Low glycemic index diet reduces symptoms of mouse autism

A quote to begin: "Overall, the manuscript supports the idea that ASD [autism spectrum disorder] results from gene–environment interactions and that in the presence of a genetic predisposition to ASD, diet can make a large difference in the expression of the condition."

The manuscript in question was by Antonio Currais and colleagues [1] reporting some rather interesting results based on the 'dangermouse' that is the BTBR mouse model of autism. Researchers from the Salk Institute for Biological Studies showed that "the dietary glycemic index has a significant impact on the ASD phenotype." The dietary glycemic index (GI) by the way, is concerned with how particular foods / foodgroups affect blood glucose levels and the crux of the research was to see what happened to pregnant mice when fed either a high GI or low GI diet in terms of offspring outcomes. Offspring also followed the same diet diet post weaning.

To quote from the paper and some associated media: "The two groups of animals consumed the same number of calories and were identical in weight. But mice that ate a high-glycemic index diet showed all of the expected behavioral symptoms of autism. Their social interactions were impaired, they repeated actions that served no apparent purpose, and they groomed extensively."

Various other differences were present across the different dieting mice as per the findings that: "diet modulates plasma metabolites, neuroinflammation and brain markers of neurogenesis in a manner that is highly reflective of ASD in humans." This included the finding that "the brains of the high-glycemic index diet mice appeared to have greater numbers of activated microglia, the resident immune cells of the brain" and various inflammation-related genes being more readily expressed in comparison to the low-glycemic index diet mice. Microglia and autism remains a complex topic (see here) but with the advent of recent research findings [2] complete with headlines such as ''Missing link' between brain and immune system discovered' I dare say that we'll be hearing more about this is times to come.

The compound doublecortin also receives a mention in the Currais results as per the suggestion that those mice living on the high-glycemic diet had less of the stuff and the significance of this finding given the link between doublecortin and neurogenesis for example [3]. Bearing in mind the BTBR mouse model of autism might already be more prone to reductions in the levels of doublecortin [4] it might be useful to see how this finding pans out when applied to real people in the real world.

"The new study found that the diet might directly influence the ecosystem of bacteria in the gut." It perhaps goes without saying that any sort of dietary change is likely to affect the composition of those trillions of wee beasties that call our gastrointestinal (GI) tract home. This also applies to mice and probably every other type of animal. "'We were really surprised when we found molecules in the blood that others had reported could only be generated by gut bacteria,' Maher says. 'There were big differences in some of these compounds between the two diets.'" Metabolites of gut bacteria found in general circulation... does this imply intestinal permeability (leaky gut) might be part and parcel of any effect? If so, would that perhaps also tie into the findings reported by Elaine Hsaio and colleagues a while back on leaky mice guts, gut bacteria and autism? Add in also the idea that high glycemic index foods tend to include things like wheat and various other grains and we start to get something looking rather familiar to autism research that may well show some relationship [5].

"The group plans to analyze the gut bacteria, and its potential link with features of autism, more directly. They also hope to better understand the role of inflammation in the ability to generate new neurons." I'm very much looking forward to seeing these results, bearing in mind that mice are mice not people [6] and autism (or rather the autisms) is/are [a] very complicated condition(s).

Music: The Jesus And Mary Chain - Just Like Honey.

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[1] Currais A. et al. Dietary glycemic index modulates the behavioral and biochemical abnormalities associated with autism spectrum disorder. Molecular Psychiatry. 2015. June 9.

[2] Louveau A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015 Jun 1.

[3] Couillard-Despres S. et al. Doublecortin expression levels in adult brain reflect neurogenesis. Eur J Neurosci. 2005 Jan;21(1):1-14.

[4] Stephenson DT. et al. Histopathologic characterization of the BTBR mouse model of autistic-like behavior reveals selective changes in neurodevelopmental proteins and adult hippocampal neurogenesis. Mol Autism. 2011 May 16;2(1):7.

[5] Lammers KM. et al. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology. 2008 Jul;135(1):194-204.e3.

[6] Wong AH. & Josselyn SA. Caution When Diagnosing Your Mouse with Schizophrenia: The Use and Misuse of Model Animals for Understanding Psychiatric Disorders. Biol Psychiatry. 2015 May 6. pii: S0006-3223(15)00361-3.

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Currais A, Farrokhi C, Dargusch R, Goujon-Svrzic M, & Maher P (2015). Dietary glycemic index modulates the behavioral and biochemical abnormalities associated with autism spectrum disorder. Molecular psychiatry PMID: 26055422

Fermented foods and social anxiety?

Stumbling across a headline that reads: 'Study Finds Decreased Social Anxiety Among Young Adults Who Eat Fermented Foods' was bound to pique my blogging interest. When I eventually tracked down the source paper behind the headline I became more and more intrigued as today I bring to your attention the study findings reported by Matthew Hilimire and colleagues [1].

Implementing "a cross-sectional approach to determine whether consumption of fermented foods likely to contain probiotics interacts with neuroticism to predict social anxiety symptoms" researchers asked over 700 students - psychology students - to self-report on "fermented food consumption, neuroticism, and social anxiety." Fermented foods by the way, cover a range of foods "that contain probiotics" including yogurt and sauerkraut (a particular favourite of mine). Researchers also enquired about various other variables such as fruit and vegetable intake and the amount of exercise taken over the past 30 days.

Bearing in mind that this was a study based on self-report and that psychology students might not be entirely representative of the population in general, the results of an "interaction model, controlling for demographics, general consumption of healthful foods, and exercise frequency" did seem to suggest that there may be more to see when it comes fermented food consumption and social anxiety: "Fermented foods should be further investigated as an intervention for social anxiety."

I'm not falling hook, line and sinker for these results - correlation is not the same as causation - despite my continuing interest in the science of psychobacteriomics (my word creation) and the idea that those trillions of wee beasties that inhabit our deepest, darkest [gut] recesses might be doing so much more than just helping to digest food and making the odd nutrient or two. I do however think that we need to dedicate quite a few more resources to the idea that psychology and behaviour might not be solely rooted in the grey-pink matter floating in our skull [2] as recent news articles seem to imply.

