Sensory subtypes and anxiety and autism

"This is the first study to identify the existence of sensory subtypes among older children and adolescents with ASD [autism spectrum disorder] and explore their association with anxiety levels."

Far be it from me to question the above quote provided in the paper by Mirko Uljarević and colleagues [1] but I'm inclined to suggest that there has already been some research published on the link between sensory issues and anxiety in the context of the autism spectrum before (see here and see here). Indeed, I do wonder whether the assertions put forward by Mazurek and colleagues [2] on how gastrointestinal (GI) issues (yes, they are over-represented) might be an important part of any sensory/anxiety mix in autism could be something that is further looked at by Uljarević in their cohort?

Anyhow, the Uljarević paper is an interesting one given the idea that within the vast heterogeneity that is autism (or even the autisms) sensory issues as measured by "the short sensory profile" are not
uniform in their presentation (a shocker, I know). The finding that anxiety scores, as measured by the Spence anxiety scales, were potentially a little different according to sensory subtype (sensory adaptive, sensory moderate, sensory severe) particularly when it came to the sensory adaptive grouping - "Children and adolescents from the adaptive subtype had significantly lower anxiety scores when compared with other two subtypes" - is important. The implication being that with various other variables not differing (chronological age, expressive language, or severity of autism diagnostic features) sensory issues might be one important driver of the presentation of anxiety when it comes to autism.

As I've mentioned quite a few times on this blog, the topic of anxiety and autism is an important one (see here for example). There are a few different 'types' of anxiety (or anxiety diagnoses) that might be more applicable to autism alongside some discussion about how to measure anxiety when it comes to autism (see here). But the primary messages are: (i) anxiety is pretty rife in terms of accompanying a diagnosis of autism and (ii) the effects of anxiety can be absolutely, utterly disabling. Set in this light, if there are things that can be done to overcome anxiety over and above what might be traditionally offered (see here) by for example, 'affecting' those sensory issues, many people potentially stand to benefit.

Next question: how does one go about 'intervening' when sensory issues are present alongside autism? Well, the science is still a little sparse here outside of the odd case report on something like bumetanide showing a potential effect [3] for example. I might draw your attention to some preliminary work on how visual sensory issues might be a target for other interventions (see here) but there is still some way to go in that area too and one needs to be mindful of how ophthalmologic disorder(s) may also contribute (see here). Going back to the Mazurek paper and the 'triad' of sensory issues, anxiety and bowel problems hinted at with at least some autism in mind, one could speculate that treating said bowel issues *might* have further positive effects on sensory and anxiety issues too. Indeed, in the more general context of how anxiety and another important label - depression - may well have a functional bowel issue link (see here), there is plenty of research fodder to draw on hinting at a 'gut-brain' link in some cases. No doubt there are other ways and means to tackle sensory issues as and when they impact on quality of life and by the sounds of other research [4] sensory issues in autism as described by the DSM-5 are going to be pretty widespread.

To close, it's 'Remember, remember the 5th of November, gunpowder, treason and plot..' day here in the UK today. So here's V and his revolutionary chatter again and please, be careful this Bonfire night.

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[1] Uljarević M. et al. Sensory subtypes and anxiety in older children and adolescents with autism spectrum disorder. Autism Res. 2016 Oct;9(10):1073-1078.

[2] Mazurek MO. et al. Anxiety, sensory over-responsivity, and gastrointestinal problems in children with autism spectrum disorders. J Abnorm Child Psychol. 2013 Jan;41(1):165-76.

[3] Grandgeorge M. et al. The effect of bumetanide treatment on the sensory behaviours of a young girl with Asperger syndrome. BMJ Case Rep. 2014 Jan 31;2014. pii: bcr2013202092

[4] Green D. et al. Brief Report: DSM-5 Sensory Behaviours in Children With and Without an Autism Spectrum Disorder. J Autism Dev Disord. 2016 Nov;46(11):3597-3606.

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Uljarević M, Lane A, Kelly A, & Leekam S (2016). Sensory subtypes and anxiety in older children and adolescents with autism spectrum disorder. Autism research : official journal of the International Society for Autism Research, 9 (10), 1073-1078 PMID: 26765165

Hyperhomocysteinemia as a significant risk factor for autism?

