Saturday, 21 January 2017

"no evidence that the probiotic formulation is effective in treating low mood"

I'm a great believer in balance when it comes to this blog and its content. As enthusiastic as I might be about a particular topic or topics, I don't want to lose sight of the fact that peer-reviewed science is a messy business and often filled with contrary findings.

With 'contrary' in mind, I want to talk today about a paper by Amy Romijn and colleagues [1] detailing the results of a double-blind, randomised, placebo-controlled trial of a probiotic mix which contained "freeze-dried L. helveticus R0052 (strain I-1722 in the French National Collection of Cultures of Microorganisms [CNCM], Institut Pasteur, Paris, France) and B. longum R0175 (CNCM strain I-3470) bacteria at a dosage of three billion colony-forming units (⩾3 × 109 CFU) per 1.5 g sachet" with a sample of participants selected for 'low mood'. Probiotics, just in case you don't know, are those various live bacteria and yeasts that are supposed to confer some health benefit.

The reason for this study? Well, as the authors note, the specific probiotics under study were "previously found to improve emotional behaviour in animals and psychological outcomes and humans" as per other findings [2]. So with [prospective] trial registration (see here) in hand, researchers set out to look at what 8 weeks worth of probiotics might do for 'low mood' and other psychological parameters when pitted against a placebo formulation (that contained only the excipients included in the probiotic formulation). Blood samples were also provided by participants at baseline (before intervention) and at 8 weeks post-intervention "to measure levels of high-sensitivity C-reactive protein (hsCRP), IL-1β, IL-6, TNF-α, vitamin D and BDNF."

Results: "Intent-to-treat analysis (n = 79) showed no significant group differences on any outcome measure." The scores for the groups - probiotic (n=40) & placebo (n=39) - did not seem to differ significantly on any of the measures used during the trial. Indeed, when taking into account individual scores on the primary outcome measures called the Montgomery–Åsberg Depression Rating Scale (MADRS) - something used to measure "the severity of depressive episodes" - the results actually (non-significantly) seemed to favour the placebo in terms of those who "showed a ⩾60% change on the MADRS (responders)."

Insofar as adverse effects, well taking this probiotic probably won't do any harm if we rely on the Romijn findings, as authors describe "three serious adverse events over the course of the trial, all of which were suicide attempts by one participant from the placebo group. There were no serious adverse events in the probiotic group."

But all was not completely negative when it came to the trial as a little gem was potentially uncovered: "Among those randomized to the probiotic group, those who had high vitamin D at baseline showed greater improvement in mood and functioning than those who had low vitamin D at baseline." Without trying to make mountains out of molehills, the authors speculate that: "the vitamin D status of the host could have an effect on the relationship between the gut microbiota and the immune system: low vitamin D could limit response to probiotic treatment as any changes to the microbiome composition would not necessarily be translated to the immune system." A rather interesting sentiment given the increasingly vocal link between vitamin D and depression for example in the research literature (see here).

These results do represent a bit of a set-back for the idea of psychobiotics [3] but I'm not ready to poo-poo the whole area just yet. Among the various caveats raised by the study authors (samples size, length of intervention, etc) it is possible that 'low mood' over and above something a little more clinically 'transforming', might not be a suitable target for such intervention (indeed, other research might also be relevant [4]) despite the fact that other research on subclinical psychological symptoms have been seemingly affected by probiotic administration (see here). The specific formulation used might also be a factor as the authors quite correctly suggest that: "It is important that the results of the current study are not generalized to all potential probiotic strains." Baby and bathwater eh?

But these results stand, and given some important names on the authorship list (see here), this is one study that cannot and should not be just swept under the scientific carpet...

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[1] Romijn AR. et al. A double-blind, randomized, placebo-controlled trial of Lactobacillus helveticus and Bifidobacterium longum for the symptoms of depression. Aust N Z J Psychiatry. 2017 Jan 1:4867416686694.

[2] Messaoudi M. et al. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br J Nutr. 2011 Mar;105(5):755-64.