Finally, and without wishing to make too many sweeping generalisations from the Hilimire results, I did think about whether such findings may be particularly 'useful' for certain groups of people where social anxiety might be over-represented. Autism is an obvious label given the suggestion that at least a quarter of those on the autism spectrum might also fulfil the diagnostic criteria for social anxiety disorder (see here). That such anxiety might also have knock-on effects to the presentation of more core autism symptoms (see here) is also noteworthy bearing in mind that a diet rich in fermented foods might not be for everyone and that social anxiety with or without autism is bound to be a very complicated process.

We await further research in this area.

Music: The Flaming Lips - Do You Realize??

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[1] Hilimire MR. et al. Fermented foods, neuroticism, and social anxiety: An interaction model. Psychiatry Res. 2015; 228: 203-208.

[2] Dinan TG. et al. Collective unconscious: how gut microbes shape human behavior. J Psychiatr Res. 2015 Apr;63:1-9.

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Hilimire MR, DeVylder JE, & Forestell CA (2015). Fermented foods, neuroticism, and social anxiety: An interaction model. Psychiatry research, 228 (2), 203-8 PMID: 25998000

Probiotics, schizophrenia and inflammation

I have to say that I was initially pretty interested to read the paper by Jakub Tomasik and colleagues [1] (open-access available here) discussing results examining the "possible immunomodulatory effects of probiotic supplementation in chronic schizophrenia patients."

Interested because not only was this a partnership paper including Robert Yolken and Faith Dickerson on the authorship list (names who have appeared a few times on this blog) but also because of the subject matter extending some research interest into how gastrointesinal (GI) 'functions' may very well have some important implications for at least some cases of schizophrenia (see here) particularly linked to the concept of inflammation. This area of research on a 'gut-brain connection', also links into a body of work with autism in mind (see here) and with that autism connection, mention of one Sabine Bahn as a co-author and some research she has published [2] is also worth noting.

In the current paper, Tomasik et al describe work following on from a previous study by Dickerson and colleagues [3] suggesting that adjuvant probiotic use may "help to prevent severe bowel difficulty in patients with schizophrenia" even if not significantly affecting the behavioural presentation of schizophrenia on that research occasion. With no endorsement given or intended, the probiotic preparation in question was called Bifiform Balance and contained "the probiotic organism L. rhamnosus GG and... colony forming units of the probiotic organism Bifidobacterium animalis subsp. lactis BB12 (Ferrosan)." Lactobacillus rhamnosus GG has appeared before on this blog (see here) so I was intrigued as I always am when it comes to gut bacteria and health / behaviour.

Authors describe how blood samples from 58 participants who completed the previous Dickerson trial ("31 in the probiotic arm and 27 in the placebo arm") were collected pre- and post-trial (after 14 weeks) and serum samples analysed by immunoassay "targeting selected inflammatory markers, including cytokines, chemokines, and acute-phase reactants."

Results: "Probiotic add-on treatment significantly reduced levels of von Willebrand factor (vWF) and increased levels of monocyte chemotactic protein-1 (MCP-1), brain-derived neurotrophic factor (BDNF), RANTES, and macrophage inflammatory protein-1 beta (MIP-1) beta with borderline significance (P ≤ 0.08)." Actually, the only significant effect was noted for vWF (p=0.047) for which levels seemed to drop following probiotic use. Also interesting was the finding that within the group taking the placebo (although I'm not altogether sure what this contained) there were significant pre- and post-intervention differences for compounds such as vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1); both showing reductions.

The authors note that the significant reduction in levels of vWF within the context of probiotics as an add-on treatment alongside more commonplace pharmacotherapy for schizophrenia might have some important implications for "certain cardiovascular risk parameters" for example. This statement is rooted in the idea that vWF has some research history when it comes to schizophrenia both outside [4] and inside this connection [5]. Certainly, vWF shows a link to inflammation and with mention of the words adhesion too. In the context of schizophrenia, inflammation is of growing interest...

"We conclude that probiotics have immunomodulatory effects in schizophrenia patients, affecting molecules that do not respond to standard antipsychotic therapy." If one goes by the statistical book, I'm not entirely sure that the current findings are completely in line with that last statement. Yes, vWF showed something of a 'relationship' to the probiotic use but the other results with "borderline significance" and the fact that authors "were not able to detect all targeted cytokines in [their] clinical samples", I'd be a little cautious about saying too much more.

Music: House Of Love - Destroy The Heart.

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[1] Tomasik J. et al. Immunomodulatory Effects of Probiotic Supplementation in Schizophrenia Patients: A Randomized, Placebo-Controlled Trial. Biomark Insights. 2015 Jun 1;10:47-54.

[2] Schwarz E. et al. Sex-specific serum biomarker patterns in adults with Asperger's syndrome. Mol Psychiatry. 2011 Dec;16(12):1213-20.

[3] Dickerson FB. et al. Effect of probiotic supplementation on schizophrenia symptoms and association with gastrointestinal functioning: a randomized, placebo-controlled trial. Prim Care Companion CNS Disord. 2014;16(1). pii: PCC.13m01579.

[4] Hope S. et al. Similar immune profile in bipolar disorder and schizophrenia: selective increase in soluble tumor necrosis factor receptor I and von Willebrand factor. Bipolar Disord. 2009 Nov;11(7):726-34.

[5] Dieset I. et al. Cardiovascular risk factors during second generation antipsychotic treatment are associated with increased C-reactive protein. Schizophr Res. 2012 Sep;140(1-3):169-74.

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Tomasik J, Yolken RH, Bahn S, & Dickerson FB (2015). Immunomodulatory Effects of Probiotic Supplementation in Schizophrenia Patients: A Randomized, Placebo-Controlled Trial. Biomarker insights, 10, 47-54 PMID: 26052224

Early sex differences are not autism-specific

The title of this post mirrors the title of the paper published by Daniel Messinger and colleagues [1] (open-access available here) that reported on "younger sibling sex differences and proband sex differences on the odds of ASD [autism spectrum disorder] in a large sample of prospectively followed high-risk siblings."

Researchers found that alongside "a three-to-one male:female odds ratio in ASD recurrence... the emergence of ASD symptoms in high-risk siblings—both with and without eventual ASD outcomes—occurs in the context of naturally occurring sex-related variability." Further that their results cast "doubt on a female protective effect among high-risk ASD siblings."

Based on participant data derived from the Baby Siblings Research Consortium (BSRC) [2], a collaborative initiative focused on identifying the earliest signs and symptoms of autism, researchers assessed cognitive functioning and autism symptom severity in over 1800 infants, over 1200 of whom were categorised as 'high risk' insofar as being a "younger sibling of a proband with an ASD diagnosis." Of those 1241 high-risk siblings "252 had ASD outcomes" on the basis of a clinical best estimate diagnosis derived from the various data sources available for each participant.