The findings reported by Naushad Shaik Mohammad and colleagues [1] provide some blogging fodder today and the suggestion of a link between some of the genetics of the folate pathway and the finding of elevated levels of homocysteine with [some] autism in mind.

OK, from the start, the genetics of folate metabolism mentioned in the context of autism typically means reference to the quite well replicated finding of issues with the gene methylenetetrahydrofolate reductase (MTHFR) (see here for some background). This gene (product) serves an important purpose in relation to the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate; the latter helping to convert the amino acid homocysteine to methionine. Outside of the importance of methionine to the process of DNA methylation (yep, some of that epigenetics stuff that you keep hearing about), there is quite a body of literature emerging to suggest that elevated levels of homocysteine might also have some important health effects.

For quite a few years now, a specific genetic issue with MTHFR - MTHFR C677T - has been reported in quite a few people on the autism spectrum (see here). This allied to other independent research suggesting that the downstream effects of issues with MTHFR linked to elevations in levels of homocysteine may not also be an uncommon finding (see here). Shaik Mohammad et al therefore set about looking at the relationship between genetic issues with MTHFR and hyperhomocysteinemia in the context of autism.

They did this by use of an "artificial neural network (ANN) model" where data initially from "138 autistic and 138 nonautistic children" on various genetic issues linked to folate metabolism (including MTHFR) were used as potential "predictors of autism risk." We are also told that: "Meta-analyses were carried out on 1361 ASD children and 6591 nonautistic children to explore the association of MTHFR C677T and homocysteine with the risk for ASD [autism spectrum disorder]."

Results: well, the model wasn't exactly brilliant at predicting the risk of autism (63.8% accuracy). The authors call this a 'moderate' finding but I'd probably suggest that their results are yet another very good example of how heterogeneous the autism spectrum actually is. The idea of not using the term 'autism' as a research starting point in this context (see here) also receives support. Perhaps of greater importance were their findings linked to homocysteine and autism and how: "Hyperhomocysteinemia was observed in autistic children" to a greater extent that controls. They did also confirm that the MTHFR C677T genetic polymorphism was linked to 'inflating homocysteine levels' alongside another genetic issue called MTRR A66G (methionine synthase reductase). This is not an unusual finding in the context of what is already known about MTRR and homocysteine. The MTRR bit potentially linked to autism is however, something that this research group have previously suggested to 'reduce the risk' of autism [2].

In terms of what these results mean in the context of autism, there are a few possibilities. First, screening. Knowing what we now seem to know about MTHFR and homocysteine in relation to quite a lot of people with autism, I would have thought it would be good practice to screen genetics/biochemistry. Minus any scaremongering or sweeping generalisations, the observation that hyperhomocysteinemia 'may' have links to cardiovascular disease and other adverse states for example, also perhaps implies screening save any further charges of health inequality when it comes to the label of autism. Next management. Far from being a 'nothing can be done about it' state, there is some good evidence that small adjustments to nutrition can potentially have positive effects on some of these parameters. With no medical or clinical advice given or intended, high levels of homocysteine seem in some cases, to be reactive to certain vitamin supplementation. The focus on vitamin B12 could also be set in the context of other recent studies of this vitamin (and its vitamers) with autism in mind (see here) (but I am careful not to link the two parameters just yet). And just recently there is news that there is a new way of assaying for vitamin B12 on the horizon which could also be useful. Finally, more research is indicated. As per my discussions not so long ago about another potentially important link to folate metabolism and autism (see here), there does appear to be quite a bit more to see when it comes to the folate cycle intersecting with homocysteine metabolism (and it's downstream effects). Yes, we can talk about whether folate is 'protective' or not when it comes to 'risk' of autism (see here and see here) but what this latest work suggests is that this area is complicated and potentially includes many genetic/epigenetic/biochemical variables that need to be taken into account.

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[1] Shaik Mohammad N. et al. Clinical utility of folate pathway genetic polymorphisms in the diagnosis of autism spectrum disorders. Psychiatr Genet. 2016 Oct 17.

[2] Mohammad NS. et al. Aberrations in folate metabolic pathway and altered susceptibility to autism. Psychiatr Genet. 2009 Aug;19(4):171-6.

