Is anhedonia a key component of depression comorbid to autism?

Anhedonia: the inability to experience pleasure from activities usually found enjoyable.

Although by no means an expert on anhedonia (or much else), I believe that it is a concept quite important when it comes to making a diagnosis of depression although the precise hows and whys of connecting anhedonia to other symptoms are still the source of some discussion [1].

The paper from Vicki Bitsika & Christopher Sharpley [2] brings the concepts of anhedonia and depression into view with autism in mind. Based on the analysis of self-reported symptoms on the "Depression subscale of the Child and Adolescent Symptoms Inventory (CASI-D)" for 70 males diagnosed with an autism spectrum disorder (ASD) and 50 asymptomatic controls matched for age, authors reported that: "The MDD [major depressive disorder] profiles for the ASD participants were dominated by anhedonia."

Accepting that the label of autism seemingly very rarely exists in a diagnostic vacuum (see here) and that there is still some debate about whether comorbidity is just that or something rather more integral to parts of the growing pluralisation of autism (see here), the Bitsika/Sharpley paper is a potentially important one. Getting into the nitty-gritty details of how issues such as depression manifest on top of a diagnosis of autism is important as per the discussions by Vannucchi et al [3] (see here) on the "atypical presentation" of bipolar disorder with Asperger syndrome in mind. Knowing for example, that anhedonia might be more characteristic of MDD in cases of autism or even more centrally to autism [4], may offer not only a more detailed perspective on screening for and managing such issues as and when they occur, but also a little bit more detail about the mechanisms through which such symptoms may come about.

Music: Mercury Rev - Goddess on a Highway.

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[1] Gaillard R. et al. Anhedonia in depression. Encephale. 2013 Sep;39(4):296-305.

[2] Bitsika V. & Sharpley CF. Differences in the Prevalence, Severity and Symptom Profiles of Depression in Boys and Adolescents with an Autism Spectrum Disorder versus Normally Developing Controls. International Journal of Disability, Development and Education. 2015; 62: 158-167.

[3] Vannucchi G. et al. Bipolar disorder in adults with Asperger׳s Syndrome: A systematic review. J Affect Disord. 2014 Jul 8;168C:151-160.

[4] Chevallier C. et al. Brief report: Selective social anhedonia in high functioning autism. J Autism Dev Disord. 2012 Jul;42(7):1504-9.

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Bitsika, V., & Sharpley, C. (2015). Differences in the Prevalence, Severity and Symptom Profiles of Depression in Boys and Adolescents with an Autism Spectrum Disorder versus Normally Developing Controls International Journal of Disability, Development and Education, 62 (2), 158-167 DOI: 10.1080/1034912X.2014.998179

Asthma and ADHD (again)

"Asthmatic children had a higher risk of also having ADHD."

That was the conclusion reached by Kirsten Holmberg and colleagues [1] based on their analysis of rates of ADHD, and other variables found "through the Swedish Twin Register, linked to the Swedish Medical Birth Register, the National Patient Register and the Prescribed Drug Register." Said data came from over 20,000 twins who's parents were questioned when children were aged 9 or 12 years.

For those unfamiliar with the proposed connection [2] between the respiratory condition(s) headed under the label of asthma and the presentation of attention-deficit hyperactivity disorder (ADHD), this is not the first time that peer-reviewed research has hinted at some kind of relationship. The 'big data' studies coming out of Taiwan for example, have similarly reported an association (see here). That part of any relationship between asthma and ADHD might also be mediated by the comorbid appearance of autism (see here) has also been proposed, although the the idea that autism (singularly) and asthma might overlap has been recently questioned (see here).

Holmberg et al also reported that: "The association [between asthma and ADHD] was not restricted to either of the two dimensions of ADHD" following their analysis of the 'inattentive' and 'hyperactive/impulsive' domains that made up ADHD. They did find that asthma severity might however mediate the association with ADHD as per their reporting on an increased odds ratio (OR) "for >4 asthma attacks in the last 12 months."

What's more to say about this possible connection? Well, preferential screening for ADHD when a diagnosis of asthma is received might be something for healthcare professionals to consider first and foremost. Acknowledging also that there may be several facets to ADHD including those related to sleep for example (see here) one might also entertain some further clinical investigations here also in light of what asthma can also do to sleeping patterns and routines [3].

"Asthma medication seems not to increase the risk of ADHD" was another conclusion from Holmberg et al so to some degree allaying any fears that pharmacotherapy for asthma is 'causative' of ADHD. That being said, the idea that certain medicines might be 'linked' to both asthma and/or ADHD [4] is still deserving of further research consideration as has been previously mentioned on this blog (see here and see here). I might also put forward the idea that when it comes to overlapping variables potentially spanning asthma and ADHD, one might have a look at issues such as vitamin D availability (see here and see here) or even food (see here and see here) as potentially showing some shared involvement for some.

For whatever reason, the evidence linking asthma and ADHD is growing...

Music: Some Might Say from Oasis.

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[1] Holmberg K. et al. Impact of asthma medication and familial factors on the association between childhood asthma and ADHD A combined twin- and register-based study. Clin Exp Allergy. 2015 Mar 13.

[2] Chou CJ. et al. Asthma in patients with attention-deficit/hyperactivity disorder: a nationwide population-based study. Ann Clin Psychiatry. 2014 Nov;26(4):254-60.

[3] Teodorescu M. et al. Association between asthma and risk of developing obstructive sleep apnea. JAMA. 2015 Jan 13;313(2):156-64.

[4] Tiegs G. et al. New problems arising from old drugs: second-generation effects of acetaminophen. Expert Rev Clin Pharmacol. 2014 Sep;7(5):655-62.

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Holmberg K, Lundholm C, Anckarsäter H, Larsson H, & Almqvist C (2015). Impact of asthma medication and familial factors on the association between childhood asthma and ADHD A combined twin- and register-based study. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology PMID: 25772649

Sera from children with autism inducing autistic features in rats?

"The autism sera injected rats demonstrated developmental delay and deficits in social communication, interaction, and novelty."