[3] Dinan TG. et al. Psychobiotics: a novel class of psychotropic. Biol Psychiatry. 2013 Nov 15;74(10):720-6.

[4] Kleiman SC. et al. The Gut-Brain Axis in Healthy Females: Lack of Significant Association between Microbial Composition and Diversity with Psychiatric Measures. PLoS One. 2017 Jan 19;12(1):e0170208.

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ResearchBlogging.org Romijn AR, Rucklidge JJ, Kuijer RG, & Frampton C (2017). A double-blind, randomized, placebo-controlled trial of Lactobacillus helveticus and Bifidobacterium longum for the symptoms of depression. The Australian and New Zealand journal of psychiatry PMID: 28068788

Friday, 20 January 2017

Diagnosing ME/CFS the machine learning way?

In today's post I want to draw your attention to the findings reported by Diana Ohanian and colleagues [1] (open-access available here) talking about "the use of machine learning to further explore the unique nature"of various conditions/labels including those typically headed under the label of chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME).

Including one 'Jason LA' on the authorship list, researchers set about looking at "what key symptoms differentiate Myalgic Encephalomyelitis (ME) and Chronic Fatigue syndrome (CFS) from Multiple Sclerosis (MS)."You may be wondering why such a comparative study was undertaken but a quick trawl of the research literature reveals that these different clinical labels may well have some important commonalities [2].

This was an internet-based research project whereby "106 people with MS and 354 people with ME or CFS fully completed the [DePaul Symptom Questionnairequestionnaire" and based on the responses received "decision trees were used to determine what symptoms differentiated those with MS from those with ME or CFS." Decision trees, as the name suggests, is a statistical technique where binary (0 or 1, no or yes) choices make branches and: "At each branch the computer decides what symptom would best predict classifications, in this case whether someone has MS or ME or CFS." This process continues and continues through the different levels of branches "until the tree reaches a balance between classification accuracy and generalizing to new data." Such a machine learning tool has been previously discussed quite recently on this blog (see here).

Results: "Five symptoms best differentiated the groups." These were: flu-like symptoms, tender lymph nodes, alcohol intolerance, inability to tolerate upright position and next day soreness after strenuous activity. The first two symptoms - flu-like symptoms and tender lymph nodes - were pretty good by themselves at correctly categorising MS or CFS/ME (~80% correct). Indeed, these seemed to be the core differentiators that were examined and as the authors note: "The most important two symptoms that differentiated MS versus ME or CFS existed within the immune domain."

Of course further investigations are warranted to potentially build on these findings. One has however to be slightly cautious about the use of the internet and social media when undertaking such research, especially when very little information about the formal diagnoses of participants is included in the current paper. This is a particular issue when it comes to CFS/ME and the various ways that it can be defined and diagnosed [3].

Still, I can't quibble with the continued rise and rise of machine learning being applied to many areas of medicine, and not before time that it starts to reach ME/CFS. And just before I go, it appears that the research team at DePaul University have been quite busy...

To close, on what retiring Presidents of the USA should do next. I think I would go with George Washington and his whisky business... 🍻

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[1] Ohanian D. et al. Identifying Key Symptoms Differentiating Myalgic Encephalomyelitis and Chronic Fatigue Syndrome from Multiple Sclerosis. Neurology (ECronicon). 2016;4(2):41-45.

[2] Morris G. & Maes M. Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics. BMC Medicine. 2013; 11: 205.

[3] Jason LA. et al. Case definitions integrating empiric and consensus perspectives. Fatigue. 2016;4(1):1-23.

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ResearchBlogging.org Ohanian D, Brown A, Sunnquist M, Furst J, Nicholson L, Klebek L, & Jason LA (2016). Identifying Key Symptoms Differentiating Myalgic Encephalomyelitis and Chronic Fatigue Syndrome from Multiple Sclerosis. Neurology (E-Cronicon), 4 (2), 41-45 PMID: 28066845

Thursday, 19 January 2017

The correlates of regressive autism

"A more homogeneous subgroup with regression between 18 and 36 months (n = 48) had higher rates of intellectual disability, epilepsy, and special education, more socially restrictive educational settings, and more severe ASD [autism spectrum disorder] communication deficits and schizophrenia spectrum symptoms than non-regressed youth (n = 136)."