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Shaik Mohammad N, Sai Shruti P, Bharathi V, Krishna Prasad C, Hussain T, Alrokayan SA, Naik U, & Radha Rama Devi A (2016). Clinical utility of folate pathway genetic polymorphisms in the diagnosis of autism spectrum disorders. Psychiatric genetics PMID: 27755291

Antibiotic brain part 3

"This study demonstrates an association between antibiotic use in the first year of life and subsequent neurocognitive outcomes in childhood."

So said the findings reported by Slykerman and colleagues [1] who relied on data from the Auckland Birthweight Collaborative Study (an initiative set up to determine whether "internationally recognized risk factors for small-for-gestational-age (SGA) term babies were applicable in New Zealand") to examine the suggestion that early life antibiotic use might be associated with a "detrimental effect on later neurocognitive outcomes."

Relying on maternal report of antibiotic use among offspring "between 12 months and 3.5 years of age" researchers compared data with that derived from "Intelligence test scores and measures of behavioural difficulties" when children were 3.5, 7 and 11 years of age. They found that antibiotic use during the first 12 months of life was high in their cohort (70%) and that: "Those who had received antibiotics had more behavioural difficulties and more symptoms of depression at follow up." I've highlighted the 'relying on maternal report' bit because although parents are typically the experts on their own children (yes, they are), the reliance on parental report is not the same as reliance on objective medical or prescribing records for antibiotic use and important information on antibiotic type, dose and reason for such use that they typically contain. Indeed, I might also stress that correlating antibiotic use and developmental outcome whilst interesting should also be mindful of the myriad of other variables that might play a role, including the idea that 'behavioural difficulties' often don't present until later infancy for whatever reason. Be careful with single associations.

But... I've labelled this post 'Antibiotic brain part 3' because I feel that the Slykerman findings are another important piece of evidence potentially pertinent to the idea that antibiotics may be pretty good at tackling bacterial infection but that also that they may have some quite potent effects on behaviour and development as well as physiology (see here for antibiotic brain part 1 and antibiotic brain part 2).

What's the possible mode of action linking [early] antibiotic use and behaviour and development? Well, far be it from me to speculate too much but I'm minded to bring in the idea that those trillions of wee beasties that inhabit our deepest, darkest recesses (the gut microbiome) might play some role in any process. Minus hype [2] we're for example, already finding out how gut bacteria 'might' show some important behavioural connections (see here for example) and specifically how certain strains of bacteria might link to important states such as depression (see here and see here). It's not outside the realms of possibility that 'swallowing a grenade' (although not literally) designed to kill bacteria rather willy-nilly, might influencing either bacterial diversity in the gut or impact on specific strains that could be consider more rather than less beneficial.

One more idea for science to perhaps consider relates to why antibiotics were given in the first place. If for example we assume that ear infection might be a common reason, could it not be that the actual symptoms over and above the [antibiotic] treatment might be the more important variable in relation to 'behavioural difficulties'? [3]

There is much more to do in this area, but alongside the dangers of antibiotic resistance perhaps science might also be more open to the idea that antibiotics might do so much more than just impact on physiology?

To close, for those in Blighty who might remember Hastings, 1066 and a certain Tapestry, things were a whole lot more complicated/gory that you might have expected...

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[1] Slykerman RF. et al. Antibiotics in the first year of life and subsequent neurocognitive outcomes. Acta Paediatr. 2016 Oct 4.

[2] Bik EM. The Hoops, Hopes, and Hypes of Human Microbiome Research. Yale J Biol Med. 2016 Sep 30;89(3):363-373.

[3] Niclasen J. et al. Associations between otitis media and child behavioural and learning difficulties: Results from a Danish cohort. Int J Pediatr Otorhinolaryngol. 2016 May;84:12-20.

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Slykerman RF, Thompson J, Waldie KE, Murphy R, Wall C, & Mitchell EA (2016). Antibiotics in the first year of life and subsequent neurocognitive outcomes. Acta paediatrica (Oslo, Norway : 1992) PMID: 27701771

ADHD (symptoms) and pain

If a primary goal of medicine is to relieve pain and suffering then the paper by Andrew Stickley and colleagues [1] might provide an important insight into how medicine might be missing some important groups when it comes to the experience of pain "assessed by the degree to which it interfered with work activity in the previous month."

