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...

----------

[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.

----------

Vitamin D supplementation and autism: more work needed on the biochemistry of vitamin D metabolism

The findings reported by Conor Kerley and colleagues [1] provide the brief blogging fodder today. Researchers, who are no stranger to the research area that is vitamin D and autism (see here), decided to conduct a 'post-hoc analysis' of data from two controlled trials where vitamin D supplementation was experimentally tested for children with autism and children with asthma. They were specifically looking at the "serum response to vitamin D supplementation" rather that the amount of vitamin D supplemented as potentially being important to the clinical results obtained. They concluded that "children with ASD [autism spectrum disorder] had a lower increase in 25(OH)D levels with supplementation." Further: "Potential mechanisms include altered absorption/metabolism as well as well genetic factors."

Bearing in mind the relatively small participant group numbers used and comparisons between kids with autism and kids with asthma without any other 'asymptomatic' group involvement, I was really rather interested in the Kerley findings. This was a research group who previously concluded that vitamin D supplementation did little for their cohort of autistic children under experimental conditions [2]. Now they're perhaps suggesting that there may have been valid biological reasons behind such results with respect to the biochemistry/metabolism behind vitamin D with such issues potentially affecting how much vitamin D supplementation is required to suitably raise vitamin D levels.

Of course this is not necessarily a new finding. Science has already started to look at the genetics/biology of vitamin D metabolism in relation to autism (see here and see here) and continues to do so [3]. It also converges with the idea that a deficiency/insufficiency of vitamin D is an important clinical finding but does not necessarily mean that a universal dose of vitamin D supplementation will 'fix anything' (see here for another example in another label).

"Clinical and research work relating to vitamin D is ASD should measure 25(OHO)D response to supplementation to assess therapeutic doses." I can't argue with such sentiments on the basis of the results observed. Working back from sayings such as 'the dose makes the poison', it appears that for some on the autism spectrum, that dose may not be the same as everyone else...

----------

[1] Kerley CP. et al. Blunted serum 25(OH)D response to vitamin D3 supplementation in children with autism. Nutr Neurosci. 2018 Oct 10:1-6.

[2] Kerley CP. et al. Lack of effect of vitamin D3 supplementation in autism: a 20-week, placebo-controlled RCT. Arch Dis Child. 2017 Nov;102(11):1030-1036.

[3] Biswas S. et al. Fok-I, Bsm-I, and Taq-I Variants of Vitamin D Receptor Polymorphism in the Development of Autism Spectrum Disorder: A Literature Review. Cureus. 2018 Aug 29;10(8):e3228.

----------

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.

----------

[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.

----------

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

Project TENDR and chemical exposures

Yes, I know I'm writing on a Sunday again, but it will be a short-ish post I promise you. The reason for the entry is this brief communication [1] reporting: "The TENDR [Targeting Environmental Neuro-Developmental Risks] authors agree that widespread exposures to toxic chemicals in our air, water, food, soil, and consumer products can increase the risks for cognitive, behavioral, or social impairment, as well as specific neurodevelopmental disorders such as autism and attention deficit hyperactivity disorder (ADHD)."

The press release accompanying the paper is here. Given the focus on neurodevelopmental disorders including autism it is perhaps not surprising that several of the signatories on the paper are stalwarts of the idea that 'environment' may play a not insignificant role when it comes to at least some autism. If you need examples, look no further than here and here.

I know there are still often heated discussions/arguments (delete as appropriate) about how environment - or non-genetic factors - might fit into the quite marked increase in the numbers of people being diagnosed with autism and various other developmental conditions. I think most people will appreciate that although there are clues in the current peer-reviewed literature to possible effects for some, a lot more science is needed to substantiate specific environmental risks and importantly, potential mode(s) of action when it comes to something like autism or ADHD as a clinical endpoint. There are however signs that science is starting to move in the right direction (see here)...

Set within changes to some of the regulatory affairs when it comes to how countries ensure 'chemicals' are safe (being careful about how one uses the word 'chemical') and perhaps because years of looking for the 'genetics of autism' has yielded only partial results (see here), it is starting to become better accepted that elements of our environment might also affect risk for many conditions, including those potentially affecting development.