That was one of the findings reported in the paper by Syed Faraz Kazim and colleagues [1] (open-access) who, among other things, injected intracerebroventricularly sera collected from children with autism into newborn rats and examined behavioural effects compared with injections of sera from asymptomatic controls. Actually, that was only one part of the research from Kazim et al but it does invite some further interesting questions...

In brief, and bearing in mind the paper is open-access, a few details:

• A caveat first: "Based on studies described in this manuscript, the authors submitted a patent application to the United States Patent and Trademark Office on 12/11/2014, entitled: “Treatment of Autism Spectrum Disorders with Ciliary Neurotrophic Factor Peptide Mimetic”; application number US62/083,570; Inventors: Khalid Iqbal and Inge Grundke-Iqbal." The authors report a potential competing interest and good on them for doing so.
• As noted, there were several aspects to this research focused to a large extent around neurotrophins including something called ciliary neurotrophic factor (CNTF) or rather "a CNTF small peptide mimetic, P6" which might have the ability to increase levels of BDNF (brain derived neurotrophic factor ), a compound that has cropped up before on this blog (see here).
• So: sera from children with autism were initially added to "mouse primary cultured cortical neurons grown for 72 hours in medium" and resulted in "gross morphological changes". Pretreatment of said mouse neurons with P6 - "which corresponds to amino acid residues 146–156 of human CNTF" - seemed to have an effect that: "resulted in a significant reduction in cell death in cultured neurons treated with sera from autistic children." Another detail derived from this experiment: "Primary cortical neurons grown in the presence of autistic sera showed higher levels of oxidative stress." Interesting in light of other research in this area with autism in mind (see here)...
• Next: what was it in the sera from autistic children which seemed to be having effects on mouse neurons which weren't seen in control sera? Well it's possible that: "the presence of neurotrophic abnormalities in the sera from autistic children that could have contributed to altered development of neurons and increase in cell death and oxidative stress found." By neurotrophic abnormalities, the authors meant issues with "mature CNTF and BDNF" among other things.
• Next were the results from those studies where rat pups were injected with autism or control sera "with or without P6". More quotes: "alterations in the levels of neurotrophic factors in the sera from autistic individuals could contribute to neurobehavioral phenotype of autism in rats". By that the authors reported some potential differences in rat behaviour focused on things like grooming behaviour (repetitive behaviour) and ultrasonic calls (akin to social communication). P6 potentially rescuing functions was also reported for some of the tests.
• Conclusion: with the caveats of much more investigation required and that rats are rats and not humans (see here) "this study provides evidence regarding the neurotrophic abnormalities in autism and the potential role they play in the pathophysiology" of the condition. Further: "Ameliorating the neurotrophic imbalance during early stages of brain development can serve as a potential therapeutic approach for autism. P6 represents a new class of neurotrophic peptide mimetics that has potential therapeutic value for ASD and related conditions."

I'm rather interested in this work and the potential for at least some cases of autism as and when replicative work is undertaken. I note in other patents from this group (see here) the idea that peptides with a neurotrophic link might have some application to "neural pathologies where BDNF levels are dysregulated" is one that has been embraced.

The authors, the late Inge Grundke-Iqbal & Khalid Iqbal, have a pretty impressive peer-reviewed track record based to a large extent on their work on neurodegeneration and "abnormally hyperphosphorylated tau" as the main component of the tangles in Alzheimer's disease. Indeed, these findings have particular relevance recently (see here). Applying their, and their research groups, expertise to autism is most definitely an asset, albeit with the requirement for quite a bit more research in this area.

To close: The Stone Roses - She Bangs the Drums.

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 [1] Kazim SF. et al. Sera from Children with Autism Induce Autistic Features Which Can Be Rescued with a CNTF Small Peptide Mimetic in Rats. PLoS ONE. 2015; 10(3): e0118627.

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Kazim, S., Cardenas-Aguayo, M., Arif, M., Blanchard, J., Fayyaz, F., Grundke-Iqbal, I., & Iqbal, K. (2015). Sera from Children with Autism Induce Autistic Features Which Can Be Rescued with a CNTF Small Peptide Mimetic in Rats PLOS ONE, 10 (3) DOI: 10.1371/journal.pone.0118627

Screening for autism in preterm infants

"A positive screen on the M-CHAT [Modified Checklist for Autism in Toddlers] occurs more commonly in very preterm infants than those born at term."

So said the study by Peter Gray and colleagues [1] as the topic of preterm status - that is, babies born alive before 37 weeks of pregnancy - potentially being linked to a greater risk of autism or at least, increased risk of screening positive for autism, crops up yet again on this blog (see here).

Gray et al examined a cohort of children born at the very boundaries of the definition of preterm ("≤30weeks gestation") when aged 2 years old, questioning mums of preterm children (n=97) and mums of term infants (n=77) with a whole range of questionnaires / schedules including the M-CHAT and the Child Behaviour Checklist (CBCL) among other things. "Previously collected data from the mothers at 12months - the Edinburgh Postnatal Depression Scales (EPDS)" were also analysed.

Authors reported that a higher percentage of preterm kids "screened positive on the M-CHAT" compared with term controls (13.4% vs. 3.9% respectively). These statistics decreased somewhat as a consequence of "an M-CHAT follow-up interview by phone" with only one child with membership of the preterm group subsequently receiving a diagnosis of autism from the entire cohort. The authors discuss some of the whys and wherefores of those pretermers who initially screened positive on the M-CHAT and how they were: "born to younger, non-Caucasian mothers and were of lower birth weight and had a higher incidence of being small for gestational age."

As per my discussion on the paper by Alexa Guy and colleagues [2] (see here again), the message coming through about using M-CHAT with the preterm population is again one of 'use with caution'. Indeed, the Gray paper illustrates how the follow-up consultation is a pretty important part of M-CHAT, something further developed on by the findings from Diana Robins and colleagues [3] and the whole M-CHAT-R/F thing (see here). I wouldn't necessarily say that M-CHAT is completely useless as a screen for autism under certain conditions. Merely that looking for the early red flags that might denote autism is very much still a work in progress potentially confounded by length of gestation. YouTube video anyone?