Drawing on data from the English 2007 Adult Psychiatric Morbidity Survey (APMS) (a resource that has cropped up on this blog before), authors set about examining "the association between ADHD [attention-deficit hyperactivity disorder] symptoms and pain in the general adult population" to ascertain any connection or not. Bearing in mind a 'screener' was employed when it came to ADHD symptoms (and the problems that other screeners have had when it comes to APMS (see here)) authors concluded that even after adjustment for "comorbid common mental disorders" those adults presenting with self-reported ADHD symptoms had "higher odds for experiencing pain."

This is of course not the first time that pain has been suggested to be more frequent where ADHD symptoms or even ADHD is concerned. Fuller-Thomson and colleagues [2] reported that women diagnosed with ADHD were quite a bit more likely to report 'chronic pain' than not-ADHD controls alongside a spectrum of other adversities and issues. Even children / young adults with 'attention problems' have been reported to show a higher frequency of "chronic multisite pain" [3] thus potentially extending the relationship further through the age-groups.

So what could be the reason(s) behind such an association? Well, outside of the large body of peer-reviewed evidence suggesting that the risk of injury is enhanced in relation to ADHD (see here) and what influence this might have, other work is potentially revealing. So, traumatic dental injuries and ADHD [4], the persistence of headaches and ADHD [5], the list goes on with regards to potential factors that could influence the presentation of pain. I might also draw your attention to the idea that the perception of pain may be 'altered' [6] when it comes to ADHD or the presentation of ADHD symptoms as demonstrated under experimental conditions. Indeed, this side of things might have some rather important implications for autism too (see here) given the 'over-representation' of ADHD in autism (see here). The idea also that use of something like methylphenidate, traditionally indicated for ADHD, might affect pain responses in ADHD is also worthy of greater research consideration [7].

Finally, I'm also minded to suggest that rather than 'blaming it all on ADHD' pain accompanying ADHD or ADHD symptoms could also be due to other coexisting conditions. It's not for example, completely unknown for ADHD to coexist alongside conditions such as fibromyalgia for example [8] bearing in mind that fibromyalgia has a very definite connection to pain. I'm also wondering whether the quite strong link between ADHD and something like asthma (see here), might also be an additional source of pain either directly or indirectly too?

The bottom line: yet another case of screening for / asking about other things when a psychiatric / behavioural diagnosis is given and treating / managing accordingly. Screen don't assume.

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[1] Stickley A. et al. ADHD symptoms and pain among adults in England. Psychiatry Res. 2016 Oct 3;246:326-331.

[2] Fuller-Thomson E. et al. Attention-deficit/hyperactivity disorder casts a long shadow: findings from a population-based study of adult women with self-reported ADHD. Child Care Health Dev. 2016 Jul 20.

[3] Skrove M. et al. Chronic multisite pain in adolescent girls and boys with emotional and behavioral problems: the Young-HUNT study. Eur Child Adolesc Psychiatry. 2015 May;24(5):503-15.

[4] Sabuncuoglu O. & Irmak MY. The ADHD modeL for traumatic dental injuries: A critical review and update of the last 10 years. Dent Traumatol. 2016 Oct 17.

[5] Parisi P. et al. Headache and attention deficit and hyperactivity disorder in children: common condition with complex relation and disabling consequences. Epilepsy Behav. 2014 Mar;32:72-5.

[6] Treister R. et al. Alterations in pain response are partially reversed by methylphenidate (Ritalin) in adults with attention deficit hyperactivity disorder (ADHD). Pain Pract. 2015 Jan;15(1):4-11.

[7] Wolff N. et al. Reduced pain perception in children and adolescents with ADHD is normalized by methylphenidate. Child Adolesc Psychiatry Ment Health. 2016 Jul 22;10:24.

[8] Derksen MT. et al. High frequency of adult attention deficit hyperactivity disorder among fibromyalgia patients in the Netherlands: should a systematic collaboration between rheumatologists and psychiatrists be sought? Clin Exp Rheumatol. 2015 Jan-Feb;33(1 Suppl 88):S141.

