"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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Psychiatric symptoms in minimally verbal kids with autism: filling a gap

The findings reported by Daniela Plesa Skwerer and colleagues [1] (open-access available here) provide the blogging fodder today. They include some important information on an under-studied group on the autism spectrum (see here) with regards to the "overall burden of psychiatric comorbidities and emotion dysregulation" in those diagnosed with an autism spectrum disorder (ASD) "who had limited verbal abilities (i.e., few to no words used spontaneously)." Such work follows the recent publication of a paper by Ginny Russell and colleagues [2] who observed that those diagnosed with autism + intellectual (learning) disability were not exactly well-represented in the peer-reviewed autism research arena.

The Plesa Skwerer paper started with the observation that various psychiatric symptoms and conditions seem to be over-represented when it comes to a diagnosis of autism (see here for example). They noted that much of the research on this topic tended look at those who could be considered to be at the 'more able end' of the autism spectrum based on skills like self-report ability. They noted that "the population most severely affected, the ~30% of individuals with ASD who remain non- or minimally verbal beyond school-age" are not particularly well-represented in such comorbidity studies. The specific words they use are the "neglected “severe end of the spectrum”."

So: "Sixty-five participants diagnosed with ASD who had limited verbal abilities" were invited to participate in their study. They were already part of a larger research initiative. When I say 'invited' what I really meant is that: "Informed consent was obtained from the parents." All were diagnosed with an autism spectrum disorder (ASD) and the group was fairly equally split between children (5-11 years old) and young adults (12-18 years old). Parents/caregivers had a big role to play in the Plesa Skwerer study as we told that they were asked to complete various questionnaires about their children, including the Child and Adolescent Symptom Inventory (CASI-5) to "examine the frequency and severity of comorbid psychiatric symptoms." Completing the CASI-5 is no mean feat as per it having "173 items, which rate behaviors as occurring never, sometimes, often and very often."

Results: "All participants met cutoff criteria for at least one CASI-5 classification, and the number of categorical classifications parents endorsed ranged from 1 to 15, with a mode and a median of 6 classifications." This is an important detail. It tells us that, based on proxy reporting, every participant, child or young adult, presented with potentially clinically significant symptoms for one or more psychiatric/behavioural disorder. Some of the most popular labels that featured were things like vocal tics, phobia and the various types of attention-deficit hyperactivity disorder (ADHD). Further: "except oppositional defiant disorder and conduct disorder, more participants showed clinically concerning severity scores than expected based on general population norms." Authors concluded that: "The overall picture to emerge from this study is that minimally verbal children and adolescents present with extremely heterogeneous profiles of co-morbid psychopathology that are not easily predicted by autism symptom severity, intellectual disability, or limitations in communication."

There are some important caveats to the Plesa Skwerer findings, not least that proxy-reporting was the method used to ascertain the presence of not of such psychiatric comorbidity. This point tells us that a lot more needs to be done to help those who are minimally-verbal to be able to communicate much more readily. Yes, it's a tall order but where there's a will, there's a way. Also, researchers admit that they "excluded those with the most severe behavior problems including aggression, self-injury or non-compliance, and therefore our findings must be viewed in the context of whom our participants represent." Personally I see this is being a pretty issue across quite a lot of research on autism. Indeed, in light of legal rulings here in the UK (see here) talking about aggression 'not being a choice for children with autism' I daresay that by excluding those who present with such issues means that many, many children and adults on the autism spectrum are under-represented in autism research as it stands.

Still, the important message from Plesa Skwerer et al stands: those with autism who are described (defined?) as minimally-verbal seem to show a similar profile of psychiatric comorbidity and a "high degree of maladaptive behavior" as that identified in other parts/regions of the autism spectrum. Screening is implied and, so as to ensure that health inequalities are minimised, access to intervention is also indicated.

Bravo to the researchers who look at the under-studied parts of the autism spectrum.

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[1] Plesa Skwerer D. et al. Prevalence and Correlates of Psychiatric Symptoms in Minimally Verbal Children and Adolescents With ASD. Front Psychiatry. 2019 Feb 18;10:43.

[2] Russell G. et al. Selection bias on intellectual ability in autism research: a cross-sectional review and meta-analysis. Molecular Autism. 2019; 10: 9.

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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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Is 'escape' the most common function of challenging behaviours in autism?

'Challenging behaviour', 'disruptive behaviour' and 'behavioural crises' are terms that have been used to describe a range of behaviours "that are not culturally or socially acceptable, put the physical safety of the individual and/or others in jeopardy, affect learning, and/or limit access to community setting" in the context of autism and beyond.

A recent paper published by Esther Hong and colleagues [1] continued the research interest in this area (see here and see here) specifically focusing on gaining "perspective on what are the most commonly treated topographies of challenging behaviors" and "to identify the most commonly reported functions of those challenging behaviors." I'm assuming use of the word 'topography' in this context means 'profile' in terms of what types of challenging behaviours were noted.

Relying on behavioural data from over 3200 people diagnosed with an autism spectrum disorder (ASD) who were "receiving a minimum of 20 h of ABA [applied behavior analysis] treatment per month", researchers examined data on a range of behaviours falling into the category of 'challenging'. These included: "(a) aggression, (b) disruption, (c) elopement, (d) inappropriate sexual behavior, (e) lying, (f) noncompliance, (g) obsessive behaviors, (h) pica, (i) self-injurious behavior, (j) stealing, (k) stereotypy, (l) tantrums, and (m) teasing/bullying." Accepting that ABA in the context of autism is not everyone's cup of tea (despite some important data emerging [2]), one of the 'benefits' to this study at least, was that behaviour was recorded in some detail as a function of the implementation of ABA using something called The Skills™ database. This also allowed researchers to examine the potential 'function' of such behaviours too: "Skills™ also contains a field denoting the function of the behavior as identified by the supervising behavior analyst at the time of observation. Functions are classified as “attention,” “automatic,” “escape,” or “tangible.”."