So said the findings reported by Kenneth Gadow and colleagues [1] taking on one of the more important issues in relation to autism: developmental regression (see here). I say 'more important' in that last sentence because whilst it has taken autism research and science quite a while to accept that regression in skills/behaviour can occur in cases of autism, there is now a realisation that such regression can impact on various other areas of investigation, not least the discussions on the potential [very] early detection of autism (see here). And still researchers continue to talk about very early autism detection...

Gadow (a name not unfamiliar to this blog in terms of autism and schizophrenia spectrums potentially colliding) et al set out to examine "the psychiatric and clinical correlates of loss of previously acquired skills (regression) as reported by parents of youth with autism spectrum disorder (ASD)." They relied to quite a large extent on data derived from the Child and Adolescent Symptom Inventory partly created by Dr Gadow, that assesses for the presence of various behaviours linked to various developmental and psychiatric labels. Some 213 6- to 18-year old children and adolescents with ASD were included for study; 77 (36%) of them defined as showing some parent-reported regression in skills coincidental to the presentation of their autism.

As per that opening sentence, there did appear to be some differences in clinical presentation when using regression as a characterising feature. A few additional details: 37% of those "whom parents indicated had regressed (whether or not they indicated age of regression and type of skill)" fell into the intellectual/learning disability category vs. 18-19% of non-regressed participants. Significantly more participants who regressed were 'ever hospitalised' (48% vs 29%); a statistic that probably ties into the rates of epilepsy/seizure disorder also described in this cohort (18% vs 5-6%). Although the authors talk about 'a more severe ASD communication deficit' being linked to reports of regression, the data obtained from both parent and teacher ratings in relation to the presentation of autistic traits were mainly 'more severe' in the regression group when examined as a whole: social deficits, communication deficits and perseverative behaviours; albeit not significantly so.

Then to the suggestion that schizophrenia spectrum symptoms were more pronounced in the regression group. Appreciating that there is some history when it comes to autism and schizophrenia (think Mildred Creak for example) but also some controversy, this is something potentially quite important, not least when one considers the rise and rise of research interest into something like psychosis and [some] autism (see here and see here) and also how [some] regressive autism might not be a million miles away from a condition like anti-NMDA-receptor encephalitis (see here) typically encompassing a psychotic element to it. I also wonder whether the talk about regression accompanying autism might set the tone for further regression potentially accompanying the onset of something like schizophrenia for example. Could a life of 'regression in skills' be a feature of this group?

Of course further investigations are required to independently verify the findings reported by Gadow and colleagues; such work should really also include more professionally-derived ratings (bearing in mind parents are generally the experts on their own children). I wonder too if it's time to start including a few more 'biological' measures when it comes to looking at regression vs. no regression in the context of autism to see if genetics/epigenetics/biochemistry variables might also tie up with some of the behavioural findings. Indeed, this should really be a must.

Finally: "A brief parent report of developmental regression may be a useful clinical indicator of later general functioning." I agree that this might be a rather good idea based on the current data; perhaps allied to some further chatter about ESSENCE and autism also (see here).

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[1] Gadow KD. et al. Parent-Reported Developmental Regression in Autism: Epilepsy, IQ, Schizophrenia Spectrum Symptoms, and Special Education. J Autism Dev Disord. 2017 Jan 10.

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ResearchBlogging.org Gadow KD, Perlman G, & Weber RJ (2017). Parent-Reported Developmental Regression in Autism: Epilepsy, IQ, Schizophrenia Spectrum Symptoms, and Special Education. Journal of autism and developmental disorders PMID: 28074354

Wednesday, 18 January 2017

Physical activity levels and autism (again)

"Adolescents with ASD [autism spectrum disorder] spent less time in MVPA [moderate and vigorous physical activity] compared to TD [typically developing] adolescents (29 min/day vs. 50 min/day, p < 0.001) and fewer met the Physical Activity Guidelines for Americans (14 vs. 29%, p > 0.05)."