Results: well, there were quite a few of them as previously discussed but I'm going to pick out a few highlights:

• "The male rate of ASD recurrence in the high-risk siblings was approximately 1 in 4 (26.7 %) while the female rate was 1 in 10 (10.3 %)." Further: "The overall—combined male and female—ASD recurrence rate of 19.5 % yielded an ASD outcome for approximately one in five high-risk siblings." This is an important addition to the previous research done on sibling recurrence rates (see here) bearing in mind the potential effect of variables such as reproductive stoppage and multiplex status.
• "Challenging accounts of greater female affectedness, there was no evidence that girls exhibited lower levels of cognitive functioning or higher levels of symptom severity than boys." The idea that there may be a female phenotype of autism has gained significant research traction in recent times (see here) partially based on the idea that it may take 'more genetic issues to trigger autism in girls than boys'. Alongside the idea that females may somehow possess greater protection against autism is the suggestion that autism when it does appear in females, may show differences in terms of severity perhaps as a function of that larger genetic load required. Messinger et al however, report that things might not be so simple.
• "Boys across all groups exhibited slower growth trajectories and lower levels of cognitive performance than girls in fine motor, visual reception, receptive and expressive language functioning." Harking back to some previous musings on the 'fragile male' (see here) Messinger et al showed small but notable difference across the sexes and across ages suggesting female superiority of somewhere between "1.06 to 3.3 months on age-equivalent scores" compared to males. That's not to say males did not develop - everyone developed - rather that girls seemed to develop skills at a faster rate.
• "With respect to the ASD symptom severity indices, males exhibited higher levels of repetitive behaviors than females, but there were no sex differences in social affect severity scores." This finding tallies with other research in this area (see here). The indication being that aspects such as stereotyped language, hand and finger mannerisms or complex mannerisms may be quite a bit more prevalent in 'boy autism' compared to 'girl autism'. More than that however, such repetitive behaviours might be more present in boys over girls (taking out the variable of autism diagnosis) "consistent with a male focus on regularity in the behavior of non-social objects and events." 'Boys and their toys' is a phrase that springs to mind.

The authors conclude that their results "suggest that male:female ASD differences are not ASD-specific but instead reflect more general sex differences reflected through a prism of autism-linked symptoms."

These are interesting results that gain some scientific traction as a function of the large participant numbers included for study and the prospective nature of the study initiative. The authors have made quite a bit of the fact that their results provide "no overall evidence of a female protective effect" in their high-risk siblings group but acknowledge the need for further investigations in this area specifically where female autism is present and how "female probands in multiplex families (two or more female siblings) [may] confer greater risk for ASD in successive offspring." I wonder if this might include some further thought on how sex differences in brain plasticity [3] might potentially be linked to autism?

Once again, autism reveals just how complicated a condition it is...

Music: The Slits - Typical Girls.

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[1] Messinger DS. et al. Early sex differences are not autism-specific: A Baby Siblings Research Consortium (BSRC) study. Mol Autism. 2015 Jun 4;6:32.

[2] Messinger D. et al. Beyond autism: a baby siblings research consortium study of high-risk children at three years of age. J Am Acad Child Adolesc Psychiatry. 2013 Mar;52(3):300-308.

[3] Mottron L. et al. Sex differences in brain plasticity: a new hypothesis for sex ratio bias in autism. Molecular Autism. 2015. 6; 33.

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Messinger DS, Young GS, Webb SJ, Ozonoff S, Bryson SE, Carter A, Carver L, Charman T, Chawarska K, Curtin S, Dobkins K, Hertz-Picciotto I, Hutman T, Iverson JM, Landa R, Nelson CA, Stone WL, Tager-Flusberg H, & Zwaigenbaum L (2015). Early sex differences are not autism-specific: A Baby Siblings Research Consortium (BSRC) study. Molecular autism, 6 PMID: 26045943

Stalking and 'unexpected subthreshold autism spectrum'

I deliberated for quite a while as to whether or not I should write this post on the back of the findings reported by Liliana Dell’Osso and colleagues [1] detailing the experiences of a "25-year-old man with a diagnosis of delusional disorder, erotomanic type" who was hospitalised when presenting with psychotic symptoms "in the framework of a repeated stalking behavior towards his ex girlfriend." Said man was assessed for "adult autism spectrum symptoms" via the Ritvo Autism and Asperger Diagnostic Scale (RAADS-14) and came out with something approaching autism spectrum symptoms.

My blogging hesitancy was in the most part due to the risk of stigmatising and generalising on the basis of the words 'stalking' and 'autism' appearing in the same sentence even in the context of a case report and not necessarily including a formal diagnosis of autism. I'd like to make it very clear that this is/was not my intention at all. As in previous occasions when science has been covered on this blog that falls into a slightly uncomfortable area (see here and see here) I did however eventually choose to cover this topic on the basis that [peer-reviewed] science is science irrespective of particular emotions around topics.

Stalking - the unwanted or obsessive attention by an individual or group toward another person - is a life-changing experience that has profound effects on its victims. The precise hows and whys of stalking behaviour are still the topic of discussion, although thought to be variably mediated by social and personal factors potentially combining with other, more neurobiological processes [2]. As per the description provided in that last sentence and the use of the word 'obsessive' one might be able to see how such fixative behaviours might 'overlap' with some of the clinical description of autism or 'nearly autism' and particularly the idea that obsessions and compulsions might not be totally unfamiliar to the spectrum [3] including those around certain people.

I first came across discussions about stalking and the autism spectrum following my reading of the excellent overview by Tom Berney [4] (open-access). Describing the possible forensic presentation of Asperger syndrome, Dr Berney talked about "Overriding obsessions [that] can lead to offences such as stalking... Admonition can increase anxiety and consequently a ruminative thinking of the unthinkable that increases the likelihood of action." Anxiety and rumination, I might add, are areas crying out for more focused research with autism in mind (see here).

Other more experimental work looking at stalking in the context of autism has pointed to the possibility of an increased risk of such behaviours as per the findings reported by Stokes and colleagues [5]. They reported that individuals with autism were "more likely to engage in inappropriate courting behaviours... and were more likely to focus their attention upon celebrities, strangers, colleagues, and ex-partners... and to pursue their target longer than controls." All this is set in the context of researcher reporting on a small participant group and being based on parental reports.