Results: "The most commonly treated challenging behaviors were stereotypy, noncompliance, aggression, tantrums, SIB, elopement, disruption, and obsessive behaviors, respectively." Although 'stereotypy' ('the persistent repetition of an act) was the most frequently observed 'challenging behaviour', I'd personally be a little reluctant to put it into this category. I say this because there have been some reports suggesting that such a behaviour serves an important purpose in terms of being calming and aiding coping in certain situations for certain people. The majority of those challenging behaviours were coded most frequently in terms of 'escape' when it came to perceived function by the therapists who were doing the coding. Interestingly, and going back to my point about stereotypy, this behaviour was most frequently coded as 'automatic' alongside another behaviour that probably shouldn't be seen as a challenging behaviour: obsessive behaviours. Automatic, I assume, means just that: involuntary and well, automatic.

Alongside such information, authors also detail some nice Venn diagrams to illustrate how various categories of behaviours (and their specific manifestations) might meet and *correlate* based on their acquired data. Certainly, in the context of aggression and self-injurious behaviour (another important topic), there are some potentially important details to discern.

Although ABA still remains a point of contention among some, in the context of the Hong report, I can see how the quite detailed data collection on behaviour that it accrues holds some important information in the presence of some often, quite distressing behaviours. I'm happy to think that 'escape' could be a quite common function of various challenging behaviour(s), and moves to making 'some controlled escape' from particular situations might perhaps be useful to reduce the presence of such challenging behaviours. I know others will talk about 'demand avoidance' as being important too, but I'm cautious that this might not be an effective strategy in the longer term in helping people to build up 'resilience' to certain situations and environments.

But... I also think that 'escape' is not the whole story when it comes to challenging behaviours. I do still think that issues such as 'frustration' for example, can play a role. Also moving away from a purely 'behavioural' point of view, there is other evidence pointing to biology and physiology as being potentially involved in the presence of certain challenging behaviours. Fatigue? Yep, that's been mentioned (see here). Communication? Yep, that too (see here); particularly when verbal communication might be limited. And I'm also minded to mention that challenging behaviours can also be associated with things like the expression of pain (see here) that probably ties into the communication issue(s) too. In short, it's going to be complicated [3].

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[1] Hong E. et al. Topography and Function of Challenging Behaviors in Individuals with Autism Spectrum Disorder. Advances in Neurodevelopmental Disorders. 2018; 2: 206-215.

[2] Makrygianni MK. et al. The effectiveness of applied behavior analytic interventions for children with Autism Spectrum Disorder: A meta-analytic study. Research in Autism Spectrum Disorders. 2018; 51: 18-31.

[3] Rattaz C. et al. Challenging behaviours at early adulthood in autism spectrum disorders: topography, risk factors and evolution. J Intellect Disabil Res. 2018 May 24.

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The "experiences and perspectives of people who have severe autism and are minimally verbal"

I'm not going to formulate some sort of mammoth, long-read post on the paper by Christie Welch and colleagues [1] but I did want to bring their findings to your attention. My reasoning: the authors include a quite 'under-represented' group (see here) when it comes to the public view of the autism spectrum: those who "have severe autism and are minimally verbal."

Presenting the results of a qualitative study whereby "three memoirs written by youths who have severe autism and are minimally verbal were examined using inductive thematic analysis", authors observed several important themes emerging. Principal among them: "regarding the youths' concern that the way they are perceived from the outside does not match the people they are on the inside."

"These youths emphasize concepts of embodiment and physical control as central to their experiences of autism" said Welch et al, as the message seems to be that more should be done to 'tackle' these experiences and ensuring that sweeping generalisations about language use or non-use for example, are not seen as a proxy for cognitive and intellectual abilities. Just because someone cannot speak verbally, does not mean that they have nothing to say, and vice-verse.

I'm careful not to fall into the trap of 'autism severity' on the basis of the Welch findings, where terms like 'high' and 'low' functioning unduly simplify people in a binary fashion and seemingly without regard for the complexity of how autism affects various aspects of a person's life. I do however like the idea that more effort needs to go into things like the development of communication systems for those who are minimally verbal; both for clinical and research purposes but perhaps more importantly, day-to-day purposes, given also some catastrophic examples where communication issues have severely impacted on autistic lives (see here and see here).

And to the question of 'how common is 'minimally verbal' in the context of autism', well, another recent paper [2] has come up with an estimate: about a third...

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[1] Welch C. et al. Autism inside out: lessons from the memoirs of three minimally verbal youths. Disabil Rehabil. 2018 Apr 23:1-9.

[2] Bacon EC. et al. Naturalistic language sampling to characterize the language abilities of 3-year-olds with autism spectrum disorder. Autism. 2018 May 1:1362361318766241.

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Male and female autism might not be so dissimilar?

I read with some interest the paper by Joanna Mussey and colleagues [1] concluding that "either very small or no gender differences in age at diagnosis, intelligence quotient, cognitive profiles, or autism spectrum disorder symptom severity" were detected in their cohort of males (N=566) and females (N=113) diagnosed with an autism spectrum disorder (ASD).

