that: "the study included only children with a diagnosis of “autistic disorder” by the California Department of Developmental Services, based on criteria described in the Diagnostic and Statistical Manual of Mental Disorders version IV-R." It cautions that the von Ehrenstein findings might not generalise to "milder forms of autism spectrum disorder." This 'lack of generalisation to milder forms' is a real reversal of what is typically seen in the peer-reviewed autism research literature (see here).

I don't want to linger too much on the von Ehrenstein study but a few points are worth noting. The question of what specific pesticides *might* influence risk of offspring autism is a complicated one. The researchers reported that "small to moderately increased risks for the disorder in offspring with prenatal exposure to the organophosphates chlorpyrifos, diazinon, and malathion, the pyrethroids permethrin and bifenthrin, as well as to glyphosate, avermectin, and methyl bromide" were observed. They (and the editorial) talk about how further research is required to "examine the joint effects of multi-exposure mixtures to more effectively protect human health." This is important in the context of other research (see here and see here) and also to avoid any big media headlines (see here) about specific preparations 'causing' autism (which has not yet been authoritatively established). Given that various different classes of pesticides have somewhat slightly different biological actions, there is a lot of work to be done on the possible biological mechanisms/targets and any synergistic effects.

Also: "children with autism spectrum disorder and co-occurring intellectual disability were examined as a separate outcome." The fact that von Ehrenstein et al observed something like a 'stronger association' between pesticide exposure and those at the "more severe end of the autism spectrum" (the description according to one media source) is another important point requiring further study. I say this in the context that 'comorbidity' might not always be the best description for symptoms and diagnoses accompanying autism (see here).

The authors conclude that their findings - with appropriate caveats - have implications. Namely: "Exposure of pregnant women and infants to ambient pesticides with a potential neurodevelopmental toxicity mode of action should be avoided as a preventive measure against autism spectrum disorder." I don't think too many people would disagree with the sentiments of 'avoiding pesticide exposure' particularly for pregnant women and those who might also be more vulnerable to their potential effects. The questions now turn to genetics and biology and the question of why...

Music to close: Hostiles on the Hill (apparently)...

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[1] von Ehrenstein OS. et al. Prenatal and infant exposure to ambient pesticides and autism spectrum disorder in children: population based case-control study. BMJ. 2019; 364: I962.

[2] Bakian AV. & VanDerslice JA. Pesticides and autism. BMJ. 2019; 364: I1149.

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"Our findings beg the question, what is going on with these children who no longer have an ASD diagnosis?"

The quote heading this post - "Our findings beg the question, what is going on with these children who no longer have an ASD [autism spectrum disorder] diagnosis?" - comes from some media coverage of the findings reported by Lisa Shulman and colleagues [1]. Shulman et al (bravely) set about examining an important phenomenon in autism research and practice circles: those who were previously diagnosed as being autistic / having autism but at a later date 'no longer met the diagnostic criteria for autism'.

I've talked about these so-called 'optimal outcomers' quite a bit on this blog (see here and see here and see here for examples). I know such discussions aren't everyone's cup of tea, particularly those who see autism as so much more than a diagnostic label, perhaps akin to an identity. The fact of the matter is however that there is what I would call 'substantial evidence' in the peer-reviewed science domain and beyond that the idea that 'autism is a lifelong condition/disorder' does not necessarily cover the huge heterogeneity encompassed under the label autism. Some people, for whatever reasons, do not reach critical diagnostic cut-off points for autism on a lifelong basis.

So, what did Shulman and colleagues do and find? They reviewed the clinical records of over 500 children who were diagnosed with autism or autism spectrum disorder (ASD) at a specific clinic. Most were aged around 3 years old when first diagnosed and were followed up about 3-4 years later. Importantly most of the children participated in one or more intervention programs aimed at improving skills and the like and (hopefully) quality of life. Again, although not everyone's cup of tea, the words 'applied behavioural analysis' (ABA) are also mentioned as an intervention; something that has been discussed in the context of optimal outcome before (see here).

Shulman et al noted that 38 children, equating to around 7% of their group (38/569), "subsequently experienced resolution of ASD symptomatology and no longer met diagnostic criteria for ASD at follow-up." This figure (7%) is not a million miles away from other figures noted in other independent studies (see here and see here).

Further examination of records however revealed that not meeting diagnostic cut-off points for autism did not necessarily mean 'symptom-free' as various other symptoms/conditions were noted in about two-thirds of their 'optimal outcomers'. This included language disorders, attention-deficit hyperactivity disorder (ADHD) and even the signs and symptoms of psychosis in a few. Three of the 38 optimal outcome children were noted to be completely symptom-free (described as 'recovered from autism' with no other issues); something that has again been noted in other studies too (see here).