To close, the news that Morrissey is returning to these hallowed shores naturally invites a song from the man driving a tractor...

----------

[1] Project TENDR: Targeting Environmental Neuro-Developmental Risks. The TENDR Consensus Statement. Environmental Health Perspectives. 2016.; 124: A118-A122.

----------

Bennett, D., Bellinger, D., Birnbaum, L., Bradman, A., Chen, A., Cory-Slechta, D., Engel, S., Fallin, M., Halladay, A., Hauser, R., Hertz-Picciotto, I., Kwiatkowski, C., Lanphear, B., Marquez, E., Marty, M., McPartland, J., Newschaffer, C., Payne-Sturges, D., Patisaul, H., Perera, F., Ritz, B., Sass, J., Schantz, S., Webster, T., Whyatt, R., Woodruff, T., Zoeller, R., Anderko, L., Campbell, C., Conry, J., DeNicola, N., Gould, R., Hirtz, D., Huffling, K., Landrigan, P., Lavin, A., Miller, M., Mitchell, M., Rubin, L., Schettler, T., Tran, H., Acosta, A., Brody, C., Miller, E., Miller, P., Swanson, M., Witherspoon, N., , ., , ., , ., , ., , ., , ., , ., , ., & , . (2016). Project TENDR: Targeting Environmental Neuro-Developmental Risks The TENDR Consensus Statement Environmental Health Perspectives, 124 (7) DOI: 10.1289/EHP358

Autism's environmental exposome (part 2)

Back in June 2012, I posted an entry on this blog titled: 'Autism's environmental exposome: fish and pharmaceuticals' covering some work by Michael Thomas & Rebecca Klaper [1] (open-access). In it, authors suggested that unmetabolized psychoactive pharmaceuticals (UPPs) - residues from certain medicines - present in drinking (or in the case of this work, swimming) water may "induce autism-like gene expression patterns in fish."

The UPPs in question were "FLX [fluoxetine], VNX [venlafaxine], and CBZ [carbamazepine] in a 3-component mixture" and the lucky fish volunteers were fathead minnows who got to swim with those UPPs. The data were interesting insofar as the potential "ability to induce ASD-like gene expression patterns in developing brains" as a function of exposure to those UPPs, albeit with concentrations used in the Thomas/Klaper study "higher than observed environmental concentrations". The idea being that drug residues are present in the environment around us and some, either alone or in combination, may potentially host some important biological effects.

Enter then further work from this group in the form of the paper by Gaurav Kaushik and colleagues [2] (open-access) who undertook some rather interesting network analysis among other things and concluded that: "protein products from gene sets with enriched expression in fish brains and human neuronal cells, due to an exposure of psychoactive pharmaceuticals, were comparatively more inter-connected to other neighboring proteins than protein products of non-enriched gene sets." Further: "these genes are more likely to experience altered expression upon exposure to PPCPs [pharmaceuticals and personal care products], causing further dysregulation of the whole interactome due to a ripple effect."

I'll be honest with you and say that I'm not altogether au fait with all the goings-on reported by Kaushik et al and their bioinformatics approach adopted so you'll have to take my interpretation with a pinch of salt.  What they appear to be suggesting is that the effects of UPP exposure may not be just centred on the gene expression patterns they previously reported but rather having something of a wider knock-on effect on how gene products are expressed and how this might map onto something like autism. Interestingly, this time around researchers also introduced valproate (VPA) into their investigations given the growing evidence base that "VPA is known to induce ASD [autism spectrum disorder]-like phenotypes in mice" (see here for more information) as it might in people [3]. They reported some potentially important connections - "enrichment effects of clinical doses of VPA are similar to those for environmental concentrations of pharmaceutical mixtures."

Accepting how the word 'chemical' has been very wrongly demonised over the years, the idea that environmental 'exposures' either singularly or as combinations, might have important effects on development and behaviour is something that requires quite a bit more investigation when it comes to something like autism. The idea that gene expression for example, can be modified by said exposures adds an extra layer of complexity to the rather too simplistic idea of 'genes vs. environment' when it comes to autism risk. One might also be minded to take into account gender/sex (see here) too particularly in light of some of the findings reported by Werling & Geschwind [4] recently...