Interest because, in these days of talk about a possible specific female autism phenotype emerging (see here) in light of potential sex differences in the presentation of autism (see here), one has to be quite careful not to over-generalise too much. In much the same way that terms such as 'male brains' and 'female brains' don't really do justice to the complexity of brain structure and function (see here), so one perhaps has to ensure that female autism and male autism presentation aren't offered in an 'either or' fashion despite the possibility of subtle differences in either the expression of symptoms or for example, differences in the presentation of things like over-represented comorbidity between the sexes/genders (see here).

Mussey et al reported that previous studies talking about autism 'hitting harder' when it comes to females in relation to the presence of intellectual (learning) disability and "more severe impairments" might not necessarily tell the full story. Based on the use of various instruments to to ascertain autistic traits and beyond, the authors noted some differences between the genders on measures of autism signs and symptoms but the precise significance was, in the most part, deemed "of minimal clinical significance." Such findings have also been noted in other recent research [2]. Another important message from the Mussey study results was that at least some of the instruments used to assess for autism or ASD might need some further investigation with sex/gender in mind.

Having said all that I do think there are still important issues that need to be further investigated when it comes to sex differences in autism presentation. The idea for example, of a 'female camouflage effect' (see here) still looms large in this area; where for example, verbal and non-verbal communication skills might serve to *mask* other important diagnostic features. I'm also [carefully] inclined to inquire whether gender identity over biological sex might play something of an important role in the male and female presentation of autism for some, in light of other important research (see here). There is a further scheme of work to be completed minus sweeping generalisations.

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[1] Mussey JL. et al. Are males and females with autism spectrum disorder more similar than we thought? Autism. 2017 Aug;21(6):733-737.

[2] Fulton AA. et al. Gender comparisons in children with ASD entering early intervention. Research in Developmental Disabilities. 2017. 68: 27-34.

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Living with severe autism: families share their experiences

Appreciating that the autism spectrum is truly a wide and heterogeneous one (or even several?), I'd like to direct your attention today to the findings reported by Jocelyn Bessette Gorlin and colleagues [1] on the topic of "the experiences of families living with a child with severe autism."

In particular, I'd like to highlight the six areas that emerged from the "29 interviews with 22 participants from 11 families" related to family experiences and how, minus any sweeping generalisations, moves to tackle some of the issues raised in these areas might do quite a bit for the quality of life of everyone concerned.

So, the six areas:

(1) "families experienced autism as mysterious and complex because it is an invisible and unpredictable condition with diagnostic challenges." 'Mysterious' and 'complex' are words that have always followed the label of autism and as things stand at the moment, are unlikely to change in the coming years. Sure we know a little more about autism than we did a few years ago (i.e. the 'autisms', lots of comorbidity is potentially over-represented, etc) but in terms of longitudinal course and those important discussions (and actions!) about how to maximise quality of life 'for individuals' (the stress being on 'individuals'), concrete strategies are still few and far between. Diagnostic challenges? Well, certainly there are challenges to 'getting a diagnosis' in quite a few quarters still (see here for example) which is probably just as much down to money and resources as anything else. And just before you suggest that parents might not be sensitive to early issues potentially linked to autism, you're probably wrong (see here).

(2) "families described severe autism behaviors that often caused self-injury, harm to others and damaged homes." This is the side of autism that people generally don't talk about as much as they should. Acknowledging that extremes like self-injurious behaviour (SIB) aren't exactly great dinner table conversation, such patterns of behaviour are often the ones that cause the most distress both to the person themselves and their family/loved ones around them. I don't think I can stress enough how vital it is that SIB is further (a) understood (in terms of potential meaning) and (b) acted upon, particularly where a person is at high risk of hurting themselves or others (see here for example). I might also add that important issues such as wandering (elopement) in relation to autism should also be given due consideration given its potential inclusion under the category of 'challenging behaviour'.

(3) "profound communication deficits resulted in isolation between the family and child." I think this area is pretty self-explanatory. We can talk about the emerging role for assistive technologies as part of a package of interventions to aid this issue, but a lot more needs to be done in this area and indeed, is being done. And yes, this probably includes discussions around a re-framing of the communicative relationship between child/adult and family.

(4) "families discussed the unrelenting stress from lack of sleep, managing the child's developmental delays, coordinating and financing services, and concern for the child's future." I'm a big fan of caring for the carer(s) when it comes to the quality of life for families touched by autism (see here for example). To mention words like 'parenting stress' when it comes to autism shouldn't be a taboo subject (see here) the same as it shouldn't be when talking about parenting in general. There may be many ways that professionals can intervene in this respect (see here). Insofar as parents/families looking to the future of their children/loved one and tackling the sentiments of 'why I can never die' (see here), well, this is where society also needs to step up both in terms of future planning and delivery of services appropriate, welcoming and responsive to the needs of individuals. And some parents do have to do it all themselves...

(5) "families described consequences of isolation from friends, school, the public, and health providers." Although not everyone's experience, another uncomfortable issue associated with parenting a child with severe autism can be how isolating it is. It's little surprise that in the age of social media, this medium is being used to enable families to be/feel that little less isolated from the outside world. Aside from making more support agencies 'available' to families, there are a few other suggestions that might make things a little less isolating (see here).

(6) "families portrayed their need for compassionate support and formed 'hybrid families' (nuclear, extended families and friends) to gain support." See point 5. I'd also argue that the formation of those 'hybrid families' perhaps overlap with those 'kingdoms of autism' talked about a few years back. Indeed, I get the impression that talk about families and kingdoms intersecting with how wide and heterogeneous the autism spectrum is, might be one reason why there are so many varied opinions about autism from all sorts of angles...