So said the study results published by Heidi Stanish and colleagues [1] adding yet more to another growth autism research area - physical activity and exercise - a topic also fast becoming a repetitive blogging issue for me.

It's not necessarily new news that physical activity and exercise levels are not what they could or should be for many people on the autism spectrum (see here) but rather that the use of objective measures such as accelerometers for data collection are starting to put some scientific flesh on previous 'what exercise did you do' type questionnaire studies. And the trend that is being revealed really is quite a disturbing one if one assumes that physical activity is a significant gateway to rude health and well-being, particularly in the context of ever-increasing waistlines and onward longitudinal effects. I might even point you in the direction of some new research hinting that MVPA in childhood might predict "fewer symptoms of major depressive disorders" later on; something that could be particularly relevant to autism in light of those over-represented comorbidities that I keep going on about (see here).

Stanish et al have been mentioned before on this blog in the context of physical activity / exercise and autism and particularly the ways that said activity could be made more attractive to teens diagnosed on the autism spectrum (see here). Small steps and finding the right activity were some of the routes offered in that previous paper [2].

Before I go I do want to briefly mention one point raised in the latest Stanish paper: "Walking/hiking and active video gaming were among the top activities for both groups." Both groups refers to adolescents with autism (n=35) and those described as typically developing (n=60) who were included for study (although much like the term 'neurotypical' I'm still at a loss as to the precise meaning of 'typically developing'). Walking/hiking... great, really worthwhile encouraging (see here) including exposing people to the great outdoors and that yellow thing usually high in the sky. 'Active videogaming' is something I'm a little less sure of at the moment and indeed, some people have talked about such 'exergaming' as being a poor substitute for the real thing [3]. I don't doubt that one can build up a sweat on something like those new-fangled 'watch my movement' games consoles that abound these days, but might such exergaming just further feed into the 'screen time' narrative that typically accompanies sedentary behaviours?

And of the multiple correlates potentially attached to low levels of physical activity, one might also count bone health [4] among them as being relevant to at least some autism...

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[1] Stanish HI. et al. Physical Activity Levels, Frequency, and Type Among Adolescents with and Without Autism Spectrum Disorder. J Autism Dev Disorders. 2017. Jan 9.

[2] Stanish H. et al. Enjoyment, Barriers, and Beliefs About Physical Activity in Adolescents With and Without Autism Spectrum Disorder. Adapt Phys Activ Q. 2015 Oct;32(4):302-17.

[3] Daley AJ. Can Exergaming Contribute to Improving Physical Activity Levels and Health Outcomes in Children? Pediatrics. 2009; 124: 2.

[4] Neumeyer AM. et al. Bone microarchitecture in adolescent boys with autism spectrum disorder. Bone. 2017 Jan 11. pii: S8756-3282(17)30009-1.

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ResearchBlogging.org Stanish, H., Curtin, C., Must, A., Phillips, S., Maslin, M., & Bandini, L. (2017). Physical Activity Levels, Frequency, and Type Among Adolescents with and Without Autism Spectrum Disorder Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-016-3001-4

Tuesday, 17 January 2017

Vitamin D supplementation and self-perceived fatigue

"Vitamin D treatment significantly improved fatigue in otherwise healthy persons with vitamin D deficiency."

Supplementation details, described in the paper by Albina Nowak and colleagues [1] (open-access available here), were a single dose of 100,000 IU [international units] of vitamin D or a placebo (mannitol) administered to 120 adult participants who presented with "fatigue and vitamin D deficiency (serum 25(OH)D < 20 μg/L)." This was a double-blind trial and self-perceived fatigue was measured using the fatigue assessment scale (FAS) at baseline (before intervention) and after 4 weeks.

