Melatonin pathway dysregulation driving melatonin issues associated with autism?

The paper published by Anna Maruani and colleagues [1] provides the blogging fodder today and the observation that: "melatonin variations in ASD [autism spectrum disorder] could be mainly driven by melatonin pathway dysregulation."

Melatonin has been part-and-parcel of the autism research landscape for many, many years (see here). Most people with some knowledge of melatonin will probably know of its connection to the sleep-wake cycle and the reasoning behind the use of supplemental melatonin to [hopefully] improve sleep in some people and groups of people (see here). Indeed, for some of those diagnosed as being on the autism spectrum who present with often significant sleep-related problems (see here for example), the clinical use of melatonin has been nothing short of miraculous for some when it comes to improving several parameters of sleep [2]. But melatonin is also quite the molecular handyperson too (see here) outside of just the sleep-wake cycle...

As to the precise reason(s) why melatonin appears to be an issue for 'some autism', science so far has been pretty short on firm conclusions. The Maruani study set out to try and cast some further light on the hows-and-whys around melatonin, specifically looking at both measured levels of melatonin in plasma and also pineal gland volume (PGV), on the basis that the pineal gland produces melatonin. Researchers report estimated measurement of PGV "with magnetic resonance imaging (MRI) with a voxel-based volumetric measurement method" in "78 individuals with ASD, 90 unaffected relatives and 47 controls."

Their results were interesting: "We first found that both early morning melatonin level and PGV were lower in patients compared to controls." Those early morning melatonin levels - "collected between 8:30 and 10:30 a.m." - were measured using "a radioimmunoassay" method looking at plasma samples. As well as lower plasma melatonin being described in the autism group compared with the other groups, researchers also observed that: "Relatives displayed to a lesser extent a reduced level of melatonin compared to controls, but that did not reach significance z = 0.88, p = 0.38)." Potentially also interesting.

Further: "Analysis revealed that the volume of the pineal gland was lower in patients than in controls, and lower in relatives than in controls." Some additional statistical modelling led however to the conclusion that: "PGV acted as a modest contributor to the melatonin deficit observed in ASD." In other words, as per the title of this post "melatonin variations in ASD could be mainly driven by melatonin pathway dysregulation" over and above just the physical volume of the part of the brain charged with producing melatonin.

Mention of 'melatonin pathway dysregulation' in the Maruani results got me thinking about previous study results discussed on this blog (see here). The results from Pagan and colleagues [3] provided some pretty valuable insights into the biochemistry of melatonin and some of the 'in-betweener' compounds involved in it's formation. Specifically: "a disruption of the serotonin-NAS [N-acetylserotonin] -melatonin pathway in ASD." Add in other research (see here) talking about low levels of one of the metabolites of melatonin being noted in parents, and there's a case for looking further at the biochemistry of melatonin synthesis in relation to autism over and above just volumes of brain structures. Indeed, how about beginning with examinations of the starting material for melatonin - the amino acid tryptophan - and see where this might take us (see here and see here).

Oh, and it appears that the pineal gland is probably not the only place that melatonin is synthesised [4]. Perhaps further investigation in this area might also want to look at "the enterochromaffin (EC) cells throughout the gut" for example, and their potential role/effect with melatonin (and its precursors) and autism in mind...

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[1] Maruani A. et al. Morning Plasma Melatonin Differences in Autism: Beyond the Impact of Pineal Gland Volume. Front. Psychiatry. 2019. Feb 6.

[2] Maras A. et al. Long-Term Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children with Autism Spectrum Disorder. J Child Adolesc Psychopharmacol. 2018 Oct 11.

[3] Pagan C. et al. The serotonin-N-acetylserotonin-melatonin pathway as a biomarker for autism spectrum disorders. Transl Psychiatry. 2014 Nov 11;4:e479.

[4] Chen CQ. et al. Distribution, function and physiological role of melatonin in the lower gut. World J Gastroenterol. 2011;17(34):3888-98.

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ADHD and a sunny disposition

'Light it up blue' is probably a familiar phrase to many of those involved with autism as being the message championed by Autism Speaks on World Autism Awareness Day (2 April). The intention is noble enough: to bring autism to the attention of the world at large and importantly, keep their attention and resources focused on autism. I might add that awareness is one thing; actually 'doing something about autism' - whether that means improving prospects or modifying the course of autism or just levelling the playing field - is quite another thing.

Light it up @ Wikipedia  

By a funny twist of Internet fate, I stumbled upon a review of the study published by Arns and colleagues* looking at the possibility of a link between solar intensity (SI) and the prevalence of attention-deficit hyperactivity disorder (ADHD). The very tentative light it up blue connection was a sentence or two in the study write-up which suggested that the sleep problems which apparently come with a diagnosis of ADHD might result from "exposure to blue-light during the evening" and that strong sunlight during the day "might reset the biological clock and act as an antidote to the evening exposure to artificial blue-light causing sleep onset problems". Yes, I know it isn't a great blue light pun, sorry about that.