These are all important points. Yes, I know that their relevance is going to be variably applicable to those (a) on the autism spectrum or (b) falling into that 'severe autism' bracket, but I don't doubt the lessons that could be learned would benefit quite a few people beyond the intended audience. As the authors note, their study results "could influence health care policies to improve the care for families caring for children with severe autism."

Great words indeed, but how to put words into 'life-changing' practice? Well, for a start understand that the autism spectrum is indeed a wide and heterogeneous one...

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[1] Bessette Gorlin J. et al. Severe Childhood Autism: The Family Lived Experience. J Pediatr Nurs. 2016 Oct 6. pii: S0882-5963(16)30279-2.

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Bessette Gorlin J, McAlpine CP, Garwick A, & Wieling E (2016). Severe Childhood Autism: The Family Lived Experience. Journal of pediatric nursing PMID: 27720503

Autism and the [different] expression of pain

Two papers provide some brief discussion today. The first by Janice Goldschmidt [1] titled: 'What Happened to Paul? Manifestation of Abnormal Pain Response for Individuals With Autism Spectrum Disorder' provides an account of a young man with autism who during a "pilot nutrition intervention designed to teach cooking skills to young adults with autism spectrum disorder (ASD)" fell quite seriously. We are told that: "After his accident, which resulted in broken and dislocated bones in his ankle, his demeanor was dramatically altered, program gains were lost, and staff noted the appearance of many new challenging behaviors."

The second paper by Andrea Courtemanche and colleagues [2] continues a theme looking to "measure expressions of pain among young children being evaluated for autism and other neurodevelopmental disabilities." Authors concluded that their results among other things "support that individuals with self-injury may have enhanced expressions of pain."

The commonality in these papers, aside from looking at pain, is the idea that autism might 'lead' to a "blunted pain response" is not necessarily one that fits uniformly across the autism spectrum. To quote: "The consequence is not a reduction in pain sensation, but a different expression of pain, determined by that individual's particular communicative, cognitive, or physiological challenges." Of course science already knows much of what is being said here as I've covered topics such as the fact that yes, people on the autism spectrum do get headaches (see here) and how pain may be quite a significant predictor of things like sleeping problems in relation to autism (see here). I might add that some of the source of that pain could also be linked to some of the over-represented comorbidity that can/does follow a diagnosis of autism (see here) (and hence should be perfectly treatable).

The discussions about self-injury being potentially linked to the expression of pain also ties into related topics covered on this blog insofar as such 'challenging behaviours' normally having some reasoning behind them (see here). Self-injurious behaviour (SIB) can often be a harrowing thing to see (no parent or sibling wants to see a loved one hurting themselves) but with the right investigative approach can sometimes provide important information about a person and their wants and wishes (see here). I don't say that to somehow encourage SIB nor to lessen the impact that biology can have on its expression; merely that some other person perspective-taking should accompany analysis of any behaviours that challenge as and when they present (before reaching for the anti-challenging behaviour meds) as well as making moves towards breaking down things like communication barriers (see here) that potentially contribute to such behavioural manifestations.

Pain is very much part of the human experience. Whilst efforts should indeed continue to ensure that everyone lives a life as pain-free as possible, the importance of short-term pain or rather the importance of short-term pain expression should not be under-estimated. Likewise, sweeping generalisations about altered pain sensitivity applying across the autism spectrum need not necessarily apply. I'm also happy to report that pain is a topic being discussed at IMFAR today...

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[1] Goldschmidt J. What Happened to Paul? Manifestation of Abnormal Pain Response for Individuals With Autism Spectrum Disorder. Qual Health Res. 2016 Apr 26. pii: 1049732316644415.

[2] Courtemanche AB. et al. The Relationship Between Pain, Self-Injury, and Other Problem Behaviors in Young Children With Autism and Other Developmental Disabilities. Am J Intellect Dev Disabil. 2016 May;121(3):194-203.

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Goldschmidt J (2016). What Happened to Paul? Manifestation of Abnormal Pain Response for Individuals With Autism Spectrum Disorder. Qualitative health research PMID: 27117957




Courtemanche AB, Black WR, & Reese RM (2016). The Relationship Between Pain, Self-Injury, and Other Problem Behaviors in Young Children With Autism and Other Developmental Disabilities. American journal on intellectual and developmental disabilities, 121 (3), 194-203 PMID: 27119211

Long terms effects of communication by gesture and autism: a case report

As per previous entries on this blog, I'm not at all adverse to the idea that case reports (the so-called N=1) can offer some important insights into a heterogeneous (dare I say 'plural') condition like autism. Today, I'm once again heading down this route as I bring to your attention the letter from Webster and colleagues [1] talking about a 40 year follow-up note "About a Boy with Autism Taught to Communicate by Gestures when Aged Six."

Harking back to a paper published by some of the authors in 1973 [2] (published in the same journal albeit under a different title name), Webster et al provide some important details on how Geoff, a then 6-year old boy, was taught "a sign-language program" and how "at the time, it seemed to help Geoff and many other children." Fast forward some 40+ years and the authors note that things have changed but at the same time remained pretty much the same for Geoff. So: "Geoff has hung onto the signs taught to him early on" but also: "Geoff now “speaks” as he signs some words. This speech is easier to understand if you see him every day than if you see him only now and then." Indeed his vocabulary, whilst perhaps limited by other standards, does include many important words, mostly signed but some either said verbally or paired verbally with signing. Outside of things like food preferences, I was particularly happy to see that various emotions and states are represented in his vocabulary; never underestimate the power that being able to tell someone that you are 'happy' or 'angry' can bring to a person.