Then back to that quote titling this post: what is going on with these children who no longer have an ASD diagnosis? I'm sure some people will put it wholly down to initial misdiagnosis. Y'know, something along the lines of 'they weren't autistic in the first place' despite the fact that they previously met clinical cut-off points for a diagnosis. Minus sweeping generalisations, misdiagnosing autism is not something that can be completely taken off the table as per other examples in the peer-reviewed literature and beyond (see here and see here). Indeed, if one ventures down the pathway of misdiagnosis as accounting for results such as those by Shulman and colleagues, one must logically then assume that such misdiagnosis is pretty widespread (at least in 7-12% of cases of autism). Such a situation also plays into other ideas too; particularly how self-diagnosis of autism is even more dangerous than has been hitherto suggested (see here and see here) with regards to the risk of misdiagnosis.

Other people might talk about things like 'masking' as accounting for such optimal outcome, where symptoms are merely being consciously hidden by those with autism (see here). It's an important area of study by all means but seriously ask yourself the question: how likely is it that a 6 or 7-year old child would be able to mask some fundamental signs and symptoms of autism so as to mislead a professional clinician that they didn't have autism having previously met cut-off points? Adults, yes perhaps some (see here). But young children? Be honest now...

Personally, I'm inclined to believe that at least some of those optimal outcome cases are genuine. That is, children (and adults) did meet the diagnostic criteria and clinical cut-off points for autism (including the criteria about symptoms significantly affecting day-to-day life) and then for whatever reason(s) symptoms abated. Intervention certainly could have played a role, but I'm also inclined to believe that behavioural intervention in particular, does not have the power to render someone who was autistic to be not-autistic. I know some big claims have been made about certain interventions down the years, but I've seen little [longitudinal] convincing evidence in the peer-reviewed literature yet.

There must be other factors at work. There must, for example, be a biological element to this. And as one example, just head back to all those discussions about certain types of infection potentially *leading* to the presentation of autism or autistic traits (see here and see here) as a possible template, and the outcomes mentioned for some. One possibility at least.

Much like discussions on another sometimes contentious topic - regression and autism (see here and see here) - there's enough peer-reviewed science literature to suggest that optimal outcome (or however you want to describe such 'growing out of' issues) is a very real scenario for some. Not all, but for some. And so once again the call goes out to start studying the genetics and biology of these so-called optimal outcomers, and then ascertaining whether any findings might have some important implications more widely for the [plural] label of autism...

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[1] Shulman L. et al. When an Early Diagnosis of Autism Spectrum Disorder Resolves, What Remains? J Child Neurol. 2019 Mar 12:883073819834428.

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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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Regression and autism: "The regression group was significantly more functionally impaired..."

The quote forming part of the title of today's post - "The regression group was significantly more functionally impaired..." - comes from the findings reported by Lucy Thompson and colleagues [1] (open-access available here). It continues something of an important theme in autism research circles whereby regression, as in a regression of previously acquired skills, is being seen as important not just for a few but for many (see here).

There were a few aims to the Thompson study such as establishing "the relative prevalence of regression in autism" and "possible predictors, mediators and moderators of regression in autism, including pre- and perinatal factors." The data for the study were derived from "two community-based cohorts" in Sweden totalling just over 300 participants (children) diagnosed with an autism spectrum disorder (ASD) who were observed over two different time points (T1 and T2 2 years later). Another important detail is mentioned by Thompson et al: "Given the lack of previous systematic representative studies in the field, our study sets out to be descriptive rather than hypothesis-driven." Figures and details on regression in the cohort(s) were obtained via specific questioning on this topic "defined as loss of expressive language skills (loss of 5 or more words that had been used communicatively) in connection with the onset of autism." This data was also combined with other medical records information to determine 'consistency'.

Results: "Just over 20% (62/303) of the combined sample of children had regressive autism." That's 1 in 5 children with autism experiencing some kind of regression in relation to language skills. When looking at those who regressed (n=62) compared with those with no regression (n=241), a few details emerged: "Those with regressive autism had a younger age when they first walked... had a more severe language impairment at T1... and more often intellectual disability... [and] lower mean VAB [Vineland Adaptive Behaviour Scales-II] scores." Also: "Severity of autism was higher in the regressive group, with a higher proportion of children with autism... (as opposed to autistic-like condition)."

This is important data. It kinda tallies with other studies of regression accompanying autism suggesting that those who regress tend to have a more 'severe' form of autism with accompanying learning (intellectual) disability. The diagnostic issues - as in more likely to be diagnosed with Kanner's autism rather than other diagnoses - similarly ties in with other findings.

Caveats? Well, a few: "We have chosen to focus on language regression specifically (rather than social, play or motor regression) as communication is by far the most common skill to be lost or diminished in regressive autism." That being said, regression accompanying autism seems to take many, many forms and does not always just mean a loss or partial loss of vocal communication (see here).