Music: PJ Harvey- The Words That Maketh Murder.

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[1] Gray PH. et al. Screening for autism spectrum disorder in very preterm infants during early childhood. Early Hum Dev. 2015 Mar 9;91(4):271-276.

[2] Guy A. et al. Infants Born Late/Moderately Preterm Are at Increased Risk for a Positive
Autism Screen at 2 Years of Age. J Pediatrics. 2014. 5 December.

[3] Robins DL. et al. Validation of the modified checklist for Autism in toddlers, revised with follow-up (M-CHAT-R/F). Pediatrics. 2014 Jan;133(1):37-45.

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Gray PH, Edwards DM, O'Callaghan MJ, & Gibbons K (2015). Screening for autism spectrum disorder in very preterm infants during early childhood. Early human development, 91 (4), 271-276 PMID: 25766314

Inflammation impairs social cognitive processing

A quote to begin: "acute inflammation can lead to decreases in the ability to accurately and reliably comprehend emotional information from others."

It comes from the article published by Mona Moieni and colleagues [1] who examined a concept familiar to many people with a connection to autism either personally or professionally: Theory of Mind (ToM). Rather interestingly, Moieni et al "examined whether exposure to an experimental inflammatory challenge led to changes in ToM." Inflammatory challenge refers to the artificial induction of a state of inflammation via the use of something called endotoxin, something I've covered under another name previously on this blog (see here).

As part of a larger research project on inflammation-induced depressed mood (see here) researchers set about looking at social cognition under inflammatory-inducing and placebo conditions specifically based on the "Reading the Mind in the Eyes (RME) test". The RME test has quite a firm foundation in autism research [2]. Their results indicated that using the RME test as a sort of measure of ToM "endotoxin (vs. placebo) led to decreases in performance on the RME test from baseline to the peak of inflammatory response, indicating that acute inflammation can lead to decreases in the ability to accurately and reliably comprehend emotional information from others."

With the caveats that (a) this wasn't a study of people with autism (or at least not those diagnosed with autism) and (b) acute inflammation may not be the same as chronic inflammation, these are intriguing results potentially overlaying onto several other research areas. Autism and inflammation is something that I'm quite interested in on this blog as per the idea that physiology and psychology might not be some far apart in certain cases/types of autism (see here). That other somatic manifestations might also be linked to inflammatory processes with autism in mind (see here) is something else to mention.

I hold back from saying that all those with autism who 'fail' ToM tasks are somehow in a state of inflammation given that this is a complicated area (see here). As per my previous ramblings, I'm also not necessarily the greatest fan of the sweeping generalisations made about ToM when it comes to autism (see here). Particularly when one looks at the way that ToM is examined in relation to autism [3] and how ToM issues cross quite a few different labels [4] some of which might overlap with autism (see here).

Still, if there is the remotest possibility that the physiological state of acute inflammation might correlate with issues with mentalising or completing mentalising tasks, I'd be minded to suggest that future work on ToM might be minded to take this into account. Likewise, in all those studies looking at inflammatory processes linked to something like autism, measuring ToM before and after could represent an interesting parameter when looking at potential interventions...

Some music then... The Wedding Present and My Favourite Dress.

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[1] Moieni M. et al. Inflammation impairs social cognitive processing: A randomized controlled trial of endotoxin. Brain, Behavior, and Immunity. 2015. May 10.

[2] Baron-Cohen S. et al. The "Reading the Mind in the Eyes" Test revised version: a study with normal adults, and adults with Asperger syndrome or high-functioning autism. J Child Psychol Psychiatry. 2001 Feb;42(2):241-51.

[3] Iao LS. & Leekam SR. Nonspecificity and theory of mind: new evidence from a nonverbal false-sign task and children with autism spectrum disorders. J Exp Child Psychol. 2014 Jun;122:1-20.

[4] Chung YS. et al. A meta-analysis of mentalizing impairments in adults with schizophrenia and autism spectrum disorder. Schizophr Bull. 2014 May;40(3):602-16.

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Moieni M, Irwin MR, Jevtic I, Breen EC, & Eisenberger NI (2015). Inflammation impairs social cognitive processing: a randomized controlled trial of endotoxin. Brain, behavior, and immunity PMID: 25770082

Autism increases risk of nonaffective psychotic disorder and bipolar disorder

Published at the same time and in the same journal as the 'MoBa does bowel issues in autism' paper from Bresnahan and colleagues [1], the study results from Jean-Paul Selten et al [2] reporting that "A diagnosis of ASD [autism spectrum disorder] is associated with a substantially increased risk for NAPD [nonaffective psychotic disorder] and BD [bipolar disorder]" has, at the time of writing this post, received little or no press attention in comparison despite being pretty important findings.

Continuing an important theme that a diagnosis of autism is in no way protective against the development of mental health issues (see here), the Selten results suggest that quite a bit more diagnostic vigilance might be required in order to ensure that further health inequalities do not appear for those on the autism spectrum.

Containing a familiar author name - Cecilia Magnusson, who is no stranger to autism research - the authors set about analysing data from the Stockholm Youth Cohort [3] and specifically "included cohort members ever diagnosed as having ASD (n = 9062) and their full siblings never diagnosed as having ASD." Cases were matched 10 to 1 with controls of the same sex and born in the same month/year. Researchers looked for diagnoses of NAPD and BD and importantly "adjusted for age, sex, population density of place of birth, personal or parental history of migration, hearing impairment, parental age, parental income, parental educational level, and parental history of psychiatric disorder."