Oh, and UPPs might not be the only pharmaceuticals requiring further research attention with wastewater and minnows in mind...

Music: Dinosaur Jr. - Freak Scene.

----------

[1] Thomas MA. & Klaper RD. Psychoactive pharmaceuticals induce fish gene expression profiles associated with human idiopathic autism. PLoS One. 2012;7(6):e32917.

[2] Kaushik G. et al. Psychoactive pharmaceuticals as environmental contaminants may disrupt highly inter-connected nodes in an Autism-associated protein-protein interaction network. BMC Bioinformatics 2015, 16(Suppl 7): S3.

[3] Wood AG. et al. Prospective assessment of autism traits in children exposed to antiepileptic drugs during pregnancy. Epilepsia. 2015. 11 May.

[4] Werling DM. & Geschwind DH. Recurrence rates provide evidence for sex-differential, familial genetic liability for autism spectrum disorders in multiplex families and twins. Molecular Autism 2015, 6:27.

----------

Gaurav Kaushik, Michael A Thomas, & Ken A Aho (2015). Psychoactive pharmaceuticals as environmental contaminants may disrupt highly inter-connected nodes in an Autism-associated protein-protein interaction network BMC Bioinformatics

Cleanrooms and autism?

The paper by Scott Faber and colleagues [1] (open-access) is the topic of today's post and the idea that a cleanroom sleeping environment might impact on some important issues accompanying at least some autism.

Just in case you hadn't come across the concept of a cleanroom, the concept is that a space is provided where various systems are put in place to control environmental pollutants such as dust, microbes and various chemical emissions. More readily associated with the construction of microchips, satellites or the preparation of various pharmaceutics, I was unable to find any previous studies on the use of cleanrooms 'for autism' so the Faber study seems to represent a bit of a first...

The study is open-access but here are a few details:

• Ten children diagnosed with an autism spectrum disorder (ASD) with "prior evidence of heavy metal and chemical toxicity and immune dysregulation seen through low plasma zinc/serum copper ratios and abnormal T and B cell subsets, respectively" were included for study.
• Then: "each child and a parent spent two consecutive weeks sleeping in the cleanroom 
• between May and October 2010." The cleanroom in question was based at The Children's Institute and consisted of HEPA filters, cleanroom bedding, a UV water purification system and was "furnished with ash furniture sealed with water soluble polyurethane." Cleanroom status was confirmed via particle counting.
• Behaviour, blood and hair were collected and tested pre- and post-cleanroom attendance. Blood and hair were analysed for various compounds including nutrients and externally-derived chemicals. Glutathione levels (total, reduced and oxidised) were also assayed for using everyone's favourite analytical method: mass spectrometry.
• Results: children's results were analysed on the basis of their grouping into a younger age cohort (5 and under) and an older age cohort (6 and older). Bearing in mind the small participant numbers: "The overall pattern of results indicates greater improvements in immune dysregulation and behavior in the younger children, age 5 and under." But: "The older children displayed a worsening in behavioral rating scale performance, which may have been caused by the mobilization of toxins from their tissues."
• Among the various results presented, glutathione status seemed to change for at least some of the children over the course of cleanroom residence which the authors interpreted as possibly indicating: "a reduction of oxidative stress." 
• The idea that some children actually presented with increased levels of certain toxicants following their cleanroom experience is an interesting one. "Out of the ten participants, eight decreased mean serum benzene, six increased mean serum toluene and five increased serum xylene." Further: "One possible explanation for these results is that, throughout the study, VOCs were mobilized from tissues into the serum at varying rates."
• The authors conclude: "The performance of a controlled study of 24 hour per day cleanroom exposure for children with autism appears to be an appropriate next step, given the physiologic changes from the limited exposure to a cleanroom environment noted in this study."

Whilst I did find this to be an interesting study, there are a couple of caveats to mention. This was a straight forward open trial of cleanrooms for autism so 'preliminary' is an important word to use in relation to the results. I note also that whilst the trial was registered with ClinicalTrials.org (see here) it seems to have been done pretty retrospectively ("First received: July 16, 2014").