Also: "There was also a similar level of maternal disease in pregnancy in the regressive and non-regressive groups, suggesting that prenatal exposure via maternal disease does not seem to be a key feature in the development of regressive autism." I have to question why the authors stuck to looking at just pre- and perinatal factors as possibly being *linked* to regression when regression is likely to occur quite some time after such a developmental window. Surely it would have made more sense to ask a few further questions about the timing of regression - "The average age at regression was 20.13 months... with 54 children (88.5%) showing regression by the age of 24 months" - and whether one or more event might have proceeded such regression in a similar time frame. Y'know whether infection might be a feature (see here and see here for examples) or whether other events might require further investigation (see here). I know this might take such research down some uncomfortable paths, but temporality is surely an important factor for some regression in some cases of autism? Or am I being too unreasonable?

I might also advance the idea that the time to start asking questions about the biology of regression accompanying autism is fast approaching. We've already had some clues in the recent (at the time of writing) peer-reviewed research literature (see here) but lots more needs to be done in this area. Are there important genetic and/or epigenetic variables to consider? Do mitochondrial issues play a role in some regressive autism (see here)? We just don't know enough yet. And yes, this does mean also asking about whether regression in behaviour or cognitive skills was also accompanied by any changes to somatic variables too (see here).

And then there is another question to ask/answer: does regression mean that certain 'therapeutic' options might be particularly useful? I'm thinking back to some research a few years back talking about corticosterioid therapy *potentially* being indicated for some cases of regressive autism (see here). No, I'm not making any medical or clinical claims or giving any advice on such an issue. Merely mentioning that regressive autism needs to be more of a research priority than it currently is. To quote Thompson and colleagues again: "Children with a regressive developmental trajectory, with or without autism, always need a careful neuropediatric work-up to investigate possible neurological disorders that may lead to developmental regression, taking into account possible treatable conditions." Who would argue with that?

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[1] Thompson L. et al. Autism With and Without Regression: A Two-Year Prospective Longitudinal Study in Two Population-Derived Swedish Cohorts. J Autism Dev Disord. 2019 Feb 4.

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"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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"a neurodevelopmental abnormality possibly associated with congenital Zika virus infection"

I'm a little late getting to the findings reported by Marion Rice and colleagues [1] (open-access available here) but I did want to cover them because of their current importance and perhaps future implications. The topic in question was the Zika virus and specifically the research efforts of the U.S. Zika Pregnancy and Infant Registry (USZPIR) used to track those infants exposed to the virus during the important nine months than made them. Just in case you didn't follow the hows-and-whys of the Zika virus outbreak and its effects a while back, some background can be found here.

Rice et al report findings for nearly 1500 children "of mothers with laboratory evidence of confirmed or possible Zika virus infection during pregnancy" in terms of their level of care and clinical follow-up and also "to identify Zika-associated birth defects and neurodevelopmental abnormalities possibly associated with congenital Zika virus infection." Aside from reporting that the majority of their cohort had "some follow-up care reported" ('some' that included very basic "length/height, weight, or head circumference measurements and date of measurements" reported back to the USZPIR), a few other observations were also made. This included findings such as: "approximately one in seven (14%) were identified during infancy or early childhood as having either a Zika-associated birth defect, a neurodevelopmental abnormality possibly associated with congenital Zika virus infection, or both."

Although the talk about birth defects is important to Zika virus exposure (microcephaly being only one part of this), I was specifically interested in the 'neurodevelopmental' side of things reported in the Rice paper as affecting 9-10% of the cohort depending on what laboratory testing for Zika virus exposure was carried out. Bearing in mind the age group of the cohort (1 year old and above), and that such neurodevelopmental issues covered a lot of clinical ground (e.g. "hearing abnormalities; congenital contractures; seizures; body tone abnormalities; movement abnormalities; swallowing abnormalities; possible developmental delay; possible visual impairment; and/or postnatal-onset microcephaly") it's important to understand how infections such as Zika might have the ability to affect cognitive and/or neurodevelopmental outcomes. What's also important too is the realisation that given the young age of the cohort, "the full spectrum of adverse outcomes related to congenital Zika virus infection is not yet known." So developmental delay for example, *could* eventually develop into something else, and why appropriate monitoring will continue through initiatives like the USZPIR.

From a cold, objective science perspective and without wishing to diminish the very human effects associated with this event, the 2016 Zika outbreak that struck the Americas provides an ideal opportunity to study our important interaction with the environment around us. It emphasises how facets of our environment can very much influence both physical and psychological health, particularly at critical times of development. A lesson that perhaps is transferable to many different neurodevelopmental labels [2]...