"His communications, both verbal and gestural, are constantly evolving to help him to express his wishes, and he seems very excited when he has made clear his needs or wants and we have understood them." What that sentence tells us is that communication is both a vital bridge and something that should be constantly 'worked on' when it comes to autism [3]. In these days where quite a lot of focus has turned towards the usefulness of early intervention for autism (see here for example), the message that learning is a lifelong thing can often get lost in the noise. I might add that said learning might be made a little easier by the rapid rise in technology [4].

Finally, I think it is important to draw your attention to another aspect of the Webster letter in terms of the use of residential and supported living arrangements and the autism spectrum. In line with the idea that the autism spectrum is truly wide and heterogeneous is the reality that for quite a few people, lifetime residential placement and care are an important part of their lives. Geoff, we are told "adjusted well to the residential setting" and continues to enjoy life in that setting. The authors acknowledge that despite their success in teaching sign to people like Geoff: "we tended to underestimate the long-term services that many of these children, as they grow into adolescence and adulthood, do actually require." I daresay that those sentiments ring as true today as they did 40 years ago.

To close, yet another DC comics film coming soon with an excellent trailer soundtrack...

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[1] Webster CD. et al. Lessons that Linger: A 40-Year Follow-Along Note About a Boy with Autism Taught to Communicate by Gestures when Aged Six. J Autism Dev Disord. 2016. March 28.

[2] Webster CD. et al. Communicating with an autistic boy by gestures. J Autism Child Schizophr. 1973 Oct-Dec;3(4):337-46.

[3] Mulhern T. et al. A systematic review and evaluation of procedures for the induction of speech among persons with developmental disabilities. Dev Neurorehabil. 2016 Apr 8:1-21.

[4] Lorah ER. et al. A Systematic Review of Tablet Computers and Portable Media Players as Speech Generating Devices for Individuals with Autism Spectrum Disorder. J Autism Dev Disord. 2015 Dec;45(12):3792-804.

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Webster, C., Fruchter, D., Dean, J., Konstantareas, M., & Sloman, L. (2016). Lessons that Linger: A 40-Year Follow-Along Note About a Boy with Autism Taught to Communicate by Gestures when Aged Six Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-016-2773-x

Toy preference and parent-infant communication?

I was intrigued to read the findings reported by Anna Sosa [1] who reported that "play with books and traditional toys was superior to play with electronic toys in promoting high-quality communication."

This was a study looking at communication between parents and their infants aged 10-16 months old as a function of toy type, where electronic toys - "3 battery-operated toys with buttons and switches that can be manipulated to produce lights, words, phrases, and songs" - were pitted against 'traditional' toys - "3 nonelectronic toys that also have the potential to teach animal names, colors, and shapes." Those electronic toys were also chosen on the premise that "they are marketed as educational toys that promote language development for children in this age range and are advertised as teaching animal names, colors, and shapes."

Describing results from 26 parent-infant dyads whereby pairs "engaged in 2 15-minute play sessions per toy set over a 3-day period" using electronic toys, non-electronic toys and also books (y'know those paper things), various outcomes were measured including child vocalisations, adult words and conversational turns. As per the opening sentence, toy type did seem to affect communication between parent and child. So: "Play with electronic toys is associated with decreased quantity and quality of language input compared with play with books or traditional toys." The author goes as far to say that set within other research in this area: "both play with traditional toys and book reading can be promoted as language-facilitating activities while play with electronic toys should be discouraged."

Being careful not to fall into any sweeping generalisations about how technology is 'all bad' for child development and beyond, bearing in mind where such discussions have previously led, I have to say that it there may be some important lessons to learn from the Sosa study results. That early years communication between parent and child is increasingly being realised to be pretty important is one part of discussions (see here for more information on the '30 million word gap' for example). That parents are also literally bombarded these days with various edu-toys and other gadgets often making some rather big claims is another aspect. The Sosa results hint that there might be a happy medium to strike between the old and the new when it comes to early play and communication (including reading) and that we should as parents, perhaps be mindful that electronic toys with their lights, sounds and various educational claims might not necessarily trump something a little less flashy. Similar sentiments might also apply to more pathological states too [2].

Music: William Shatner sings er... well, not for the easily offended.

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[1] Sosa AV. Association of the Type of Toy Used During Play With the Quantity and Quality of Parent-Infant Communication. JAMA Pediatrics. 2015. Dec 23.

[2] Christakis DA. Rethinking Attention-Deficit/Hyperactivity Disorder. JAMA Pediatr. 2016 Jan 4:1-2.

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Sosa AV (2015). Association of the Type of Toy Used During Play With the Quantity and Quality of Parent-Infant Communication JAMA Pediatrics : 10.1001/jamapediatrics.2015.3753

Don't give up

Appreciating that the subject matter of today's post might not necessarily align with the season that is upon us, I wanted to bring to your attention the paper by Michael Westerlund and colleagues [1] (open-access) and some rather disturbing discussions related to a young man who "decided to hang himself and to display the suicidal act" on an internet forum.