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Stickley A, Koyanagi A, Takahashi H, & Kamio Y (2016). ADHD symptoms and pain among adults in England. Psychiatry research, 246, 326-331 PMID: 27750114

Karl Ludvig Reichelt: a research pioneer

This is a short post to mark the passing of a great man of science: Karl Ludvig Reichelt who died on October 29th 2016.

Affectionately known as 'Tiny' to many, in stark contrast to his physical presence, he was quite simply a tour de force when it came to many areas of science and research, not least with an emphasis on schizophrenia and autism (see here for some of his publications). His receipt of the Norwegian 'King's Medal of Merit' was testament to his presence both as a medical doctor and researcher.

I had the pleasure of knowing Tiny for quite a few years and alongside another notable Norwegian researcher, the late Ann-Mari Knivsberg, worked with him on a few research projects and papers notably our ScanBrit project looking at the use of a gluten- and casein-free (GFCF) diet as an intervention for some autism. My colleagues and I were literally standing on the shoulders of giants with our GFCF work, as Tiny and Ann-Mari blazed a research trail stemming from the important work of Curt Dohan on a possible connection between wheat/gluten and some schizophrenia towards the dietary links potentially surrounding some autism. Indeed, there are stories that Dohan, in some of his last days, inspired Tiny to continue his important work.

Alongside his clinical and research life, Tiny had an interesting upbringing as stories of his early childhood in the Far East during World War II fascinated many at the conferences and social gatherings he attended. Indeed, his life continued an interesting family legacy. Channelling the fight and spirit of the Berserkers he was passionate about his science but at the same time always the gentle giant, no better exemplified by his technically brilliant ballroom dancing that I witnessed on several occasions.

Science has lost a true research pioneer. My condolences go to his family and friends. Rest in peace Tiny.

On the "increasing evidence for an association between vitamin D insufficiency and depression"

The quote titling this brief post - "increasing evidence for an association between vitamin D insufficiency and depression" - comes from the review by Parker and colleagues [1] who seem to be no strangers to reviewing evidence on a possible link between the sunshine vitamin/hormone and depression [2].

Affiliated to the Black Dog Institute in Oz ('black dog' being used as a metaphor for depression for quite a few years), the authors surveyed the quite voluminous peer-reviewed research literature on the topic of vitamin D and depression and concluded that there is 'adequate' evidence linking vitamin D levels and depression and also that: "Vitamin D supplementation/augmentation can be an effective treatment."

With no medical or clinical advice given or intended, regular readers of this blog won't perhaps be too surprised by this latest review offering. I've covered the topic again and again and again on this blog and quite frankly it's getting to the point where I'm getting sick of hearing myself talk/type about it. That being said, there are still questions that need answering on this issue: (1) given that 'depression' is quite a nebulous term, are there specific 'types' of depression that vitamin D levels/supplementation seem to be more associated with? (2) what is/are the mode(s) of action? bearing in mind there may be some clues in other literature linked to the possible extra-skeletal actions of vitamin D and (3) how and where do the genetics of vitamin D metabolism fit into all this?

I think it's also important to point out that depression is generally not something that just 'evaporates' when a vitamin D pill or any other pill is taken; more research needs to be done on the timing of supplementation and optimal dosage too as well as the potential use of vitamin D as an adjuvant to more traditional pharmacotherapy. There is a scheme of work to be followed but yet again, research on the possible link between vitamin D and depression continues at a pace.

And as if to further prove the point [3]...

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[1] Parker GB. et al. Vitamin D and depression. J Affect Disord. 2016 Oct 11;208:56-61.

[2] Parker G. & Brotchie H. 'D' for depression: any role for vitamin D? 'Food for Thought' II. Acta Psychiatr Scand. 2011 Oct;124(4):243-9

[3] Shin YC. et al. The associations among vitamin D deficiency, C-reactive protein, and depressive symptoms. J Psychosom Res. 2016 Nov;90:98-104.

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Parker GB, Brotchie H, & Graham RK (2016). Vitamin D and depression. Journal of affective disorders, 208, 56-61 PMID: 27750060