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[1] Rice ME. et al. Vital Signs: Zika-Associated Birth Defects and Neurodevelopmental Abnormalities Possibly Associated with Congenital Zika Virus Infection - U.S. Territories and Freely Associated States, 2018. MMWR Morb Mortal Wkly Rep. 2018 Aug 10;67(31):858-867.

[2] Lydholm CN. et al. Parental infections before, during and after pregnancy as risk factors for mental disorders in childhood and adolescence – a nationwide Danish study. Biological Psychiatry. 2018. Oct 1.

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On autism symptom trajectories and diagnosing autism late...

It's another one of my mash-up posts today, as two paper are brought to the blogging table. The first paper is from So Hyun Kim and colleagues [1] and looked at the rather interesting topic of differing symptom trajectories in the context of diagnosing autism. The second paper by Sally Ozonoff and colleagues [2] follows in a similar vein in terms of their analysis of children "who had undergone multiple comprehensive assessments in preschool and were determined to be ASD [autism spectrum disorder]-negative, only to meet criteria for ASD when tested in middle childhood."

Both these paper originate from well-respected autism research groups and appear in the same respected journal (Journal of the American Academy of Child & Adolescent Psychiatry). The common theme between them is that within the significant heterogeneity seen under the label of 'autism', there are various different developmental and presented symptoms trajectories, some of which (a) are not as stable as one might imagine, and (b) do not seemingly follow the oft-used assertion that 'autism is present and manifests from birth'. Indeed, on that last point, the implications are that autism is sometimes very much associated with regression (see here) and onward, that genetic and/or non-genetic post-natal factors may very well influence some children reaching clinical cut-off thresholds for a diagnosis of autism (see here for example).

So, to the Kim paper first: authors looked at over 900 "observations of the Autism Diagnostic Observation Schedule (ADOS)" from nearly 150 young children. They were specifically looking at symptoms trajectories based on those ADOS scores and whether or not 'clusters' of similar symptom trajectories were evident. The answer: yes, yes there were some different clusters of symptom trajectories noted. Not six developmental trajectories as per other research (see here) but four clusters: "Nonspectrum ∼25%; Worsening ∼27%; Moderately-Improving ∼25%; Severe-Persistent ∼23%)." Authors also report how: "Trajectory clusters varied significantly in the proportions of confirmatory ASD diagnosis, the level of baseline and final verbal/nonverbal abilities, and symptom severity."

Then to the Ozonoff paper: "Fourteen children met inclusion criteria for the Late Diagnosed group and were compared to a large sample of high- and low-risk siblings from the same sites who had ASD or typical development (TD) outcomes at age 3." Authors focused in on these 14 children and concluded that: "Seven showed very little evidence of ASD in preschool, while seven demonstrated subtle, subthreshold symptomatology." They also suggest that their results identifying a small but important group of children who seemingly first present with 'typical' behaviour but then 'grow into' the presentation of autism "shed light on reasons why the mean age of ASD diagnosis remains over 4 years." Indeed (see here).

I don't really need to say much more than I have already on these studies. Aside that is, from reiterating that the autism spectrum is truly wide and heterogeneous in both symptom presentation and also it seems, with regards to symptom onset and stability too. Alongside other research (see here) talking about how the presentation of autistic signs and symptoms wax and wane for some, I'm wondering when autism research is going to start looking beyond just presented behaviour, at whether for example, genetic and biological 'changes' might accompany such fluidity in behaviour and 'cluster' differences. Y'know, the same way that another group seemingly heading in the opposite direction - those who 'lose their diagnosis' (see here and see here) - also need to be closely investigated from a biological point of view too. It's only when we have such biological data that we can then start meaningfully probing the possible hows-and-whys...

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[1] Kim SH. et al. Variability in Autism Symptom Trajectories Using Repeated Observations from 14 to 36 Months of Age. Journal of the American Academy of Child & Adolescent Psychiatry. 2018. Sept 5.

[2] Ozonoff S. et al. Diagnosis of Autism Spectrum Disorder After Age 5 in Children Evaluated Longitudinally Since Infancy. Journal of the American Academy of Child & Adolescent Psychiatry. 2018. Sept 3.

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ALSPAC says... "Social communication impairments had the strongest association with a depression diagnosis at age 18 years"

ALSPAC mentioned in the title of this post refers to The Avon Longitudinal Study of Parents and Children, one of the premier research initiatives here in Blighty, that has provided all-manner of interesting and important research associations. With autism in mind, ALSPAC has opined on various different research questions (see here and see here for examples) including the issue of a possible 'real' increase in the numbers of children presenting with autistic traits (see here).