"The child and parent arrived at TCI and spent approximately ten hours each evening in the cleanroom while wearing silk or cotton clothes." What this means is that during the day, when most people are moving around various environments (including the great outdoors) participants were not contained in that sterile environment. There could have been a myriad of different variables to account for the results during this 'free time' including the idea that parents themselves may have altered their child's routines as a function of being part of the study. I say this not to somehow sabotage the results, merely to say that in a study looking at 'detoxification' in relation to autism, one can't discount other factors coming into play.

Insofar as the idea that 'a controlled study of 24 hour per day cleanroom exposure' might be indicated, I think we might have to take a small step back before this is considered. With the limited exposure I've had to cleanrooms during my career I can safely say that I would not take lightly to spending even one day/night in a cleanroom environment. Not least because of the limited living space that would be available as a result of cost considerations but also how the study is potentially talking about housing young children with autism in such an environment and what that might mean for them and an important disruption to their home/school routine among others. That being said I do like one idea discussed by the authors that: "Younger children may have felt an extra closeness to their parents during the study, leading to positive behavioral change." Yes, it's a shocker: children generally love being next to their parents.

Music from Ian Dury & The Blockheads.

-----------

[1] Faber S. et al. A cleanroom sleeping environment’s impact on markers of oxidative stress, immune dysregulation, and behavior in children with autism spectrum disorders. BMC Complementary and Alternative Medicine 2015, 15:71

----------

Faber, S., Zinn, G., Boggess, A., Fahrenholz, T., Kern, J., & Kingston, H. (2015). A cleanroom sleeping environment’s impact on markers of oxidative stress, immune dysregulation, and behavior in children with autism spectrum disorders BMC Complementary and Alternative Medicine, 15 (1) DOI: 10.1186/s12906-015-0564-0

Oxytocin and autism: the hype?

Consider some excerpts from two recent papers looking at oxytocin (OXT) - the "love hormone"(!) - and the autism spectrum disorders (ASDs)...

“It’s not the years, honey. It’s the mileage”

"These findings indicate that dysregulated OXT biology is not uniquely associated with ASD social phenotypes as widely theorized, but instead variation in OXT biology contributes to important individual differences in human social functioning, including the severe social impairments which characterize ASD" according to Karen Parker and colleagues [1]. Some media accompanying this paper can be found here.

and

"Participants who received oxytocin showed no benefit following treatment on primary or secondary outcomes" according to the findings reported by Adam Guastella and colleagues [2].

For those who have followed the autism research scene over the years, you'll know that discussions about some connection between the neuropeptide oxytocin and autism have figured quite prominently. Indeed, I've covered OXT and autism before on this blog (see here). Media headlines like the one from the BBC suggesting that the "Love hormone 'helps autistic brain'" have been quite a regular feature, building up OXT to almost Saintly proportions. Unfortunately, as has often been the case with autism (sorry, the autisms) the science has not exactly followed the hype. Take for example the paper by Dadds and colleagues [3] who, prior to Guastella et al, reported that: "Compared to placebo, intranasal oxytocin did not significantly improve emotion recognition, social interaction skills, or general behavioral adjustment in male youths with autism spectrum disorders".

I'm not saying that all the research on OXT and autism is bunk because that's obviously not true [4]. As per the meta-analysis by Preti and colleagues [5] there may, for example, be some merit in continuing looking at where and when OXT use might be indicated including that related to important comorbidity [6]. The route of administration - intranasal (via the nose) - is for me, also a really interesting drug delivery method which may be applicable to many, many different medicines indicated for autism or peripheral symptoms/conditions.

But what the Parker and Guastella studies do tell us, is that once again, grand over-arching theories of autism seemingly serve no-one well. The study by Bedford and colleagues [7] perhaps said it best with their data arguing: "against cognitive theories of ASD which propose that a single underlying factor has cascading effects across early development leading to an ASD outcome". Replace cognitive theories with biological ones and science seems to be getting a little closer to what looks like the real nature of the autisms, heterogeneity, comorbidity and all... Oh, and then there is some interesting data on how oxytocin might be affecting the "second brain" (gastrointestinal function) as well as the grey-pinkish matter [8]. Move over melatonin (see here)?