Insofar as the possible basis for stalking behaviours and the autism spectrum, the paper from Haskins & Silva [6] offers several opinions external to the involvement of obsessionality centred around the idea that empathy and perspective-taking abilities may also play a role. I'm not exactly a great fan of the exclusivity of concepts such as a lack of Theory of Mind (ToM) when applied to the autism spectrum (see here) but can see the logic in this assumption linked to stalking behaviours. Indeed, with such ideas in mind, the paper from Post et al [7] on possible strategies to prevent and overcome stalking when coincidental to autism make some sense.

Just before I bring this post to a close I'd also like to comment on the idea that psychosis or psychotic behaviour might also be an important part of any link between stalking behaviour and autism. Regular readers of this blog might already know that whilst not necessarily a mainstream opinion, I do perhaps think that autism research was historically a little hasty in burning all the bridges between autism and schizophrenia (see here) particularly when it came to the work of people such as Mildred Creak and colleagues. Science is beginning to recognise that a diagnosis of autism is in no way protective against the development of psychosis (see here) and preferential regular screening might be indicated.

Analysing the possibility of a relationship between stalking behaviour, autistic traits and psychosis sounds like something that might provide some important answers particularly in the context of the recent findings from Ho and colleagues [8] talking about ToM potentially being a trait marker of schizophrenia. Again treading carefully not to stigmatise or generalise, any moves to decreasing the likelihood and impact of stalking behaviour and the often devastating consequences that it can bring should be welcomed.

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[1] Dell'Osso L. et al. Unexpected subthreshold autism spectrum in a 25-year-old male stalker hospitalized for delusional disorder: a case report. Compr Psychiatry. 2015 Apr 14. pii: S0010-440X(15)00054-1.

[2] Marazziti D. et al. Stalking: a neurobiological perspective. Riv Psichiatr. 2015 Jan-Feb;50(1):12-8.

[3] Russell AJ. et al. Obsessions and compulsions in Asperger syndrome and high-functioning autism. Br J Psychiatry. 2005 Jun;186:525-8.

[4] Berney T. Asperger syndrome from childhood into adulthood. Advances in Psychiatric Treatment. Aug 2004, 10 (5) 341-351.

[5] Stokes M. et al. Stalking, and social and romantic functioning among adolescents and adults with autism spectrum disorder. J Autism Dev Disord. 2007 Nov;37(10):1969-86.

[6] Haskins BG. & Silva JA. Asperger's disorder and criminal behavior: forensic-psychiatric considerations. J Am Acad Psychiatry Law. 2006;34(3):374-84.

[7] Post M. et al. Understanding stalking behaviors by individuals with Autism Spectrum Disorders and recommended prevention strategies for school settings. J Autism Dev Disord. 2014 Nov;44(11):2698-706.

[8] Ho KKY. et al. Theory of mind impairments in patients with first-episode schizophrenia and their unaffected siblings. Schizophrenia Res. 2015. June 3.

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Dell’Osso, L., Dalle Luche, R., Cerliani, C., Bertelloni, C., Gesi, C., & Carmassi, C. (2015). Unexpected subthreshold autism spectrum in a 25-year-old male stalker hospitalized for delusional disorder: a case report Comprehensive Psychiatry DOI: 10.1016/j.comppsych.2015.04.003

Infant sleep duration a risk factor for autism spectrum behaviours in girls?

To quote from the study results published by Janet Saenz and colleagues [1] (open-access available here): "less sleep duration in infant girls across a period of 5 days was predictive of higher ASD [autism spectrum disorder] scores on the BITSEA [Brief Infant-Toddler Social and Emotional Assessment] in toddlerhood."

Based on a sample of 47 children - 29 males and 18 females - researchers initially studied sleep patterns for participants at 3-4 months of age using actigraphs to ascertain sleep duration and efficiency and determine whether there was any connection to later BITSEA scores at 18-24 months of age. They reported various results in the most part not significant across genders, sleeping patterns and the subsequent effect on scores of social-emotional problems. In the detail however, they did find a suggestion that "sleep duration was a significant predictor of autism spectrum behaviors" specifically in girls and "after controlling for sleep efficiency, a 1-min decrease in sleep duration resulted in a 0.01 point predicted increase in a child’s autism spectrum behaviors score." This, bearing in mind, that BITSEA scores for autism spectrum behaviours range between 0-17.

I'm not wildly enthusiastic about the results reported by Saenz et al given the relatively small sample size and the snap analysis of two variables (sleep and reported behaviour) separated by over a years worth of development. Correlation is not necessarily causation and all that jazz. Indeed, even the authors concede that their use of a "non-clinical sample" limits the applicability of their results to "the low severity end of the diagnostic spectrums."

That being said, I do wonder if these findings invite quite a bit more investigation specifically when it comes to all those resources being put into the early detection of autism as exemplified in the recent paper by Sacrey and colleagues [2]. Sleep and autism is a research topic not unfamiliar to this blog (see here) and the idea that there may be small but measurable differences in sleep parameters in cases of already diagnosed autism. I'm not aware of too much in the way of experimental research reporting on early sleep patterns as being a 'risk' factor for autism outside of results such as those reported by Humphreys et al [3]. The idea that sleep issues might become more present as a child develops is a theme explored by Sivertsen et al [4] and the behavioural 'issue' link has also been mentioned by others [5].

Finally, it is worth reiterating the focus on female autism spectrum behaviours reported by Saenz et al. As per other work by the authors [6] and findings supporting: "the hypothesis that early infancy may be another critical period for the development of gender-linked behavior" based on their examination of infancy salivary testosterone levels and toddler BITSEA ratings, there may be some important lessons to be learned. Sex differences in behavioural presentation when it comes to autism (see here) is a big talking point at the moment in light of discussions about how the gender ratios for diagnosis might be skewed by either a female autism phenotype or just plain old dogma about autism being a male-dominated label. Again, I've not come across much in the way of peer-reviewed research where sleep has been examined from the perspective of risk of autism or autism linked behaviours taking into account gender differences. Hence, another potential research project presents itself and perhaps even more intriguing: could 'alteration' of early sleep patterns offset the future risk of autism?

Music: Kelis - Caught Out There.

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[1] Saenz J. et al. Sleep in infancy predicts gender specific social-emotional problems in toddlers. Front Pediatr. 2015 May 11;3:42.