On this particular research occasion, ALSPAC was the source data for the findings reported by Dheeraj Rai and colleagues [1] who set out to "compare trajectories of depressive symptoms from ages 10 to 18 years for children with or without ASD [autism spectrum disorder] and autistic traits, to assess associations between ASD and autistic traits and an International Statistical Classification of Diseases, 10th Revision (ICD-10) depression diagnosis at age 18 years, and to explore the importance of genetic confounding and bullying." I might add that some of this authorship group are making some real research waves when it comes to investigations using population registries with autism in mind (see here).

The starting point this time around was the notion that a diagnosis of autism is in no way protective when it comes to a diagnosis of depression and/or the expression of depressive signs and symptoms. Again, it's a topic that has cropped up before on this blog (see here) and is perhaps one of the longer term associations that have been made down the years. The idea that depression or depressive symptoms *might* be something much more than just 'comorbid' in the context of at least 'some' autism is something else that has been banded around the peer-reviewed research literature before (see here) but the evidence base is not particularly big or strong in this area at the moment.

There were a few different research questions asked by Rai et al, including looking at children "with or without ASD or high scores on autistic trait measures" and any relationship(s) with depression and depressive traits. They report findings for over 6000 children ("maximum sample with complete data") where questionnaire items on bullying were also included ("Relational and overt bullying was assessed as separate yes or no items at ages 8, 10, and 13 years using the modified Bullying and Friendship Interview Schedule") alongside various other potentially confounding variables.

Results: "children with ASD and those with higher scores on all autistic trait measures had more depressive symptoms at age 10 years than the general population, and these remained elevated in an upward trajectory until age 18 years." I don't think there's anything too novel in such findings, aside from the observation that depression / depressive symptoms may start quite early on in childhood. I can remember when I started out in autism research a couple of decades ago hearing about depression being typically linked to the onset of adulthood in the context of autism. This current data suggests otherwise.

Next: "Social communication impairments had the strongest association with a depression diagnosis at age 18 years. Findings were robust to adjustment for a range of confounders, including maternal depression and anxiety and the child’s polygenic risk for autism." This is important. What it suggests is that there may something 'more than just comorbid' about depression or depressive symptoms appearing alongside autism or at least in connection to certain autistic traits. I know some people have already taken exception to this possibility alongside the use of the word 'impairment' by the authors. But much like other research on an important bedfellow to depression - anxiety - one may have to entertain the possibility that there may be some enhanced 'predisposition' to something like depression alongside the presentation of autistic traits (see here and see here) perhaps mediated by factors such as rumination and perseveration for example [2]. This doesn't mean that depression is solely a product of autistic traits; merely that certain traits may potentially form an important vulnerability factor. I'm similarly minded to bring in other work from the ALSPAC initiative [3] (including Rai and colleagues as authors) where related findings were mentioned: "Social communication impairments are an important autistic trait in relation to suicidality." This on the basis that depression and suicidality show an important association.

Also: "We found evidence of a substantial role of bullying in contributing to and explaining a higher risk of depression in individuals with ASD and autistic symptoms." Bullying in the context of autism is another long-standing topic (see here). Bullying covers a lot of ground in terms of behaviour and also source (see here). The authors opine that: "Previous work has shown strong links between the experience of bullying and later depression... although confounding could have a role, the association is considered to be at least partially causal." It's also important to note that social-communication 'issues' were reported to be potentially predictive of being bullied according to the authors. The model that then appears hints that the appearance of depression *might* be linked to "reduced self-esteem or social isolation after the bullying" accepting that causality is not established and also not accounting for other variables: "other relevant characteristics, including comorbidities with neurodevelopmental conditions (eg, attention-deficit/hyperactivity disorder) and classroom placement could be important in this association within or outside the context of bullying." That last point is important in the context that autism rarely exists in some sort of diagnostic vacuum (see here).

There are a few caveats attached to the Rai findings that need to be kept in mind outside of any 'correlation does not necessarily equal causation' sentiments. So: "atypical presentations of depression are common in ASD, and our study has the potential for outcome measurement error because we used scales... that have not been adapted for autism." Indeed. I've previously talked about how bipolar disorder for example, might not follow a typical pattern when present in the context of autism (see here). I daresay that this could also hold for other types/forms of depression too. I'm also minded to reiterate that depression, as well as being a heterogeneous condition, also seemingly has many pathways to it. Some of those pathways will include psychological and social variables such as bullying and perhaps even more extremes of 'trauma'; where a diagnosis of PTSD is for example, no stranger to autism (see here). 'Happiness' and perceived quality of life (see here) are also likely to exert an important effect too.