Results: distinguishing between cases of autism with intellectual (learning) disability and those without, those diagnosed with autism without intellectual disability (ID) were calculated to show "a substantially increased risk for NAPD and BD" compared with controls. Depending on whether ASD was "registered before age 16 or 28 years" also seemed to play a role in the risk (odds ratios, ORs) statistics. Those "non-ID ASD registered before age 28 years" presented with ORs of 12.3 and 8.5 respectively for NAPD and BD. Those "non-ID ASD registered before age 16 years" presented with ORs of 5.6 and 5.8 respectively. The comparative statistics for full siblings of those with ASD for NAPD and BD were also elevated (ORs: 1.8 and 1.7 respectively) but nothing like to the degree noted for those with a diagnosis of ASD.

As I've mentioned, these are important findings. I've talked a few times on this blog about conditions like psychosis being diagnosed alongside cases of autism (see here and see here). The data from Khandaker and colleagues [4] (see here) reporting on a "Higher risk of PEs [psychotic experiences] in early adolescence among individuals with childhood ND [neurodevelopmental disorders]" adds to the evidence that there may be shared mechanisms at work when it comes to something like autism and schizophrenia for example (see here). This might also mean that our views about autism across the lifespan should more thoroughly incorporate the higher risk of mental health issues potentially being noted. Anyone who follows this blog and my ramblings about the health inequalities associated with something like schizophrenia (see here for example) will know what this might mean for some on the autism spectrum too.

Insofar as the findings on bipolar disorder potentially being more frequently noted when autism is mentioned, I'm not at all surprised. 'Bipolar disorder is frequent in adult Asperger syndrome' was a post I previously wrote on this topic and how, based on research like that from Vannucchi and colleagues [5], anywhere between 6-20% of those with Asperger syndrome (AS) can potentially expect to be diagnosed with BD at some stage. Actually I'd probably suggest the rate might be higher than those statistics suggest given the assertion that BD in autism/AS is: "often characterized by atypical presentation, making its correct identification particularly difficult."

Need I say any more?

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[1] Bresnahan M. et al. Association of Maternal Report of Infant and Toddler Gastrointestinal Symptoms With Autism Evidence From a Prospective Birth Cohort. JAMA Psychiatry. 2015. March 25.

[2] Selten JP. et al. Risks for Nonaffective Psychotic Disorder and Bipolar Disorder in Young People With Autism Spectrum Disorder: A Population-Based Study. JAMA Psychiatry. 2015 Mar 25.

[3] Idring S. et al. Autism spectrum disorders in the Stockholm Youth Cohort: design, prevalence and validity. PLoS One. 2012;7(7):e41280.

[4] Khandaker GM. et al. A population-based longitudinal study of childhood neurodevelopmental disorders, IQ and subsequent risk of psychotic experiences in adolescence. Psychol Med. 2014 Nov;44(15):3229-38.

[5] Vannucchi G. et al. Bipolar disorder in adults with Asperger׳s Syndrome: A systematic review. J Affect Disord. 2014 Jul 8;168C:151-160.

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Selten JP, Lundberg M, Rai D, & Magnusson C (2015). Risks for Nonaffective Psychotic Disorder and Bipolar Disorder in Young People With Autism Spectrum Disorder: A Population-Based Study. JAMA Psychiatry PMID: 25806797

MoBa does bowel issues in autism

'MoBa' in the title of this post, refers to the Norwegian Mother and Child Cohort Study and a handy resource which has already impacted on autism research (see here for example).

Now MoBa has turned its epidemiological clout to an issue which less and less is encountering scientific resistance: are gastrointestinal (GI) symptoms over-represented when it comes to a diagnosis of autism? Further, when do such bowel issues start to present?

The answer, shown in the paper by Michaeline Bresnaha and colleagues [1] is yes, functional bowel symptoms are seemingly more frequently reported when it comes to autism as per the results of quite a few other studies. To quote from the authors: "maternally reported GI symptoms are more common and more often persistent during the first 3 years of life in children with ASD [autism spectrum disorder] than in children with TD [typical development] or DD [developmental delay]." Said symptoms also seemed to present pretty early on; quite a bit before many children are diagnosed with autism. Some further coverage of these findings can be seen here and here.

Including a couple of giants in research terms on the authorship list - Mady Hornig and Ian Lipkin - who also continue to push the research boundaries in relation to another diagnosis which crops up on this blog (CFS/ME or SEID as it may well be eventually known) - MoBa was put to use.

Authors "defined 3 groups of children: children with ASD (n = 195), children with DD and delayed language and/or motor development (n = 4636), and children with TD (n = 40 295)." Maternal reports garnered prospectively covering various GI symptoms including "constipation, diarrhea, and food allergy/intolerance" were analysed across the groups covering children at 6, 18 and 36 months of age.

The results suggested that constipation and food allergy/intolerance were more likely to be reported in children with autism during the 6-18 month old age range compared with typically developing controls. Diarrhoea and food allergy/intolerance were also more likely to be reported in children with autism in the 18-36 month age range again, compared with TD controls. Children with autism/ASD were also more likely to present with "1 or more GI symptom in either the 6- to 18-month or the 18- to 36-month-old age period and more than twice as likely to report at least 1 GI symptom in both age periods compared with mothers of children with TD or DD." Some might quibble about the use of maternal report in discussing the presentation of bowel issues in children but I'm not one of them (see here) as the Gorrindo findings [2] drift back into my consciousness.

The press release attached to this study also contains an intriguing quote from Mady Hornig: "Although the connection of GI disturbances to autism remains unclear, the presence of GI symptoms in early life may not only help to identify a subset of children with autism who require clinical input for their GI issues, it may also open new avenues for determining the underlying nature of the disorder in that subgroup." The implication being that (a) GI symptoms, early GI symptoms, are not a universal (or exclusive) feature of autism, but are present in quite a few infants, and (b) among the increasingly pluralised view of autism (see here), the idea that said GI symptoms might represent something quite fundamental to some cases of autism offers something of an opportunity to perhaps intervene and treat/manage both bowel symptoms and potentially impact on behavioural features linked to autism. On this point I'm drawn back to some of the research from Micah Mazurek and colleagues talking about sensory issues and anxiety completing a triad with bowel issues with autism in mind (see here).