This is an interesting paper but not without some issues. Use of the FAS is OK but I would have preferred to see something else accompanying the data derived from this schedule when it comes to something like self-reported fatigue. The authors did rely on a "short self-developed fatigue test (fatigue course assessment; FCA)" too during their study but I was thinking of something a little more standardised. Although data for some 120 participants were available for the study results , I was a little surprised to see that some 280 participants were initially screened for study inclusion; most of whom did not make the cut. The vast majority (n=103) were cut because "25-OH vitamin D levels >20 μg/L" or in other words, they were not classified as vitamin D deficient based on analysis by immunoassay. Bearing in mind the idea that deficiency is not the only categorisation when it comes to vitamin D and not everyone agrees where deficiency actually starts and stops, I'd perhaps have liked to have seen some more information about those excluded, particularly those on the periphery of being classified as deficient and what supplementation might have meant for them.

It's also interesting to see the strength of the placebo effect when it came to the study results as alongside the 70%+ who reported "amelioration" of fatigue who were actually in receipt of vitamin D, so half of the placebo group also registered the same/similar improvement. As far as I know mannitol is not known as a fatigue reducing agent so there's potentially something more going on here. "A significant increase in 25-OH vitamin D was observed in vitamin D but not in placebo-treated participants." Given the supplementation of vitamin D at such a high dose it's perhaps not surprising that vitamin D levels went up for those consuming the supplement.

The Nowak results do stand, and even though they were based on self-reported fatigue in an otherwise healthy cohort, I do wonder whether there may be some tie-ups with other independent study (see here for example). Accepting that there may be many reasons for fatigue, I'm also inclined to point out that for perhaps at least a subset of those diagnosed with something like chronic fatigue [syndrome], there could be some additional studies to undertake bearing in mind the authors assertion that: "our study results are not generalizable to CFS [chronic fatigue syndrome]."

To close, what if ‘There's Something About Mary’ was trailed as a Psychological Thriller?

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[1] Nowak A. et al. Effect of vitamin D3 on self-perceived fatigue: A double-blind randomized placebo-controlled trial. Medicine (Baltimore). 2016 Dec;95(52):e5353.

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ResearchBlogging.org Nowak A, Boesch L, Andres E, Battegay E, Hornemann T, Schmid C, Bischoff-Ferrari HA, Suter PM, & Krayenbuehl PA (2016). Effect of vitamin D3 on self-perceived fatigue: A double-blind randomized placebo-controlled trial. Medicine, 95 (52) PMID: 28033244

Monday, 16 January 2017

Autism-like traits and/or autism elevated in psychosis

"Rates of ASD [autism spectrum disorder] and ASD traits are elevated in a psychosis population."

The paper by Debbie Kincaid and colleagues [1] provides yet more [short] blogging material pertinent to the increasing interest in how psychosis may be yet another comorbidity over-represented when it comes to autism (see here) and vice-versa. I know this is another topic that has to be treated with some caution in terms of concepts like stigma but more discussions - science discussions - are needed to ensure that appropriate screening, diagnosis and also management is available to those who might need it.

A systematic review was the name of the research game for Kincaid et al as seven studies "reporting prevalence rates of Autistic-like Traits (ALTs) and ASD in populations with a diagnosis of schizophrenia or other psychotic disorder" were included. The results weren't exactly precise in terms of what was reported as anywhere between 9-61% of those diagnosed with psychosis presented with those ALTs and between 1-52% of those with psychosis were also diagnosed with an autism spectrum disorder (ASD). The authors however are correct when they point out that the "prevalence rates of ALTs and ASD in psychosis populations are much higher than in the general population." Quite a bit higher if one looks at the top end of those prevalence stats.

I'll leave it at that for now.

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[1] Kincaid DL. et al. What is the prevalence of Autism Spectrum Disorder and ASD traits in psychosis? A systematic review. Psychiatry Research. 2017. Jan 6.