Other pathways to depression seem to be more biologically defined as per depression in the context of physical ailments (see here) that may have a *link* to some autism (see here) or following the use of seemingly common medicines according to recent news reports (see here). I'll also mention that things like physical activity and exercise *seem* to show an important relationship with depression (see here). This could also be pertinent to the data suggesting that physical activity levels are typically not optimal where and when autism is diagnosed (see here). Other factors (fatigue, sleep, etc) also need to be mentioned in the context of depression. In short, there are lots and lots of potential variables to consider [4].

Outside of the important messages from the Rai findings on how depression is over-represented in relation to autism and how social factors like bullying seem to be linked  to it and thus are subsequently 'modifiable', there is another important point to consider: depression is typically treatable. Minus any medical or clinical advice being given or intended, the first step in managing/treating depression is identifying it. Perhaps the Rai findings might serve as a further call to action for preferential screening in the context of autism...

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[1] Rai D. et al. Association of Autistic Traits With Depression From Childhood to Age 18 Years. JAMA Psychiatry. 2018 Jun 13.

[2] Patel S. et al. Association between anger rumination and autism symptom severity, depression symptoms, aggression, and general dysregulation in adolescents with autism spectrum disorder. Autism. 2017 Feb;21(2):181-189.

[3] Culpin I. et al. Autistic Traits and Suicidal Thoughts, Plans, and Self-Harm in Late Adolescence: Population-Based Cohort Study. J Am Acad Child Adolesc Psychiatry. 2018 May;57(5):313-320.e6.

[4] Köhler CA. et al. Mapping risk factors for depression across the lifespan: An umbrella review of evidence from meta-analyses and Mendelian randomization studies. J Psychiatr Res. 2018 May 25;103:189-207.

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Regression in autism: the rule rather than the exception?

"Declining trajectories of development, consistent with a regressive onset pattern, are common in children with ASD [autism spectrum disorder] and may be more the rule than the exception."

So said the findings reported by Sally Ozonoff and colleagues [1] who reported results based on a study of developmental / behavioural regression in autism, and specifically: "how rates of regression differed by measurement method."

Regression in relation to autism is a topic I've covered a few times on this blog (see here and see here for examples). I've followed the [peer-reviewed] story from where behavioural and/or developmental regression was initially thought to be a figment of the [parental] imagination, right up to these days where regression is pretty much accepted as being part and parcel of quite a few cases of autism. The road has not been a smooth one; but the question of whether autism is universally something inborn and hereditary for everyone is slowly starting to be answered: no, it is probably not. The reason(s) for regression still remain fertile grounds for discussion / debate / argument, but there are some important clues in the science literature (see here and see here for examples) with the caveats that autism is a very heterogeneous condition and onset patterns are likely to be influenced by all-manner of different variables. Think different phenotypes in the context of autism (see here) for example; and that's outside of the label previously known as Heller's syndrome.

Anyhow, Ozonoff et al report results for infants "with (n = 147) and without a family history of ASD (n = 83)" who were "seen prospectively for up to 7 visits in the first three years of life." Various different ways and means of assessing reports of symptom onset were collected, "that systematically varied the informant (examiner vs. parent), the decision type (categorical [regression absent or present] vs. dimensional [frequency of social behaviors]), and the timing of the assessment (retrospective vs. prospective)."

Depending on who said what and how they said it, patterns of regression in skills were noted in quite a large proportion of the Ozonoff cohort. So: "A majority of the sample was classified as having a regressive onset using either examiner (88%) or parent (69%) prospective dimensional ratings." The authors suggest that their observations highlight how quite a few more resources (and cautions) need to go into looking at symptom onset patterns in relation to autism.

For quite a few people, the findings reported by Ozonoff et al are 'catch-up' rather than something novel. I can think of quite a few instances where parents / guardians have had their important observations - very important observations - described as being 'talked down' when it came to reporting a regression in previously acquired skills in the context of autism. This should no longer be the case; particularly when also set in the context of the increasing pluralisation of the label of autism (see here) and perhaps even, the changing face of autism (see here) compared with yesteryear.

Then to the next important questions: how and why? I've already alluded to a role for infection in relation to the onset of regressive autism for some, but much more data is required on the specific details and mechanisms. There is also the issue of what *might* potentially be done to minimise factors linked to regression in autism too. Minus any sweeping generalisations, I'd also direct your attention to other mentions of regressive autism in the peer-reviewed science literature [2] and where, minus any hype, there could be some important clues for some. The important point once again, is that the diagnosis of autism should be the start of further investigations, not the finishing line.

To close, don't ask me how or why but one of my brood has started watching and enjoying an old staple part of the weekend TV quiz scene in 1980s Blighty... BFH by the way, is most classically referred to as your 'bus fare home'.

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[1] Ozonoff S. et al. Onset patterns in autism: Variation across informants, methods, and timing. Autism Res. 2018 Mar 10.

[2] Poling JS. et al. Developmental regression and mitochondrial dysfunction in a child with autism. J Child Neurol. 2006 Feb;21(2):170-2.