It should be noted that the Arns paper appears in a pretty good journal (Biological Psychiatry) so whilst you might be thinking, 'solar intensity... eh?' this is a correlation which has passed what one would expect to have been quite a rigorous peer-review battlefield. I could at this point offer you some more detailed description of the paper but it seems that the authors have already done that on their website (see here - no endorsement given or intended).

In effect, they mapped the prevalence figures for ADHD across various parts of the US and beyond and cross-referenced them with official figures relating to SI. Yes, prevalence of ADHD were partly based on "self-report of professional diagnoses" but this was to some degree countered by the use of more formal assessment data in other sites. They found a correlation (negative correlation) between ADHD prevalence and SI when controlling for various potential confounders: "a lower prevalence of ADHD in areas with high SI for both U.S. and non-U.S. data".

Bearing in mind the issue of correlation/causation (see here), one could construe this data several ways. If for example you work for the tourist boards of Arizona, Nevada or California you have a potentially interesting advert: 'Come live here, we've got lots of solar resource and potentially less risk of your children developing ADHD'. Or words to that effect. And indeed, the CDC figures do seem to suggest that those high SI states might have a lower prevalence of ADHD (assuming that this doesn't reflect other issues such as awareness, identification, etc). On a more serious note are the suggestions that (a) ADHD might be related to circadian clock disturbances, and (b) that exposure to the various new-fangled technologies we are surrounded by might be part and parcel of those circadian clock disturbances.

Just before you reach for the click away button, like I almost did, mumbling 'blame it all on technology', there are a few papers to bring to your attention. Yes, sleep issues are associated with ADHD** and indeed if the recent paper from Blesch and Breese McCoy*** is anything to go by, we might also assume that ADHD - some cases of ADHD - could be mistaken for things like sleep apnoea. True also that issues with circadian function seem also to be tied into cases of ADHD as per studies like this one from Gamble and colleagues****. On balance, sleep seems to show some connection with ADHD.

That the part of the light spectrum labelled blue emanating from various technology use is the primary cause or significant contributor to the sleep issues noted even in some cases of ADHD is the slightly more difficult proposition for me to whole-heartedly (hoof hearted!) accept from this work. I don't doubt that many children and adults with ADHD use this kind of technology. But I have to ask whether their use and exposure to the artificial blue light is really any more significant than that of everyone else? Indeed, without being an expert on the different ranges or wavelengths of light and their physiological effects, are we just talking blue or are we talking other parts of the light spectrum too?

There are details from this study which I would like to see further explored given the potential for a relationship between SI and ADHD prevalence. Readers for example, might know that I am more than a little intrigued by another sun related variable, vitamin D, and its various connections (or not) to conditions like autism or chronic fatigue syndrome among others. The question would have to be whether the sunshine vitamin / steroid hormone might also show some relationship to the latest findings? Are vitamin D levels likely to be greater / the same / reduced in cases of ADHD dependent on the specific geography and SI? Vitamin D receptors all in good working order*****? No significant drug interactions where medication is being used? Indeed, whether other correlates such as altitude - which also seem to map onto the SI exposure plots - might come into play?

There are questions which require some follow-up from this work but for now, and with all caveats in good working order when it comes to population studies of association - as with other recent results too, I'm intrigued by the Arns data and the suggested overlap. And also that ADHD might not be the only condition being looked at with a sun-related variable (see this study by Davis & Lowell******, full-text).

To close, after recently watching the quite brilliant film 'Rock of Ages' which satisfied all my 1980s rock needs, a taste of Sheffield's finest.

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* Arns M. et al. Geographic Variation in the Prevalence of Attention-Deficit/Hyperactivity Disorder: The Sunny Perspective. Biol Psychiatry. March 2013.

** Yürümez E. & Kiliç BG. Relationship Between Sleep Problems and Quality of Life in Children With ADHD. J Atten Disord. March 2013.

*** Blesch L. & Breese McCoy SJ. Obstructive Sleep Apnea Mimics Attention Deficit Disorder. J Atten Disord. March 2013.

**** Gamble KL. et al. Delayed Sleep Timing and Symptoms in Adults With Attention-Deficit/Hyperactivity Disorder: A Controlled Actigraphy Study. Chronobiol Int. February 2013.

***** Malik S. et al. Common variants of the vitamin D binding protein gene and adverse health outcomes. Crit Rev Clin Lab Sci. 2013; 50: 1-22.

****** Davis GE. & Lowell WE. Variation in ultraviolet radiation and diabetes: evidence of an epigenetic effect that modulates diabetics' lifespan. Clinical Epigenetics. 2013; 5: 5.

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Arns M, van der Heijden KB, Arnold LE, & Kenemans JL (2013). Geographic Variation in the Prevalence of Attention-Deficit/Hyperactivity Disorder: The Sunny Perspective. Biological psychiatry PMID: 23523340