I'm probably repeating myself here but quite a bit more research is required on the relationship between autism and the presentation of GI issues. I'd be inclined to suggest that a few research areas might be useful to explore: (a) the link between functional bowel issues and more pathological bowel states (see here), (b) the link between inflammation / inflammatory markers and bowel issues (see here) taking into account the work of people like Harumi Jyonouchi for example (see here), (c) the possibility that bowel issues might have some connection back to the gut microbiota as per other work by Hornig/Lipkin (see here), and (d) how said GI issues might impact on issues such as pharmacotherapy in terms of drug availability and absorption issues (see here). This isn't an exhaustive list, just a few ideas to play around with.

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[1] Bresnahan M. et al. Association of Maternal Report of Infant and Toddler Gastrointestinal Symptoms With Autism Evidence From a Prospective Birth Cohort. JAMA Psychiatry. 2015. March 25.

[2] Gorrindo P. et al. Gastrointestinal dysfunction in autism: parental report, clinical evaluation, and associated factors. Autism Res. 2012 Apr;5(2):101-8.

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Bresnahan, M., Hornig, M., Schultz, A., Gunnes, N., Hirtz, D., Lie, K., Magnus, P., Reichborn-Kjennerud, T., Roth, C., Schjølberg, S., Stoltenberg, C., Surén, P., Susser, E., & Lipkin, W. (2015). Association of Maternal Report of Infant and Toddler Gastrointestinal Symptoms With Autism JAMA Psychiatry DOI: 10.1001/jamapsychiatry.2014.3034

Autism and depression: interlinked?

"A possible implication is that interventions aimed at either autism symptoms or symptoms of depression may improve the other."

That was the intriguing statement made by Per Normann Andersen and colleagues [1] who "investigated the course of and association among changes in autism symptoms, depression symptoms and executive functions (EF) in children with high-functioning autism (HFA)." Aside from frowning a little at the mention of the concept of 'high-functioning' I assume to denote those who have "relatively mild symptoms which, despite their mildness, are significant enough to merit an autism spectrum diagnosis" according to one description (see here), I was interesting in the Andersen findings. Specifically, the idea that the spectrum of depression (depressive illness if you will) might be something rather more integral to the presentation of autism at least for some people.

I've talked before about depression as one of several mental health issues/problems perhaps over-represented following a diagnosis of autism (see here). The paper by Vannucchi and colleagues [2] covered in a previous post (see here) did particularly well bringing into sharp focus the fact that bipolar disorder may very well be a frequent comorbidity in cases of Asperger syndrome albeit "often characterized by atypical presentation, making its correct identification particularly difficult."

Of course this is not the first time that something of a rather intimate relationship has been reported when considering depression and autism together. Takara & Kondo [3] (open-access) reported that: "Depressed adults with comorbid atypical autistic traits are at higher risk for suicide attempts and may engage in methods that are more lethal" based on their case-control study. This is perhaps one of the more extreme outcomes potentially associated with depression but also highlights something of a growing realisation that suicide ideation may not be an uncommon issues reported by some on the autism spectrum (see here) and may to some extent tie into the presentation of depression.

Further work is required to better categorise depression comorbid to a diagnosis on the autism spectrum as per the the findings from Gotham and colleagues [4]. Additional work is also required on the best way(s) to tackle depression in cases of autism whether based on pharmacotherapy or other more psychological approaches. I might also advance the case that several other potentially important variables be also examined, such as vitamin D (see here) in light of the evidence related to autism in this area and the various anti-inflammatory strategies (see here) also tentatively put forward as management options for depression. Inflammation and autism, as some readers might know, is a topic in the research ascendancy (see here). There may be other areas slightly outside of the mainstream that might also be considered as research targets too.

Without any medical advice given or intended, I'm also going to link you to the case study (stress: case study) presented by Philip Bird [5] (open-access) talking about the use of the anti-epileptic phenytoin with a young man with autism. Aside from some interesting positive effects recorded on autism presentation, Bird also noted that: "Post-treatment, there was robust change in all domains, with an absence of depressive symptoms and with both anxiety and stress being recorded as moderate." I'm not saying that this will be for everyone (personalised medicine and all that). Merely that there may be many different ways of tackling such issues when combined and some thinking 'outside of the box' might be required.

The next questions: how does depression combine with something like anxiety with autism in mind, and what happens to depressive and other symptoms when anxiety is 'treated'? Further, given the connection between depression and other diagnoses such as schizophrenia [6] and acknowledging that a diagnosis of autism is seemingly not protective against developing schizophrenia (see here), are there other lessons that could be learned about the relationship(s) between various diagnostic labels?

More research is indicated...

So: Black Grape - Reverend Black Grape.

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[1] Andersen PN. et al. Associations Among Symptoms of Autism, Symptoms of Depression and Executive Functions in Children with High-Functioning Autism: A 2 Year Follow-Up Study. J Autism Dev Disord. 2015 Mar 13.

[2] Vannucchi G. et al. Bipolar disorder in adults with Asperger׳s Syndrome: A systematic review. J Affect Disord. 2014 Jul 8;168C:151-160.

[3] Takara K. & Kondo T. Comorbid atypical autistic traits as a potential risk factor for suicide attempts among adult depressed patients: a case-control study. Ann Gen Psychiatry. 2014 Oct 16;13(1):33.

[4] Gotham K. et al. Depression and its measurement in verbal adolescents and adults with autism spectrum disorder. Autism. 2014 Jun 10. pii: 1362361314536625.

[5] Bird PD. The treatment of autism with low-dose phenytoin: a case report. J Med Case Rep. 2015 Jan 16;9:8.

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Andersen PN, Skogli EW, Hovik KT, Egeland J, & Øie M (2015). Associations Among Symptoms of Autism, Symptoms of Depression and Executive Functions in Children with High-Functioning Autism: A 2 Year Follow-Up Study. Journal of autism and developmental disorders PMID: 25763986

More extremes of a limiting diet and autism

In a previous post a while back, I discussed some examples in the peer-reviewed literature of where a self-limiting diet in the extreme can lead to with autism in mind. Today, I'm adding a further example of what food faddism might mean, to further forward the point that "a low threshold for vitamin level testing should be undertaken in autistic spectrum disorder cases, highlighting the importance of enquiring about dietary habits."