Published in the British Journal of Psychiatry, the paper set about examining how "participants on an internet forum act and react faced with suicidal communication and while witnessing the suicidal act." This was done via "a qualitative investigation of the messages that were posted before the TS's [thread starter] suicide and a combined qualitative–quantitative analysis of the messages posted during and after the suicide." A total of 30 posts before the suicide and 608 posts during and after the suicide were examined.

Several themes are discussed in the paper in terms of the authenticity of the discussions, attitudes towards the suicide, opportunities for prevention and: "Responsibility for the TS's suicide." There are some, quite frankly, awful comments discussed in this paper that I won't be repeating on this blog. Importantly however, the authors highlight a few lessons that might be learned from such events based on the fact that "the internet has developed as the main channel for suicide communication" and the possibility that lives could be potentially saved with the right tools for identifying and responding to "individuals who communicate suicide intentions on different forums on the internet." As per another quote from the paper: "the internet can be a facilitator of the suicidal process, but it can also be a venue where opportunities for prevention of suicide loom large."

Although not the main topic of this blog, suicide is something that has cropped up before (see here and see here for example). It is a complicated issue to talk about given that not only are there multiple pathways that bring someone to the position of contemplating taking their own life but also that attempted and completed acts can and do profoundly affect the people around the person in question.

The idea that the internet can be a source of positive information when it comes to reducing the risk of suicide is evident in the peer-reviewed domain [2]. Sueki & Ito [3] discussed the idea of on-line gatekeeping to prevent suicide "by placing advertisements on web search pages to promote consultation service use among Internet users with suicidal ideation." Social media has also been discussed as a good tool to deliver "a range of suicide prevention activities" [4]. The trick, it seems, is getting the relevant information and expertise to those who are currently vulnerable whilst at the same time avoiding issues like possible contagion. I might add that whilst the internet might have a significant role to play in suicide, it does not and should not represent the sum total of discussions about suicide and any potentially related issues (see here).

Bearing in mind the caveats of this blog about not giving medical or clinical advice, I did wonder if it might be useful to link to something like this page containing quite a few points and further links if and when discussions about suicide are raised. For anyone here in Blighty in need, details for the Samaritans can also be found here.

A song to close from Kate Bush and Peter Gabriel.

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[1] Westerlund M. et al. Case study of posts before and after a suicide on a Swedish internet forum. Br J Psychiatry. 2015; 207: 476-482.

[2] Robert A. et al. Internet use and suicidal behaviors: internet as a threat or opportunity? Telemed J E Health. 2015 Apr;21(4):306-11.

[3] Sueki H. & Ito J. Suicide Prevention Through Online Gatekeeping Using Search Advertising Techniques. Crisis. 2015 Jul;36(4):267-73.

[4] Robinson J. et al. Social media and suicide prevention: findings from a stakeholder survey. Shanghai Arch Psychiatry. 2015 Feb 25;27(1):27-35.

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Westerlund, M., Hadlaczky, G., & Wasserman, D. (2015). Case study of posts before and after a suicide on a Swedish internet forum The British Journal of Psychiatry, 207 (6), 476-482 DOI: 10.1192/bjp.bp.114.154484

Karate and autism continued: Kiai!

Gichin Funakoshi

"We concluded that teaching Karate techniques to children with ASD [autism spectrum disorder] leads to significant reduction in their communication deficit."

That was the [research] bottom line from Fatimah Bahrami and colleagues [1] continuing their very interesting voyage into looking at how aspects of the martial arts might well benefit some people on the autism spectrum. I mention the word 'continuing' because this authorship group from Iran have some research form in this area previously covered on this blog (see here).

In their latest paper, the authors took to looking at how another core area of autism - communication issues - may also be impacted by kata training (that is, the various structured movements against an invisible opponent(s) practised as part of karate). This time as previously, the kata in question was Heian Shodan, the kata normally used to grade transition from orange belt to red belt in Shotokan karate. Helpfully, the authors also provide their own video of the kata used as supplementary material to their paper.

Their results, based on a similarly small group of children with autism assigned to kata training (n=15) or a control (n=15) as in previous papers, suggested that after 14 weeks of training the "Exercise group showed significant reduction in communication deficit compared to control group." Such gains seemingly persisted at 1 month follow-up too.

Appreciating that there is quite a bit more science to do in this area, including that taking on board how issues with simulative skills with autism in mind [2] might interact with the practise of martial arts training (being careful about over-generalisation [3]), I continue to find this an area of real interest. Associated research hinting that regular exercise and motor skills training might benefit quite a few aspects of autism (see here) emphasises how something like practising kata could represent a 'good fit' for quite a few children and adults diagnosed on the autism spectrum. This alongside the wider potential benefits to be had from martial arts training (see here), bearing in mind aspects like kumite might not be to everyone's taste. Dare I also even start to talk about the more 'spiritual' side of some of the martial arts (Zen played a role apparently) intersecting with some interesting case reports with autism in mind (see here)? (being careful not to fall into the bull**** trap [4]).

To close, I note that one of the national governing bodies for the martial arts here in Blighty has already come around to the idea of further opening up the sport to those on the autism spectrum.

Why not give it a try? Kiai!

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[1] Bahrami F. et al. The Effect of Karate Techniques Training on Communication Deficit of Children with Autism Spectrum Disorders. J Autism Dev Disord. 2015 Nov 17.

[2] Conson M. et al. Body Constraints on Motor Simulation in Autism Spectrum Disorders. J Autism Dev Disord. 2015 Nov 16.

[3] Torres EB. Atypical signatures of motor variability found in an individual with ASD. Neurocase. 2013 Apr;19(2):150-65.