[2] Sacrey LA. et al. Can parents' concerns predict autism spectrum disorder? A prospective study of high-risk siblings from 6 to 36 months of age. J Am Acad Child Adolesc Psychiatry. 2015 Jun;54(6):470-8.

[3] Humphreys JS. et al. Sleep patterns in children with autistic spectrum disorders: a prospective cohort study. Arch Dis Child. 2014 Feb;99(2):114-8.

[4] Sivertsen B. et al. Sleep problems in children with autism spectrum problems: a longitudinal population-based study. Autism. 2012 Mar;16(2):139-50.

[5] Schwichtenberg AJ. et al. Behavior and sleep problems in children with a family history of autism. Autism Res. 2013 Jun;6(3):169-76.

[6] Saenz J. & Alexander GM. Postnatal testosterone levels and disorder relevant behavior in the second year of life. Biol Psychol. 2013 Sep;94(1):152-9.

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Saenz J, Yaugher A, & Alexander GM (2015). Sleep in infancy predicts gender specific social-emotional problems in toddlers. Frontiers in pediatrics, 3 PMID: 26029685

Toxoplasma seropositivity and pediatric cognitive functions

A brief post for you today as I keep a promise made in a previous entry to cover the paper by Angelico Mendy and colleagues [1] who concluded that: "Toxoplasma seropositivity may be associated with reading and memory impairments in school-aged children."

Based on the analysis of over 1700 children/young adults aged 12-16 years old "who participated to the Third National Health and Nutrition Examination Survey" researchers examined the possibility of a relationship between various psychometric test scores - "including math, reading, visuospatial reasoning and verbal memory" - and Toxoplasma seropositivity (that is, showing immunological evidence of either past or current infection by Toxoplasma gondii). Finding that approximately 7% of participants were seropositive for contact with the protozoan, researchers also highlighted a possible correlation between infection history and issues with both reading ability and memory capacity. This 'relationship' also appeared to be mediated by serum vitamin E levels in that: "Toxoplasma-associated memory impairment was worse in children with lower serum vitamin E concentrations." A good write-up of the study can be found here.

As regular readers might know (and are probably pretty bored of hearing about) I'm really rather interested in T. gondii and in particular the growing tide of peer-reviewed research hinting at a possible link between this organism and [some] schizophrenia. Accepting there is still quite a bit more to do looking at the possibility of link between the gondii and schizophrenia - including answering important questions about whether childhood cat ownership might be a risk factor - I'd like to think that the Mendy results might have a further role to play. I'm specifically thinking about the idea that cognitive decline (if I can call it that) might be part and parcel of schizophrenia and even something that pre-dates the onset of symptoms [2]. I draw back from making too many speculations in this area bearing in mind correlation is not the same as causation and the requirement for replicative investigations but would be rather interested to see if Mendy et al will be producing any follow-up data of their participants with a view to say, the prevalence of schizophrenia as a function of T. gondii seropositivity and/or psychometric scores?

Music: My Bloody Valentine - You Made Me Realise.

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[1] Mendy A. et al. Toxoplasma gondii seropositivity and cognitive functions in school-aged children. Parasitology. 2015 May 20:1-7.

[2] Keefe RS. The longitudinal course of cognitive impairment in schizophrenia: an examination of data from premorbid through posttreatment phases of illness. J Clin Psychiatry. 2014;75 Suppl 2:8-13.

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Mendy A, Vieira ER, Albatineh AN, & Gasana J (2015). Toxoplasma gondii seropositivity and cognitive functions in school-aged children. Parasitology, 1-7 PMID: 25990628

Office workers of the world stand up!

A quote to begin: "for those occupations which are predominantly desk based, workers should aim to initially progress towards accumulating 2 h/day of standing and light activity (light walking) during working hours, eventually progressing to a total accumulation of 4 h/day (prorated to part-time hours)."

That was the recommendation made in the consensus statement published by John Buckley and colleagues [1] aiming to: "provide guidance for employers and staff working in office environments to combat the potential ills of long periods of seated office work."

Co-commissioned by Public Health England, the body charged with protecting and improving the nation's health "and to address health inequalities" in England, the statement from Buckley et al has already garnered some significant press attention (see here for example). The move comes after quite a bit of peer-reviewed evidence has suggested that frequent and prolonged sitting is perhaps not the best activity for humankind (see here) and office workers chained to their desks from 9 to 5 might actually be a risk group for various adverse health outcomes as a result of their occupational inactivity.

As well as championing the health benefits of walking (which is always a good thing on this blog) the authors are also suggesting that far greater use could be made of sit-stand desks [2] and the use of "standing-based work". I might add that there are various other ways and means that office inactivity has been tackled in the peer-reviewed literature [3] and innovation leads the way as per the smart chair.

Appreciating the concerns of business about a possible reduction in productivity as a result of workers taking regular exercise breaks and the musings of others, I'm personally very happy to see the document from Buckley et al. If one assumes that this guidance builds on other occupational health advice such as smoking bans in public places including the workplace and other 'elf and safety laws, one can see how healthier workers in the long-term will be more productive workers as a function of less days lost to ill-health for example. That also aspects of psychological health may benefit too from a bout or two of regular workplace activity / exercise, and one gets the feeling that this might turn out to be something rather important. Indeed, Finland has taken a lead on this...

Music: REM - Stand.

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[1] Buckley JP. et al. The sedentary office: a growing case for change towards better health and productivity. Expert statement commissioned by Public Health England and the Active Working Community Interest Company. Br J Sports Med. 2015. June 1.

[2] Dutta N. et al. Using sit-stand workstations to decrease sedentary time in office workers: a randomized crossover trial. Int J Environ Res Public Health. 2014 Jun 25;11(7):6653-65.

[3] Parry S. et al. Participatory workplace interventions can reduce sedentary time for office workers--a randomised controlled trial. PLoS One. 2013 Nov 12;8(11):e78957.

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John P Buckley, Alan Hedge, Thomas Yates, Robert J Copeland, Michael Loosemore, Mark Hamer, Gavin Bradley, & David W Dunstan (2015). The sedentary office: a growing case for change towards better health and productivity. Expert statement commissioned by Public Health England and the Active Working Community Interest Company British Journal of Sports Medicine : 10.1136/bjsports-2015-094618

1000 blog entries or thereabouts

Although perhaps being a little self-indulgent, I'm taking a little time out today to reflect on a few milestones reached by this blog and some advice to be imparted.