That last quote comes from the paper in question by Emma Duignan and colleagues [1] (open-access available here) who describe two case reports of teenagers with autism "with a background of moderate autistic spectrum disorder who were diagnosed with a multivitamin deficiency, including vitamin A." Said nutritional deficiency manifested as ophthalmic issues - relating to the physiology of the eye - that importantly seemed to abate following vitamin supplementation.

Aside from the idea that several factors might align to bring a person diagnosed with autism to a deficiency state, I was interested in the Duignan results for a few other reasons. I've talked about vitamin and mineral deficiencies a few times on this blog; more generally as per the results from Jim Adams and colleagues back in 2011 (see here) following the publication of their double-blind, placebo-controlled trial of supplementation through to more specific issues with something like the vitamin-of-the-hour, vitamin D (see here) or even the scurvy-preventer that is vitamin C (see here). There is quite a bit of literature out there to suggest that particularly in cases where dietary issues are noted to accompany a diagnosis of autism or autism spectrum disorder (ASD), one perhaps should expect nutritional deficiencies to follow.

The other thing that struck me about the Duignan results was the focus on ophthalmic issues as manifestations of those vitamin deficiency issues. It's not new news that among the various effects linked to something like vitamin A deficiency for example, vision and eye health may suffer. Although still in need of quite a bit of research, issues related to the eyes and knock-on effects for things like visual perception are no stranger to autism research as per my ramblings about the findings reported by Ikeda and colleagues [2]. The paper from Pineles and colleagues [3] on optic neuropathy due to vitamin B12 deficiency in cases of autism is also worth mentioning at this point and the question of whether at least some of the visual perceptual issues discussed with autism in mind might have a nutritional link?

We don't currently know how widespread nutritional deficiencies are when a diagnosis of autism is received because, at the moment, this is not something that is routinely tested for. On the basis of the Duignan and other results, I'd be minded to repeat my suggestion that where dietary issues are present for people on the autism spectrum, modern medicine could do a lot worse than find out whether there may be biological effects to come from a limited or restricted diet save any further charges of health inequality being levelled...

Music to close. Paul Simon - Me and Julio Down by the Schoolyard.

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[1] Duignan E. et al. Ophthalmic manifestations of vitamin a and d deficiency in two autistic teenagers: case reports and a review of the literature. Case Rep Ophthalmol. 2015 Jan 24;6(1):24-9.

[2] Ikeda J. et al. Brief report: incidence of ophthalmologic disorders in children with autism. J Autism Dev Disord. 2013 Jun;43(6):1447-51.

[3] Pineles SL. et al. Vitamin B12 optic neuropathy in autism. Pediatrics. 2010 Oct;126(4):e967-70.

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Duignan, E., Kenna, P., Watson, R., Fitzsimon, S., & Brosnahan, D. (2015). Ophthalmic Manifestations of Vitamin A and D Deficiency in Two Autistic Teenagers: Case Reports and a Review of the Literature Case Reports in Ophthalmology, 6 (1), 24-29 DOI: 10.1159/000373921

Early life probiotics reducing the risk of subsequent neuropsychiatric disorder?

With my continued interest in all-things gut microbiome on this blog (see here for example) it is little wonder that I was taken to blog about the study findings from Anna Pärtty and colleagues [1] reporting that: "Probiotic supplementation early in life may reduce the risk of neuropsychiatric disorder development later in childhood." Probiotic by the way, refers to various 'live' organisms (bacteria, yeasts) thought to confer some positive effect on health and/or wellbeing.

Not only does such a conclusion weigh into the increasingly vocal debate about the gut-brain axis (whereby the gut and it's contents may play quite an important role outside of just digesting food and providing fuel for the body) but also the idea that supplementation during early infancy with Lactobacillus rhamnosus GG (ATCC 53103) might actually offset risk of diagnoses such as attention deficit hyperactivity disorder (ADHD) and/or Asperger syndrome (AS) being received up to 13 years later is potentially pretty important. Potentially.

At the time of first tweeting about the paper by Pärtty et al, one of the first replies concerned another sentence in the paper abstract: "At the age of 13 years ADHD or AS was diagnosed in 6/35 (17.1%) children in the placebo and none in the probiotic group (p=0.008)." Not only was no-one diagnosed with AS or ADHD in the probiotic group, but a whopping 17% of those in the control group subsequently received a diagnosis "by a child neurologist or psychiatrist were based on ICD-10 diagnostic criteria". Accepting the small participant groups included for study, that figure of 17% far exceeds anything that I'm aware of when it comes to the population estimates for AS and/or ADHD. The pediatric ADHD estimates normally come in at between 5-8% (see a post I wrote about this here) and although reliable figures for AS are few and far between outside of the umbrella 'autism spectrum disorder' I don't think the rate [2] is going to be anything like that reported by Pärtty et al. I say this accepting that in the latest version of DSM (DSM-5) AS does not exist as a specific categorical label any more.

A few further details about the Pärtty study might be in order:

• I believe their latest paper is part of a wider research initiative by this group looking at "probiotic intervention in the perinatal period and risk of allergic and inflammatory diseases later in life" [3]. The ClinicalTrials.gov entry can be seen here. Findings based on probiotic supplementation for crying and fussing in preterm infants [4] have also been reported on using the same probiotic preparation compared against a prebiotic and a placebo ("microcrystalline cellulose and dextrose anhydrate").
• This time around Lactobacillus rhamnosus GG (ATCC 53103) or placebo was supplemented to infants during early infancy (first 6 months) and at various points particularly in the first two years of life, the gut microbiome was assessed.
• Aside from that label or no label outcome at 13 years old, the authors reported that: "The mean (SD) numbers of Bifidobacterium species bacteria in feces during the first six months of life was lower in affected children... than in healthy children."