[4] Pennycook G. et al. On the reception and detection of pseudo-profound bullshit. Judgment and Decision Making. 2015; 10: 549-563.

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Bahrami F, Movahedi A, Marandi SM, & Sorensen C (2015). The Effect of Karate Techniques Training on Communication Deficit of Children with Autism Spectrum Disorders. Journal of autism and developmental disorders PMID: 26577688

Theatre-based intervention for autism?

"All the world's a stage, And all the men and women merely players."

So said Bill (to his friends) Shakespeare in the comedy 'As You Like It'. Personally, I think William Shakespeare was spot on with that comment, and how we all spend our lives 'acting' out various roles; fine tuning our performance depending on the context and environment we find ourselves in.

With acting and the theatre specifically in mind, I'm talking today about the paper from Blythe Corbett and colleagues [1] reporting results following the use of "a peer-mediated, theatre-based intervention on social competence in participants with autism spectrum disorder (ASD)." Using a randomised - "assigned to the treatment... or a wait-list control group" - study design, researchers explored how a 10-week theatre-based intervention might affect various aspects of their cohort diagnosed with autism. It did indeed seem to have some effects in relation to social ability and in some cases, these effects were sustained, at least in the area of communicative abilities. I might add that some of this authorship group have some previous research form in this area [2] including on some previous description on the use of the SENSE theatre intervention [3].

On the face of it, drama or theatre-based intervention potentially seems like quite a good idea when applied to autism. Whilst trying to avoid sweeping generalisations about all autism or all performers, luvvies - a very melodramatic stereotype of some theatre types - are usually quite an outgoing group on the outside as part of their job in terms of the social requirements of performances and overcoming the stresses and strains of playing live to a paying audience day after day. Most theatrical performances involve public speaking and most involve the adoption of a persona or character typically different from that of the actress/actor. You can perhaps see how some of the qualities that coincide with the adoption of the theatrical profession may well 'enable' some people on the autism spectrum to navigate the complex social world a little easier; or at the very least, provide a safe training forum for practising such skills. That and providing an arena where children and adults on the autism spectrum can become a part of something and perhaps boost important aspects such as life satisfaction [4] (see here too) and I'm finding it difficult to name too many negatives for such a proposed intervention.

To close, having watched a great theatre production of The Shawshank Redemption recently, some opera for you...

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[1] Corbett BA. et al. Improvement in Social Competence Using a Randomized Trial of a Theatre Intervention for Children with Autism Spectrum Disorder. J Autism Dev Disord. 2015 Sep 29.

[2] Corbett BA. et al. Brief Report: Theatre as Therapy for Children with Autism Spectrum Disorder. Journal of Autism and Developmental Disorders. 2011;41(4):505-511.

[3] Corbett BA. et al. Peer-Mediated Theatrical Engagement for Improving Reciprocal Social Interaction in Autism Spectrum Disorder. Frontiers in Pediatrics. 2014;2:110.

[4] Schmidt L. et al. Psychosocial Functioning and Life Satisfaction in Adults With Autism Spectrum Disorder Without Intellectual Impairment. J Clin Psychol. 2015 Sep 25.

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Corbett BA, Key AP, Qualls L, Fecteau S, Newsom C, Coke C, & Yoder P (2015). Improvement in Social Competence Using a Randomized Trial of a Theatre Intervention for Children with Autism Spectrum Disorder. Journal of autism and developmental disorders PMID: 26419766

Anti-NMDA-receptor encephalitis and autism: research ascendancy

The paper by Reza Kiani and colleagues [1] (open-access available here) detailing the presence of anti-N-methyl-d-aspartate (NMDA) receptor encephalitis in two people "with autism and intellectual disability presenting with neuropsychiatric symptoms of catatonia and neuroleptic malignant syndrome" caught my eye recently.

Having previously talked about anti-NMDA-receptor encephalitis and autism in a previous blog post (see here) back in 2013 with the emphasis on a possible link to 'autistic regression', I've been intrigued by the rise and rise of peer-reviewed material on this subject in the intervening years. Subsequent descriptions such as the one from González-Toro and colleagues [2] again talking about children diagnosed with anti-NMDA receptor encephalitis after suffering a "regression of previously acquired abilities that developed into autism" further adds to my interest in this potentially important connection. That also there may be several roads leading to a diagnosis of autism is also an important take-away point from such work.

Kiani et al continue with the idea that there may be an "aetiological role of the immune system in the pathogenesis of various psychiatric disorders" on the back of various studies looking at anti-NMDA receptor encephalitis. On this occasion, they detail two case reports where autism and learning (intellectual) disability were already diagnosed but deteriorations in behaviour were noted. The first case report of a woman in her early-30s who "presented with social withdrawal and a persistently low mood" that subsequently led into "objective evidence of hallucinations" illustrates how various tests followed various symptoms ultimately leading the authors to suspect anti-NMDA receptor encephalitis. Importantly, they detail how psychotropic medication was the first choice of intervention and how, only after this 'failed', did they look for anti-NMDA-receptor antibodies. Of importance to the female presentation of anti-NMDA receptor encephalitis were the further investigations looking for any signs of "an underlying tumour, particularly an ovarian teratoma" given previous suggestions of a possible link [3].

The second case report focused on a middle-aged man "with moderate intellectual disability, autism and a history of affective psychosis in remission." Again, antipsychotic medication was the first thing to be reached for when "his condition deteriorated and he displayed aggressive outbursts and insomnia." Alas, this did not improve his state and neuroleptic malignant syndrome (NMS) was eventually diagnosed as a result of such intervention. Anti-NMDA-receptor encephalitis was finally considered when "further investigations revealed positive anti-NMDA-receptor antibodies."