Not so long ago I posted the 1000th entry on Questioning Answers and with it over 4 years of riding the roller coaster that is peer-reviewed science with an autism research slant. Allied to a page view count rising above 1.1 million (hopefully not all junk feeds!), I'd like to think that my science writing skills are being honed as well as there being some appetite for my various musings. Certainly, I have a lot more appreciation for the huge wealth of information that is out there in science land when it comes to the autism spectrum and beyond as a result...

Reflecting on the research blogging experience so far and in particular, remembering the fateful evening when it all started (see here), I'm minded to offer a few observations about the whole thing particularly with a view to encouraging more people to put on-line pen to on-line paper specifically with autism research in mind:

• Where does the time go? One question that has come up more than most about my blogging experience is 'where do you get the time to write?' The simple reply is: 'how long do you think it takes?' Depending on the size of the chosen paper and topic for blogging, it can take anywhere between 1-2 hours to get a post right. This includes reading said paper(s) and some light reading around the topic. Often there is some light tinkering to a post after a few hours break but this doesn't take long. Precisely when this writing gets done is very much dependent on the day and my mood. Aside from a day job, quite a big family and an exercise routine to maintain among other things, I tend to fit in bits of writing as and when I can. Early mornings and late nights have been previously experienced but timing very much depends on me. I've learned to live without watching old re-runs of Buck Rogers or endless news programmes in favour of doing something a little more intellectually stimulating...
• Picking a paper/topic. I don't have any strict criteria for what (or who) to blog about. There is a constant stream of peer-reviewed science published daily that never seems to dry up, always with something eye-catching to me. I am a great believer in evidence-based medicine and its application to the autism spectrum but for me, such evidence does not just have to include randomised-controlled trials or systematic reviews / meta-analyses. The humble case report and N=1 is often as revealing as 'big data' particularly given the heterogeneity of autism and its important 'add-ons'. That's why I will blog about many types of study based on different degrees of evidence. There are some topics/papers that are more appealing to me than others and I might prioritise them above others. That being said, I'd like to think I cover quite a broad spectrum of autism research on the blog.
• Social media strikes. Much like blogging, I've also come to embrace social media as part of my professional life. No longer just the place for 'cat videos' or the like, platforms like Twitter, Facebook and Google+ are veritable gold mines of information when it comes to science. Outside of some interesting discussions down the years, social media has also been a great way of promoting my blog to a large audience. Given that I'm a stand alone sort of blogger, social media has been instrumental in getting my musings out to a wider audience.
• Research qualifications? Research, as it currently is, was a part of my professional life before blogging, eventually leading up to the receipt of a PhD. Some of the most valuable lessons I learned during my PhD (aside from how to handle the term 'major corrections') were how to think and write with a critical eye, not to take anything at face value and to understand that science is by no means an absolute process or concept in terms of the data produced. Science is only as good as the people who do it and the techniques they use to do it, and just because something gets through peer-review, does not mean that it should be taken as Gospel. Having gone through the process of a PhD (alongside other post graduate academic experiences) has held me in good stead all these years but I wouldn't want anyone to think that it is a pre-requisite for science blogging. It's not. Some of the cleverest and most astute people I've met over the years of my research and blogging career have never been anywhere near a University lab or carried out something like a structured assessment. They are logical thinkers; many of them also quickly realising that science is all about probability, and that absolutes are few and far between. In other words, science blog as a critical thinker.

I'm gonna leave it at that with the self-indulgence and fatherly advice about blogging. I'd very much like to thank all those who've interacted with me and my blog over the various platforms of debate and years of doing it. I very much intend to keep going with the blog and hopefully provide a similar update when 2000 blog entries comes up. Hopefully at that time, I'll also be able to link to lots and lots of new autism research blogs too...

And in the grand tradition of this blog, here is a song by a favourite band: Frankly Mr Shankly by The Smiths ("a flatulent pain in the ass").

Autoimmune disease or anti-nuclear antibodies and non-coeliac wheat sensitivity

"Higher proportions of patients with NCWS [wheat sensitivity among people without celiac disease] or celiac disease develop autoimmune disorders, are ANA [anti-nuclear antibodies] positive, and showed DQ2/DQ8 haplotypes compared to patients with IBS [irritable bowel syndrome]."

Those were the conclusions reached in the paper by Antonio Carroccio and colleagues [1] who sought to evaluate: "the prevalence of autoimmune diseases among patients with NCWS, and investigated whether they carry anti-nuclear antibodies (ANA)." Continuing a theme that the classic autoimmune condition known as coeliac (celiac) disease (CD) may be only one part of a 'issues with gluten' spectrum, researchers reviewed the files of over 100 participants diagnosed with NCWS (or even NCGS) "to identify those with autoimmune diseases" and compare rates with those diagnosed with CD and/or IBS. Further, serum samples were analysed prospectively for 42 participants diagnosed with NCWS and "ANA levels were measured by immunofluorescence analysis" again, compared with CD / IBS control data. ANA by the way, are antibodies against 'self' tissue and in particular, antibodies against the contents of the cell nucleus.

Results. The rates of autoimmune disease in cases of NCWS were comparable with those reported in CD, hovering around the 20-30% frequency mark in each case. The frequency rates for autoimmune disease in the IBS group were quite a bit lower; between 2-4%.

Testing positive for ANA was however a slightly different ballgame as per the findings that those with NCWS were quite a bit more likely to show ANA than either CD or IBS participants. Depending on which arm of the study was used (retrospective vs. prospective) researchers reported that: "serum samples tested positive for ANA in 46% of subjects with NCWS..., 24% of subjects with celiac disease..., and 2% of subjects IBS... ; in the prospective study, serum samples were positive for ANA in 28% of subjects with NCWS, 7.5% of subjects with celiac disease..., and 6% of subjects with IBS." They also noted a relationship between ANA positivity and the presence of DQ2/DQ8 haplotypes (part of the so-called genetics of CD).

These are interesting results. Not only because of the overlap between autoimmune diseases and CD and NCWS (birds of an autoimmune feather flocking together and all that) but also that a higher burden of anti-nuclear antibody positivity might accompany NCWS in even greater frequency than CD. That Hashimoto's thyroiditis was the most common autoimmune condition identified is also an interesting prospect and ripe for further study in light of some research history in this area [2].