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Breastfeeding and autism meta-analysed

"This meta-analysis provides evidence that breastfeeding (exclusively or including additional supplements) may protect against ASD [autism spectrum disorder]. Prospective longitudinal research is required to disentangle the complex relationships and to explore potential pathophysiological mechanisms."

So said the systematic review and meta-analysis published by Ping-Tao Tseng and colleagues [1] covering a [complicated] topic that has been discussed on this blog before (see here). I should mention that I was part of the 'and colleagues' bit to this latest paper; something that will in no way interfere with my hopefully critical musings on this latest publication.

Bearing in mind "a controversial relationship between ASD and breastfeeding" that exists in the peer-reviewed literature and the strong requirement not to make new mums feel bad just because they don't want to or can't breastfeed, the aim of the meta-analysing game was to synthesise the collected research literature into something like a coherent 'where we're at' statement. Seven studies out of a possible 20 were included for review, together including nearly 1500 children diagnosed with ASD and nearly 1200 not-diagnosed-with-autism controls.

Results: "Cumulatively, children with ASD, either in the form of clinical diagnosis or self-report, were significantly less likely to have been breastfed than children without ASD." I should add that 'self-report' refers to parents reporting on their child receiving a diagnosis of autism but not necessarily being independently confirmed by researchers or medical records. The strength of the association/effect was not to be sniffed at; with results even holding up when taking into account those "who were breastfed with additional supplementation."

Another important quote: "one should note the observational nature of these preliminary findings, whereby causation can clearly not be determined." What this means is that whilst variable A (breastfeeding) and variable B (autism or ASD) might be *associated* it is nigh on impossible to definitively say whether variable A *causes* or *protects against* variable B on the basis of the studies analysed. I might also suggest that the call for 'prospective longitudinal research' is also not likely to provide a definitive answer any time soon either, when taking into account how many other variables might be associated with risk of offspring autism and indeed, the plurality of the label and some related discussions on that topic (see here and see here). It's also noteworthy that autism rarely exists in some sort of diagnostic vacuum (see here) and how breastfeeding trends might be important there too [2] thus complicating any 'causative' picture.

Still, the Tseng results do provide some further information about this issue and a reiteration of the value of breastfeeding for many different reasons. Other studies have arrived at a similar conclusion insofar as the impact that breastfeeding *might* have on 'autistic traits' [3]; again, with more research to do.

Mechanisms of effect? Well, once again we're faced with a 'we don't know yet' scenario. Tseng et al speculated on various possible factors linked to breastfeeding and breast milk 'ingredients' that may be important (neurotrophic factors, oxytocin, fatty acid constitution, casomorphins) and could conceivably impact on risk of offspring autism. I'm also minded to add in the idea that the early presentation of autism in the first months of life [for some] could also potentially affect breastfeeding patterns; perhaps making breastfeeding practices more difficult and/or contributing to the early cessation of breastfeeding in some cases. Relevant mechanisms are likely to be complicated.

I appreciate that not everyone is going to be enthralled with this study or topic - no, it doesn't say that a lack of breastfeeding causes all autism - particularly when words like "protect against ASD" are also included in the text. All I can say is that we faithfully looked at the existing peer-reviewed research available to us in this area and went where the data instructed us to do so without fear or favour...

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[1] Tseng P-T. et al. Maternal breastfeeding and autism spectrum disorder in children: A systematic review and meta-analysis. Nutritional Neuroscience. 2017. Oct 18.

[2] Bar S. et al. Long-term neurodevelopmental benefits of breastfeeding. Curr Opin Pediatr. 2016 Aug;28(4):559-66.

[3] Boucher O. et al. Association between breastfeeding duration and cognitive development, autistic traits and ADHD symptoms: a multicenter study in Spain. Pediatr Res. 2017 Mar;81(3):434-442.

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Subgroups in autism (without intellectual disability)

"Children with ASD [autism spectrum disorder] without ID [intellectual disability] could be differentiated into Moderate and Severe Social Impairment subgroups when core ASD symptoms were more closely examined."

So said the findings reported by Felicity Klopper and colleagues [1] looking at an important part of the autism research scene related to the 'plurality' of the term autism and the seemingly vast range of presentations included under the label. Reliant on data obtained from "the ‘gold standard’ ASD diagnostic instruments" (including the ADOS and ADI), researchers looked at the "presence of phenotypic subgroups" in their cohort.

As per the opening sentence to this post, there were some differences to be seen in the cohort, and in particular, how social interaction issues might be a key part of any differentiation. The authors talk about how social interaction issue differences seemed to tie into other core behavioural features such as communication and the presence of restricted/repetitive behaviours. They concluded: "both categorical and dimensional approaches may be useful in classifying ASD, with neither alone being adequate."