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ResearchBlogging.org Kincaid, D., Doris, M., Shannon, C., & Mulholland, C. (2017). What is the prevalence of Autism Spectrum Disorder and ASD traits in psychosis? A systematic review Psychiatry Research DOI: 10.1016/j.psychres.2017.01.017

Saturday, 14 January 2017

No significant difference in circulating cytokines in autism vs controls?

"As compared with 54 typically developing controls, we found no evidence of differences in the blood profile of immune mediators supportive of active systemic inflammation mechanisms in participants with autism."

That was the unexpected research bottom-line published by Carlos Pardo and colleagues [1] (open-access) examining whether various immune-related chemicals - "cytokines, chemokines, or growth factors in serum and cerebrospinal fluid" - might be linked to autism following longitudinal assessment. By longitudinal I mean that: "Up to four serum samples and up to two CSF samples were obtained from participants, at intervals ranging from 9–24 months, and stored until simultaneous laboratory analysis."

"Participants were drawn from a longitudinal study of autism" we are told, the aim of which was 'to learn more about autism and its subtypes'. Indeed, some of the research attached to this cohort has been previously discussed on this blog (see here) and for example, the suggestion that the horror that is a gluten- and/or casein-free diet used in the context of autism might not be as horrible as many people might think [2]. This time around serum samples were available for over 100 children diagnosed with autism and some 54 not-autism controls. Sixty-seven of the children with autism also provided a cerebrospinal fluid (CSF) sample taken via a lumbar puncture. The authors note: "Ethical constraints prevented lumbar punctures in the TYP [control] group" so make of that what you will.

Bearing in mind that no participants had a history of immunodeficiency or autoimmune disorder (important concepts to some autism) but that "Food, environmental, and seasonal allergies were present in a minority of participants, but were more common in AUT [participants with autism]" the results are interesting. First, when comparing results based on the analysis of CSF samples and serum samples researchers noted that there were "striking differences in the expression of selected cytokines, immune-related growth factors, and chemokines in the CSF compartment compared to the circulating bloodstream compartment." So basically what goes on in serum might not necessarily be the same as that going on in CSF in a biochemical sense.

Next and as per the title and headline of this post: "we found no evidence for major differences in the expression of circulating cytokines and chemokines between children with autism and typically developing controls." This contrasts with quite a bit of other research in the area of immune-related compounds and autism (see here for example) but one has to be a little careful with the wording here, specifically the term 'major differences'. I say that because the authors do report that EGF - epidermal growth factor - did come out as 'different' between the groups (greater in the autism group) for example. EGF has been mentioned before in the context of autism but levels of the stuff have tended to be lower in autism not higher (see here). Puzzling.

This is important work not least because of the cautions highlighted by the authors: "about the lack of relationship between central and peripheral immune markers, signaling that caution should be taken when interpreting the available studies implicating current immune dysfunction in the phenomenology of ASD [autism spectrum disorder], as few have included direct measures of CNS [central nervous system] status." Bearing in mind that there were no CFS comparison samples from controls included in this study (quite a big research flaw by all accounts) it is something else to suggest that if one really wants to see what is going on with immune function and autism, one needs to be looking to a far more invasive sample media. That some of this research group have some 'form' when it comes to the immune system potentially being linked to autism [3] and even more invasive tissue types is also worth noting as further investigations are very carefully merited...

The immune system and autism continues to intrigue.

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[1] Pardo CA. et al. Serum and cerebrospinal fluid immune mediators in children with autistic disorder: a longitudinal study. Molecular Autism. 2017. 8: 1.

[2] Graf-Myles J. et al. Dietary adequacy of children with autism compared with controls and the impact of restricted diet. J Dev Behav Pediatr. 2013 Sep;34(7):449-59.

[3] Vargas DL. et al. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005 Jan;57(1):67-81.

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ResearchBlogging.org Pardo, C., Farmer, C., Thurm, A., Shebl, F., Ilieva, J., Kalra, S., & Swedo, S. (2017). Serum and cerebrospinal fluid immune mediators in children with autistic disorder: a longitudinal study Molecular Autism, 8 (1) DOI: 10.1186/s13229-016-0115-7