Wearing my autism research hat, I might also forward the idea that the Carroccio data intersects with quite a few potentially important papers published with [some] autism in mind. So, NCGS as a feature of some autism... well, there have been some hints of this in the peer-reviewed research literature as per the 'not quite coeliac disease' paper (see here) and other commentaries (see here). What I will also say is that although there are some gaps in the research in this area including how one clinically defines NCGS, we can perhaps assume that autism is not protective against developing something like NCGS. ANA and autism... I can direct you to the paper by Mostafa and colleagues [3] covered in a previous post (see here) and how: "anti-ds-DNA antibodies and ANA were found in the sera of a subgroup of autistic children." It strikes me that further study of NCGS, autoimmune comorbidty and anti-nuclear antibodies in cases of autism is a way to resolve any correlation or not.

Music: Oasis - Champagne Supernova.

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[1] Carroccio A. et al. High Proportions of People with Non-Celiac Wheat Sensitivity Have Autoimmune Disease or Anti-nuclear Antibodies. Gastroenterology. 2015 May 27. pii: S0016-5085(15)00767-2.

[2] Hakanen M. et al. Clinical and subclinical autoimmune thyroid disease in adult celiac disease. Dig Dis Sci. 2001 Dec;46(12):2631-5.

[3] Mostafa GA. et al. Systemic auto-antibodies in children with autism. J Neuroimmunology. 2014; 272: 94-98.

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Carroccio A, D'Alcamo A, Cavataio F, Soresi M, Seidita A, Sciumè C, Geraci G, Iacono G, & Mansueto P (2015). High Proportions of People with Non-Celiac Wheat Sensitivity Have Autoimmune Disease or Anti-nuclear Antibodies. Gastroenterology PMID: 26026392

Atypical enterovirus encephalitis and 'autism-like' (again)

"The autism spectrum disorder or autism-like clinical symptoms are extremely rare, but they may be a clear manifestations of enterovirus encephalitis."

That was the finding reported in a poster by Akcakaya and colleagues [1] submitted as part of the 11th European Paediatric Neurology Society Congress 2015. In it, they detail a case report of an adolescent young woman "who developed behavioural changes and autistic features such as impairment of communication, mutism and lack of eye contact" following "chronic, atypical enterovirus encephalitis."

Providing only a few details about the young lady concerned and her clinical experiences, the authors highlight how the diagnosis for enterovirus was confirmed by PCR although not providing information on the specific serotype. The authors do report how her clinical picture "gradually improved" during her hospital stay, helped along (I assume) by administration of "IVIg [intravenous immunoglobulin] treatment of 20 mg/kg." Further: "At discharge the patient was able to speak and communicate. Six months after discharge, her clinical status was improved."

Although the authors do emphasise the rarity of the enterovirus encephalitis / autism-like clinical picture, I was interested in this work because it is not the first time that it has cropped up in the peer-reviewed research arena. Indeed on a previous post (see here) covering the findings reported by Filipa Marques and colleagues [2] I talked about 'autism secondary to enterovirus encephalitis' and how a complicated relationship might exist between some of the autisms (plural) and various infective agents. This on top of other 'associations'.

At the same conference as the poster from Akcakaya et al I also came across the offering from Gadian and colleagues [3] discussing some of the current literature on the use of IVIg "in paediatric neurological and neurodevelopmental conditions." They reported "growing evidence" for the usefulness of IVIg for a few neurological conditions including various types of encephalitis. That being said: "well designed, prospective, multi-centre studies with standardized outcome measures are now required to evaluate the efficacy and cost effectiveness of this expensive and resource limited therapeutic agent."

Combined these posters, which I hope will eventually see the full peer-reviewed paper treatment at some point, provide further evidence for the ideas that (a) there may be many roads potentially leading to autism or autistic-like behaviours and (b) 'treatment' might be an option for specific cases based on the use of something like IVIg assuming no religious exemptions [4]. I might add that other examples of encephalitis-linked onset to autism (see here) might similarly benefit from quite a bit more investigation in this area particularly when one considers the limited study of IVIg and [some] autism [5].

Music: Regina Spektor - Us.

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[1] Akcakaya H. et al. P103 – 2340: Atypical enterovirus encephalitis causing behavioral changes and autism-like clinical manifestations: Case report. European Journal of Paediatric Neurology. 2015; 19: suppl. 1: S123.

[2] Marques F. et al. Autism Spectrum Disorder Secondary to Enterovirus Encephalitis. J Child Neurology. 2014; 29: 708-714.

[3] Gadian J. et al. PP13.7 – 2337: Atypical enterovirus encephalitis causing behavioral changes and autism-like clinical manifestations: Case report. European Journal of Paediatric Neurology. 2015; 19: suppl. 1: S84.

[4] Cleland N. et al. A 16-year-old girl with anti-NMDA-receptor encephalitis and family history of psychotic disorders. Acta Neuropsychiatr. 2015 Jun 1:1-5.

[5] Plioplys AV. Intravenous immunoglobulin treatment of children with autism. J Child Neurol. 1998 Feb;13(2):79-82.

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Akcakaya, H., Tekturk, P., Tur, E., Eraksoy, M., & Yapici, Z. (2015). P103 – 2340: Atypical enterovirus encephalitis causing behavioral changes and autism-like clinical manifestations: Case report European Journal of Paediatric Neurology, 19 DOI: 10.1016/S1090-3798(15)30416-5

Antipsychotic drugs as epigenetic modifiers?

The paper by Blaga Rukova and colleagues [1] (open-access available here) published last year (2014) caught my eye recently and their observations of: "major differences in methylation profiles between male schizophrenia patients in complete remission before and after treatment and healthy controls" as potential evidence that: "antipsychotic drugs may play a role in epigenetic modifications."

The process of methylation, as in DNA methylation where methyl groups are added to specific segments of the genome thus potentially altering the function of certain genes, as one facet of the emerging science of epigenetics, is something that interests me on this blog. Over and above the considerable 'hype' about epigenetics, there are some interesting details emerging from the various epigenetic studies of autism (see here for example) and schizophrenia (see here) that may well turn out to be important assuming appropriate independent scientific replication.