Obviously one has to be a little cautious about accepting the Pärtty results at face value in terms of modifying the risks of ADHD or AS (or anything else). As much as some people would like to think that the gut microbiome is the be-all-and-end-all of autism research, it is more likely to be one part of a very complicated picture for some. The paper by Daniel McDonald and colleagues [5] (open-access) talks about the journey still required for gut microbiome research with autism in mind.

I might also direct you to the findings reported by Rinne and colleagues [6] talking about how probiotic supplementation "administered for 6 months postnatally" did not seem to have as much of an effect on "long-term composition or quantity of gut microbiota" as one might think. Whether this ties into the sentiments from Pärtty et al when they talked about "mechanisms not limited to gut microbiota composition" to account for their results is a question open to some debate. One could conceivably assume that there may be some critical period during early infancy when gut bacteria may modify (directly or peripherally) biological mechanisms pertinent to risk of neuropsychiatric disorder. But evidence of such an effect is fairly thin on the ground at present outside of the various reports of early and repeated antibiotic administration (which would impact on the gut microbiome) being talked about in the histories of some people who went on to receive a diagnosis (see here). Oh and the idea of psychobacteriomics too (see here).

Still, I'd be minded to suggest that the recent results should be inviting a lot more inquiry into the area of the gut and psychology/behaviour as not being as distant as one might first imagine [7].

Music: Eric B. & Rakim - Paid In Full.

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[1] Pärtty A. et al. A possible link between early probiotic intervention and the risk of neuropsychiatric disorders later in childhood - a randomized trial. Pediatr Res. 2015 Mar 11.

[2] Suzuki Y. & Saito K. Epidemiology of Asperger's syndrome. Nihon Rinsho. Japanese Journal of Clinical Medicine. 2007; 65: 419-423.

[3] Pärtty A. et al. Infant distress and development of functional gastrointestinal disorders in childhood: is there a connection? JAMA Pediatr. 2013 Oct;167(10):977-8.

[4] Pärtty A. et al. Effects of early prebiotic and probiotic supplementation on development of gut microbiota and fussing and crying in preterm infants: a randomized, double-blind, placebo-controlled trial. J Pediatr. 2013 Nov;163(5):1272-7.e1-2.

[5] McDonald D. et al. Towards large-cohort comparative studies to define the factors influencing the gut microbial community structure of ASD patients. Microbial Ecology in Health & Disease 2015; 26: 26555.

[6] Rinne M. et al. Probiotic intervention in the first months of life: short-term effects on gastrointestinal symptoms and long-term effects on gut microbiota. J Pediatr Gastroenterol Nutr. 2006 Aug;43(2):200-5.

[7] Severance EG. et al. Gastroenterology Issues in Schizophrenia: Why the Gut Matters. Current Psychiatry Reports. 2015; 17: 27.

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Pärtty A, Kalliomäki M, Wacklin P, Salminen S, & Isolauri E (2015). A possible link between early probiotic intervention and the risk of neuropsychiatric disorders later in childhood - a randomized trial. Pediatric research PMID: 25760553

Toxoplasma gondii and schizophrenia (again and again)

The findings reported by Ainsah Omar and colleagues [1] (open-access available here) adding further weight to the notion of a "strong association between the active Tg [Toxoplasma gondii] infection and schizophrenia" are set out for your reading consumption today.

Continuing a research topic that has already enjoyed quite a bit of air time on this blog (see here and see here) whereby the parasite T. gondii known to cause the condition toxoplasmosis might also be implicated in at least some cases of schizophrenia, Omar et al report some pretty stark differences in rates of seropositivity between cases of schizophrenia (n=101) and asymptomatic controls (n=55).

"The serofrequency of Tg IgG antibodies (51.5%, 52/101) and DNA (32.67%, 33/101) among patients with schizophrenia was significantly higher than IgG (18.2%, 10/55) and DNA (3.64%, 2/55) of the controls." IgG antibodies refers to immune status with regards to a particular agent with the focus on past or recent exposure to said pathogen. In this respect, the results suggest that over half of participants with schizophrenia had met with T. gondii at some point compared with nearly 20% of controls. Insofar as active infection measured by IgM antibodies to T. gondii, the authors reported no significant difference in rates between the groups. DNA, as in measurement for the presence of T. gondii DNA as evidence of infection, also showed some interesting differences between the groups in favour of the schizophrenia group.

"In our study, the OR [odds ratios] of having schizophrenia among those with positive Tg DNA (OR=12.9) was much higher than those with positive Tg IgG antibody (OR=4.8)." This sentence in particular hints at some of the novelty behind the results from Omar et al with their focus on both antibody response to T. gondii infection and their more direct method of looking for T. gondii DNA.

"Although there was significant difference in the seropositivity of Tg IgG and Tg DNA between the 2 groups, however, there was no significant difference between the serointensity of Tg IgG antibody and DNA between schizophrenia patients and controls. These could possibly be due to the effects of antipsychotic medications which caused the reduction in the level of Tg IgG antibody and DNA by inhibiting the replication of Tg." I've talked before on this blog about how a wide variety of the medicines we use in modern times may have so many more 'effects' than those listed on the package insert. Certain antipsychotic drugs are known to possess "anti-toxoplasmic activity" [2] and one might entertain the fact that when used for some with schizophrenia there is the potential for some effect mediated via this pathway. I would like to see a lot more medicines tested for their anti-parasitic effects [3] that's for sure.

Of course one has to be a little cautious not to make too many generalisations from the findings from Omar and other research groups [4] (several other research groups [5]) about the idea that T. gondii might be linked to cases of schizophrenia. But as part of a wider research strategy [6] and accepting the moves towards the possible pluralisation of schizophrenia (see here), I believe there is quite a bit more to see in this area...

Music: The Cure - Pictures Of You.

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[1] Omar A. et al. Seropositivity and Serointensity of Toxoplasma gondii Antibodies and DNA among Patients with Schizophrenia. Korean J Parasitol. 2015 Feb;53(1):29-34.