Of note for both these individuals was the effect of treating anti-NMDA receptor encephalitis. This involved the use of methylprednisolone, an anti-inflammatory compound, normally administered for various autoimmune conditions. Interestingly, as a corticosteroid, prednisolone (the un-methylated version of methylprednisolone) has been talked about with 'regressive autism' in mind before in the peer-reviewed literature (see here). Kiani et al note that delivery of methylprednisolone was associated with a gradual recovery in behavioural symptoms "with no evidence of psychosis or cognitive deficit."

"In both patients the diagnosis was made with delay owing to the complexity of their presentation." This is an important sentence from Kiani and colleagues. Not only in respect to the various behavioural and somatic issues that were present (including comorbid diagnoses) but also insofar as issues with communication for example. I've talked about similar things before on this blog (see here). Further, the authors reiterate "the complex presentation of anti-NMDA-receptor encephalitis in... patients with intellectual disability and autism" and how further research is required to see whether diagnostic conditions such autism and/or learning disability "are more prone to develop this type of encephalitis or have a worse prognosis in comparison with the rest of the population." I struggle to disagree with such sentiments.

Music: Hozier - Take Me To Church.

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[1] Kiani R. et al. Anti-NMDA-receptor encephalitis presenting with catatonia and neuroleptic malignant syndrome in patients with intellectual disability and autism. BJPsych Bull. 2015 Feb;39(1):32-5.

[2] González-Toro MC. et al. Anti-NMDA receptor encephalitis: two paediatric cases. Rev Neurol. 2013 Dec 1;57(11):504-8.

[3] Dabner M. et al. Ovarian teratoma associated with anti-N-methyl D-aspartate receptor encephalitis: a report of 5 cases documenting prominent intratumoral lymphoid infiltrates. Int J Gynecol Pathol. 2012 Sep;31(5):429-37.

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Kiani R, Lawden M, Eames P, Critchley P, Bhaumik S, Odedra S, & Gumber R (2015). Anti-NMDA-receptor encephalitis presenting with catatonia and neuroleptic malignant syndrome in patients with intellectual disability and autism. BJPsych bulletin, 39 (1), 32-5 PMID: 26191422

Screening for autism in young children: 6 questions to ask

Question 1: Does your child ever point with their index finger to ask for something?
Question 2: Is your child able to imitate you or your actions, for example if you pull a face?
Question 3: Does your child ever use pretend play, for example to talk on a phone or take care of a doll?
Question 4: Does your child look at something across a room when you point to it?
Question 5: Does your child understand what people say?
Question 6: Does your child ever bring an object to you to show you something?

The paper from Yoko Kamio and colleagues [1] (open-access) suggests that these 6 questions taken from the 23-item M-CHAT Japanese version (JV) might have the methodological strength to screen for possible autism in toddlers -- at least in Japan. M-CHAT by the way, is one of the instruments of choice when it comes to screening for possible autism and has seen some developments in recent times (see here).

Based on data derived from "two prospective community cohorts in Japan, Fukuoka (cohort 1) and Tokyo (cohort 2)" cumulatively including some 2500 children "who received health check-ups when aged 18 months", researchers analysed data using a model of discriminant function analysis based on groupings of those who were eventually diagnosed with an autism spectrum disorder (ASD) compared with those who weren't. They concluded that their study "identified a highly discriminative 6-item set from the 23-item M-CHAT-JV and demonstrated its reliability and validity with cohort data from 2 geographically different regions in Japan." The results, I might add, were not 100% reliable in terms of the 6-item screening method used, but this is real life and, as far as I am aware, we don't have a perfectly reliable autism screen at the moment.

These are interesting results as a function of the important autism science on the best way to 'red flag' autism in its very earliest days (see here). Indeed, the focus on social-communicative functions (including pointing) follows a trend in the peer-reviewed research literature in this area, as something to focus on when it comes to early screening for autism. I say this bearing in mind that within the very heterogeneous label of autism, there are cases of regression into autism at a time later than 18 months.

"Considering the tight time constraints in primary care settings, a brief screening tool might be helpful in facilitating the integration of autism-specific screening within routine general developmental screening." These are noble sentiments from the authors and kinda accords with some increasing moves in autism practice to make things more streamlined in these resource-austere times that we live in (see here). Obviously we await further research in this area on whether the Kamio findings cross cultures and geographies with other infant cohorts or not. If they do however, combined with the rise and rise of telemedicine for example, the days of the [often] long and expensive autism screening and diagnosis process might be numbered. Oh, and screening might just start to be interactive too [2] (see here for more information on the RITA-T).

Music: iLL BLU - Lonely People ft. James Morrison.

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[1] Kamio Y. et al. Brief Report: Best Discriminators for Identifying Children with Autism Spectrum Disorder at an 18-Month Health Check-Up in Japan. Journal of Autism and Developmental Disorders. 2015. July 19.

[2] Choueiri R. & Wagner S. A New Interactive Screening Test for Autism Spectrum Disorders in Toddlers. J Pediatr. 2015 Aug;167(2):460-466.

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Kamio, Y., Haraguchi, H., Stickley, A., Ogino, K., Ishitobi, M., & Takahashi, H. (2015). Brief Report: Best Discriminators for Identifying Children with Autism Spectrum Disorder at an 18-Month Health Check-Up in Japan Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-015-2527-1