Rukova et al reported results based on an analysis of "20 individual Bulgarian patients with schizophrenia (8 females and 12 males) before and after treatment" whereby whole genome methylation analysis was used to look for differentially methylated regions (DMRs) pre- and post-antipsychotic use as a function of the remission or not of symptoms and gender. The results were not altogether clear insofar as some sort of methylomic biosignature linked to treatment response but researchers did report on several genes that may merit further investigation: "several new genes could be potential targets for new drug discovery: C16orf70, CST3, DDRGK1, FA2H, FLJ30058, MFSD2B, RFX4, UBE2J1 and ZNF311."

"The results from our investigation were shown statistically significant only for the male patient group in complete remission. This points out that epigenetic modification by DNA methylation is more important for male patients compared to females." This is another important detail described by Rukova bearing in mind the small participant group included for study. I'm not an expert on the role of gender/sex on response to antipsychotics but a quick look through the available research literature suggests that gender may be one of several 'non-modifiable' variables linked to therapeutic response [2] when it comes to schizophrenia. The idea that [some] males may benefit more from the epigenetic modifications potentially made by certain antipsychotics than [some] females potentially opens up a whole new world of drug discovery possibilities.

It's not necessarily new news that medicines such as antipsychotics may have quite a few more pharmacological actions than those listed on the PIL. Think about the idea that certain antipsychotics may have anti-parasitic qualities [3] as one example in light of all that schizophrenia - Toxoplasma gondii research (see here). That epigenetic properties should be added to the list of potential effects from antipsychotics [4] is also not necessarily new news.

What is perhaps important about the Rukova results outside of their focus on schizophrenia and antipsychotics is the way they looked at how epigenetics / methylation patterns might be implicated in schizophrenia and what it might mean for future research. If one were, for example, to apply a similar method of whole genome methylation analysis to say autism, and how said methylation patterns might change as a function of the myriad of interventions put forward for the condition, one could see how autism research might also benefit from such an approach...

Music: Magnetic Fields - The Book Of Love.

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[1] Rukova B. et al. Whole genome methylation analyses of schizophrenia patients before and after treatment. Biotechnol Biotechnol Equip. 2014 May 4;28(3):518-524.

[2] Carbon M. & Correll CU. Clinical predictors of therapeutic response to antipsychotics in schizophrenia. Dialogues Clin Neurosci. 2014 Dec;16(4):505-24.

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Rukova B, Staneva R, Hadjidekova S, Stamenov G, Milanova V, & Toncheva D (2014). Whole genome methylation analyses of schizophrenia patients before and after treatment. Biotechnology, biotechnological equipment, 28 (3), 518-524 PMID: 26019538

Gut bacteria and toddler temperament

The 'terrible twos'. Y'know, that special time in a child's development when the words 'mine' and 'no' are much more than a daily occurrence and visions of supermarket / restaurant meltdowns complete with scathing looks from strangers still linger in the rose-tinted memories of parenting.

There's still quite a bit of debate about the hows and whys of the terrible twos but new research by Lisa Christian and colleagues [1] implicates a hitherto unappreciated system potentially at work: our gut bacteria. Examining the possibility that "the community structure of the gut microbiome" might correlate with maternal measures of offspring temperament for 77 children aged between 18-27 months of age, researchers reported preliminary results looking at bacterial diversity and bacterial composition in relation to reported child behaviour across three scales of emotional reactivity according to media reports of the study (see here).

"Among both boys and girls, greater Surgency/Extraversion was associated [with] greater phylogenetic diversity." In other words, a more varied gut bacterial population seemed to correlate with scores more pertinent to an 'out-going' temperament "related with positive mood, curiosity, sociability and impulsivity." This is also the temperament style that seems to be potentially linked to later attentional issues such as ADHD (attention-deficit hyperactivity disorder) [2].

"Additional sex-specific associations between temperament and the gut microbiome were observed." So, taking into account gender/sex and temperament, certain types of gut bacteria were more commonly observed; specifically: "In boys only, researchers reported that extroverted personality traits were associated with the abundances of microbes from the Rikenellaceae and Ruminococcaceae families and Dialister and Parabacteroides genera." The exact meaning of these findings is unknown at present.

Importantly: "Some differences in dietary patterns were observed in relation to temperament, but these did not account for the observed differences in the microbiome." As anyone who has followed the recent 'Spector diet experiment' might know, there is a growing acceptance that what we eat (and drink) might have repercussions for the balance of the trillions of beasties that reside in our gut. The jury is however still out about the long-term effects of diet on the gut microbiota and indeed, what this might mean in relation to modifying risk of disease through diet affecting gut bacteria.

Assuming that the Christian results hold out following independent replication and the link between behaviour and gut bacteria keeps heading the direction it's heading (see here) there are some pretty important implications from this line of scientific thought. Minus the hype, one might reasonably ask: 'Is it possible to alter temperament by altering the gut microbiome?' as a primary question. The authors make some effort to answer this in the accompanying press about their findings: "Both researchers say that parents shouldn't try to change their child's gut microbiome just yet. Scientists still don't know what a healthy combination looks like, or what might influence its development." I agree that we don't yet know what it means to have a 'surgency/extraversion gut microbiome' but we do know that supplementation with probiotics for example, can seemingly affect aspects of behaviour and thought [3] (see my take here). Again, if we assume that diet affects gut bacterial composition, one might also acknowledge that what a young child eats is already affecting their gut bacteria populations, something that might have implications for our modern eating habits and various other issues. And then there are variable such as the issue of stool consistency to potentially take into account [4]...

Psychology textbooks perhaps might need rewriting in future eh?

Music: Hate to Say I Told You So - The Hives.

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[1] Christian LM. et al. Gut microbiome composition is associated with temperament during early childhood. Brain, Behavior, and Immunity. 2015; 45: 118-127.

[2] Bussing R. et al. Child temperament, ADHD, and caregiver strain: exploring relationships in an epidemiological sample. J Am Acad Child Adolesc Psychiatry. 2003 Feb;42(2):184-92.

[3] Steenbergen L. et al. A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain Behav Immun. 2015 Apr 7. pii: S0889-1591(15)00088-4.

[4] Vandeputte D. et al. Stool consistency is strongly associated with gut microbiota richness and composition, enterotypes and bacterial growth rates. Gut. 2015 Jun 11. pii: gutjnl-2015-309618.

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Christian LM, Galley JD, Hade EM, Schoppe-Sullivan S, Kamp Dush C, & Bailey MT (2015). Gut microbiome composition is associated with temperament during early childhood. Brain, behavior, and immunity, 45, 118-27 PMID: 25449582