[2] Fond G. et al. Comparative analysis of anti-toxoplasmic activity of antipsychotic drugs and valproate. Eur Arch Psychiatry Clin Neurosci. 2014 Mar;264(2):179-83.

[3] Fond G. et al. Treatment with anti-toxoplasmic activity (TATA) for toxoplasma positive patients with bipolar disorders or schizophrenia: A cross-sectional study. J Psychiatr Res. 2015 Feb 24. pii: S0022-3956(15)00043-6.

[4] Cevizci S. et al. Seroprevalence of anti-Toxoplasma gondii and anti-Borrelia species antibodies in patients with schizophrenia: a case-control study from western Turkey. World J Biol Psychiatry. 2015 Mar 16:1-7.

[5] Khademvatan S. et al. Toxoplasma gondii Exposure and the Risk of Schizophrenia. Jundishapur J Microbiol. 2014 Nov;7(11):e12776.

[6] Severance EG. et al. Gastroenterology Issues in Schizophrenia: Why the Gut Matters. Current Psychiatry Reports. 2015; 17: 27.

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Omar A, Bakar OC, Adam NF, Osman H, Osman A, Suleiman AH, Manaf MR, & Selamat MI (2015). Seropositivity and Serointensity of Toxoplasma gondii Antibodies and DNA among Patients with Schizophrenia. The Korean journal of parasitology, 53 (1), 29-34 PMID: 25748706

Autism genes and cognitive ability

Autism IS linked to higher intelligence: People with genes related to the condition 'scored better in mental ability tests' was one of the media headlines reporting on the study by Toni-Kim Clarke and colleagues [1].

Clarke et al reported results based on a pretty good sample size (in the thousands) whereby autism-associated genes and cognitive ability were examined in several cohorts including those taking part in The Generation Scotland : Scottish Family Health Study (GS:SFHS) (see here for further information). Polygenic risk for autism spectrum disorder (ASD), that is risk governed by several genes, "is positively correlated with general cognitive ability" was a primary finding. Ergo, among the general population omong those not diagnosed with autism, carrying some of the proposed genetic risk factors for the condition might confer something of a cognitive advantage albeit only a slight advantage. The same could not be said for the relationship between polygenic risk for ADHD (attention deficit hyperactivity disorder) and cognitive ability also reported on by the authors.

These are potentially important findings covered pretty well by the NHS Choices website (see here) which concluded that "The study is likely to be of interest to researchers, but does not have any obvious practical implications for individuals." Aside from the idea that certain genes linked to autism might not necessarily just be solely linked to 'disability' and *might* offer some explanation for the islets of ability reported in some on the autism spectrum [2], the Clarke findings could also be interpreted in a number of other ways. They could for example, be taken as evidence that to talk about 'autism-related genes' might actually be more accurately done so as referring to them as being autism-cognition related genes stressing the link between presented traits and cognitive ability. They may also suggest that carrying said risk genes does not automatically equate as receiving a label of autism as per the authors focus on those who never developed autism yet presented with the risk versions of the genes. Accepting also that 'autism genes' refers to a complicated and ever-increasing bank of risk genes, this might also open the door to other mechanisms at work related to risk of autism, perhaps other, more environmentally driven factors also having some interactive effect?

I could spend all day talking about the genetics of cognitive ability on the back of studies such as the one from Plomin & Deary [3]. Among the important points made with such research in mind is that genes linked to concepts such as intelligence or cognitive ability are also likely to similarly impact on other traits too. The paper from Eva Krapohl and colleagues [4] hinted at this with regards to education achievement and test performance scores, and how one has to take quite a wide view when it comes to the genetics of something like cognition or autism. The days of one gene = one condition / one trait are seemingly long gone. Oh, and that gene function outside of structural genomics might also be important [5] is worth mentioning...

Without wishing to dilute the positive message to come from the Clarke findings, I feel I should also raise the important issue of how enhanced cognitive ability does not necessarily automatically translate into better life outcomes. I kinda touched upon this in a post a few years back talking about outcome and autism (see here) and how we live in an age where some truly intellectually gifted individuals live among us, but this does not necessarily mean that they live the life they want or deserve. The quite depressing figures on the rates of employment for those with autism [6] who can and want to work are for example, a stark reminder of how societal and other factors play an important role irrespective of any cognitive prowess.

And of course, there may be other factors at work...

Music: Setting Sun by The Chemical Brothers. Particularly apt for today (see here).

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[1] Clarke T-K. et al. Common polygenic risk for autism spectrum disorder (ASD) is associated with cognitive ability in the general population. Molecular Psychiatry. 2015. March 10.

[2] Shah A. & Frith U. An islet of ability in autistic children: a research note. J Child Psychol Psychiatry. 1983 Oct;24(4):613-20.

[3] Plomin R. & Deary IJ. Genetics and intelligence differences: five special findings. Mol Psychiatry. 2015 Feb;20(1):98-108.

[4] Krapohl E. et al. The high heritability of educational achievement reflects many genetically influenced traits, not just intelligence. Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15273-8.

[5] Haggarty P. et al. Human Intelligence and Polymorphisms in the DNA Methyltransferase Genes Involved in Epigenetic Marking. PLoS ONE. 2010;5(6):e11329.

[6] Taylor JL. & Seltzer MM. Employment and post-secondary educational activities for young adults with autism spectrum disorders during the transition to adulthood. J Autism Dev Disord. 2011 May;41(5):566-74.

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Clarke TK, Lupton MK, Fernandez-Pujals AM, Starr J, Davies G, Cox S, Pattie A, Liewald DC, Hall LS, MacIntyre DJ, Smith BH, Hocking LJ, Padmanabhan S, Thomson PA, Hayward C, Hansell NK, Montgomery GW, Medland SE, Martin NG, Wright MJ, Porteous DJ, Deary IJ, & McIntosh AM (2015). Common polygenic risk for autism spectrum disorder (ASD) is associated with cognitive ability in the general population. Molecular psychiatry PMID: 25754080