Music to close and I'm happy to be stuck with you... (stick with the video, the music does eventually kick in).

----------

[1] Parker KJ. et al. Plasma oxytocin concentrations and OXTR polymorphisms predict social impairments in children with and without autism spectrum disorder. PNAS. 2014. August 4.

[2] Guastella AJ. et al. The effects of a course of intranasal oxytocin on social behaviors in youth diagnosed with autism spectrum disorders: a randomized controlled trial. J Child Psychol Psychiatry. 2014 August 2.

[3] Dadds MR. et al. Nasal oxytocin for social deficits in childhood autism: a randomized controlled trial. J Autism Dev Disord. 2014 Mar;44(3):521-31.

[4] LoParo D. & Waldman ID. The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: a meta-analysis. Mol Psychiatry. 2014 August 5.

[5] Preti A. et al. Oxytocin and autism: a systematic review of randomized controlled trials. J Child Adolesc Psychopharmacol. 2014 Mar;24(2):54-68.

[6] Hall SS. et al. Effects of intranasal oxytocin on social anxiety in males with fragile X syndrome. Psychoneuroendocrinology. 2012 Apr;37(4):509-18.

[7] Bedford R. et al. Additive effects of social and non-social attention during infancy relate to later autism spectrum disorder. Dev Sci. 2014 Jul;17(4):612-20.

[8] Welch MG. et al. Oxytocin regulates gastrointestinal motility, inflammation, macromolecular permeability, and mucosal maintenance in mice. Am J Physiol Gastrointest Liver Physiol. 2014 Aug 21. pii: ajpgi.00176.2014.

----------

Parker, K., Garner, J., Libove, R., Hyde, S., Hornbeak, K., Carson, D., Liao, C., Phillips, J., Hallmayer, J., & Hardan, A. (2014). Plasma oxytocin concentrations and OXTR polymorphisms predict social impairments in children with and without autism spectrum disorder Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1402236111


Guastella AJ, Gray KM, Rinehart NJ, Alvares GA, Tonge BJ, Hickie IB, Keating CM, Cacciotti-Saija C, & Einfeld SL (2014). The effects of a course of intranasal oxytocin on social behaviors in youth diagnosed with autism spectrum disorders: a randomized controlled trial. Journal of child psychology and psychiatry, and allied disciplines PMID: 25087908

A familial element to homocysteine elevations in schizophrenia?

Homocysteine - the big H - really should have its own Twitter hashtag... #thebigH.

Not only because of the range of health-related conditions which seem to be correlated with particular levels of this amino acid - think coronary heart disease and elevated homocysteine for example* or more recently cerebrovascular disease** - but also because of the body of work linking elevated homocysteine levels to diagnoses like autism and schizophrenia. (Yes, I know correlation does not equal causation).

The Benzon daughters @ Wikpedia 

In this post, I'm laying off the fairly numerous studies looking at homocysteine in relation to autism (see here and here for example) and how it potentially fits into all that folate and methionine cycle stuff.

Instead I'm concentrating on the paper by Geller and colleagues*** reporting on an interesting observation of elevated homocysteine levels in male siblings of people diagnosed with schizophrenia.

I was drawn to post about this paper for several reasons: (a) continuing the link between the big H and schizophrenia (see here), (b) the suggestion that the big H link might also have a familial element and (c) ergo, the possibility of a kind of shared biological phenotype being present in at least some families of those diagnosed with schizophrenia. This last point in particular might not necessarily just mean elevated risk of schizophrenia - if one is to assume that elevated levels of homocysteine is a factor - but also all those other health-related links being made with homocysteine.

The familial element also brought me back to autism and concepts like the broader autism phenotype (BAP) and indeed, some of the shared biochemistry that seems to be present in some cases of autism (see here). On that basis, I guess it should be no surprise about what Geller et al found if one is to assume some similar scenario also pertaining across schizophrenia or the schizophrenia spectrum.