It is not necessarily new news that the label of autism is good for diagnosis but seemingly says little about the range of presentation included under the heading (see here for example). Indeed, in these days of ESSENCE I might forward the view that even the label autism might be part of a wider heterogeneous presentation (see here) and one should further expand those subgroup notions at the label as well as symptom level. The focus on overt behaviour (as assessed by those gold-standard instruments) in the Klopper study is but one part of looking at such 'heterogeneity' (see here for example) as the authors argue that: "The dissociated profiles of ASD features could represent different underlying neurobiological mechanisms for each subgroup." At least one of the authors on the Klopper paper probably, more than most, realises that fact (see here).

There are other key areas to this focus on the presentation of autism that also need to be factored in: sex differences and comorbidity profiles. Specifically, the growing realisation that girls and boys on the autism spectrum probably show subtle differences in presentation (see here) and, minus any sweeping generalisations, should be considered in future studies in this area. Oh, and keep in mind that those diagnosed with autism with an intellectual disability (ID) could also be 'sub-grouped' according to symptom presentation too with similar caveats. The question is: how many sub-groups of autism will we eventually end up with?

Music, and because Spring has Sprung... In Bloom.

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[1] Klopper F. et al. A cluster analysis exploration of autism spectrum disorder subgroups in children without intellectual disability. Research in Autism Spectrum Disorders. 2017; 36: 66-78.

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Felicity Klopper, Renee Testa, Christos Pantelis, & Efstratios Skafidas (2017). A cluster analysis exploration of autism spectrum disorder subgroups in children without intellectual disability Research in Autism Spectrum Disorders : 10.1016/j.rasd.2017.01.006

Big names coming around to 'neuroinflammation' and autism?

I won't keep you too long today as I bring the paper by Adam Young and colleagues [1] (open-access available here) to your attention and some discussions around the concept of inflammation and autism. To quote: "An emerging focus of research into the aetiology of ASC [autism spectrum condition] has suggested neuroinflammation as one candidate underlying [the] biological model."

Including one Simon Baron-Cohen on the authorship list, I have to say that I was impressed to see this quite comprehensive review of the peer-reviewed literature covering "the mechanisms that may underlie neuroinflammation and the evidence at genetic and protein levels for each of these mechanisms." The authors concluded that whilst there are some important gaps to be filled in the research literature in this area - "the greatest area of weakness in the field is that in general, the findings tend to be from individual studies and rarely are these replicated" - to mention 'inflammation' and 'autism' in the same sentence is no longer 'crazy talk'.

I've discussed quite a bit about inflammation and autism on this blog down the years. Personally, I've seen and read enough (peer-reviewed) papers on the topic to form an opinion that for at least some on the autism spectrum ('autisms' people, autisms) there is an overwhelming case for much more detailed investigation in this area. If you don't believe me, well, take a look at some of the science and form your own opinion (see here and see here for example). And when I say that some of the genetics of 'some' autism might also implicate inflammation and inflammatory processes too (see here), there appears to be something for everyone in the field.

One area that I would like to see more study on (aside from what science can potentially do when inflammation runs amok) is inspection of the interplay between genetic and biological factors pertinent to inflammation/inflammatory processes and behaviour and psychology. We've already had some hints down the years about how inflammation might 'affect' things like social cognitive processing (see here) including mention of a concept not unfamiliar to Prof. Baron-Cohen - Theory of Mind (ToM) - and potentially pertinent to autism. I'd like to see much more investigation on whether for example, cyclical patterns of inflammation might correspond to some of the cyclical patterns of behaviour noted in some on the spectrum. This set against the idea that some of the contents of the medicine cabinet already applied to some cases of autism might have some relevant actions on facets of immune function overlapping with inflammation and inflammatory processes (see here). Much more research is indicated.

Oh, and since we are on the topic of neuroinflammation and autism, I'd also suggest you having a look at the recent review from Janet Kern and colleagues [2] (open-access) too. They've also included some important mention of anti-NMDA-receptor encephalitis and autism (see here) which I'm particularly interested in...

Music: Me First and the Gimme Gimmes - My Heart Will Go On. Please, give the song a chance...

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[1] Young AM. et al. From molecules to neural morphology: understanding neuroinflammation in autism spectrum condition. Mol Autism. 2016 Jan 20;7:9.

[2] Kern J. et al. Relevance of Neuroinflammation and Encephalitis in Autism. Front Cell Neurosci. 2016 Jan 19;9:519.

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Young AM, Chakrabarti B, Roberts D, Lai MC, Suckling J, & Baron-Cohen S (2016). From molecules to neural morphology: understanding neuroinflammation in autism spectrum condition. Molecular autism, 7 PMID: 26793298