There's little more for me to say about the Geller findings aside from replication please and perhaps detailing a little more about those siblings (i.e. did they go on to develop schizophrenia or any other related condition?) In passing I mentioned about the folate and methionine link which brings in those letter MTHFR; by all accounts, this seems to be quite an important part of that homocysteine link****. Oh and then there's the body of research which seems to imply we might be able to do something about hyper-homocysteine***** and related parameters (see here). Bearing in mind that I give no medical or clinical advice about this...

Music: Don't Stop Believin' by Journey. Please, proper English gentlemen... believing.

----------

* Humphrey LL. et al. Homocysteine level and coronary heart disease incidence: a systematic review and meta-analysis. Mayo Clin Proc. 2008 Nov;83(11):1203-12.

** Yan J. et al. Vitamin B supplementation, homocysteine levels, and the risk of cerebrovascular disease. Neurology. 2013; 81: 1298-1307.

*** Geller V. et al. Elevated homocysteine level in siblings of patients with schizophrenia. Psychiatry Res. 2013 Sep 16. pii: S0165-1781(13)00476-9. doi: 10.1016/j.psychres.2013.08.016.

**** Muntjewerff JW. et al. Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta-analysis. Mol Psychiatry. 2006 Feb;11(2):143-9.

***** Miodownik C. et al. High-dose vitamin B6 decreases homocysteine serum levels in patients with schizophrenia and schizoaffective disorders: a preliminary study. Clin Neuropharmacol. 2007 Jan-Feb;30(1):13-7.

----------

Geller V, Friger M, Sela BA, & Levine J (2013). Elevated homocysteine level in siblings of patients with schizophrenia. Psychiatry research PMID: 24051177

Parent-led early intervention and autism: what's going on?

I do love my quotes on this blog. So another quote to begin this post: "Parent-implemented intervention studies for early ASD thus far have not demonstrated the large effects seen in intensive-treatment studies".

It comes from quite a recent study by Sally Rogers and colleagues* examining "the efficacy of a 12-week, low-intensity (1-hour/wk of therapist contact), parent-delivered intervention for toddlers at risk for autism spectrum disorders (ASD) aged 14 to 24 months and their families". The reported results it seems were less than spectacular in comparison to community treatment as usual bearing in mind the relatively short study duration.

All this comes a few years after the results of PACT (Preschool Autism Communication Trial)** where the authors concluded (sorry more quotes) "we cannot recommend the addition of this PACT intervention to treatment as usual for the purpose of reduction in autism symptoms". PACT by the way is a strategy based predominantly on shared attention, where parents are encouraged to alter their communicative skills more towards their child's level of understanding (see here for a description). I'm not the first to talk about PACT by the way as per this blog entry.

Whilst based on slightly different programmes - Rogers et al looked at a parent-based version of the Early Start Denver Model (ESDM) - a primary focus of both ESDM and PACT are language and shared attention; in both these studies, delivered by parents to young children with autism. Similar to other programs such as the Hanen More Than Words® initiative (itself the subject of some study with autism in mind***) and others****, the suggestion is that subtle alterations to parent - child interactions may ameliorate the presentation of some of the core and peripheral signs and symptoms associated with early infancy autism.

Although not specifically my area of competence, I'm interested in these various studies and results for lots of different reasons, not least some increasing interest in something called VIG (video interaction guidance) albeit not necessarily with parent-child interactions in mind. Seeing parents as partners when offspring autism is present obviously plays a big role in these kinds of initiatives and their associated study. Given the way autism comes about in early infancy, together with the whole brain plasticity and under-connectivity findings***** (full-text), there is sound logic in ensuring the potential gains already noted from early intensive professional intervention****** can also be extended outside of school hours. That and the fact that parents obviously want to do the best they can to help their children's development and symptom presentation (sorry to use such cold terminology by the way).

I don't however think many people would be surprised to hear that when universally applied to all cases of autism, these programs were not entirely effective for all children as per this commentary on the Hanen results. Indeed the same goes for just about any intervention used for autism, even early intensive behavioural intervention (EIBI) if you accept the results from the latest Cochrane review******* on the subject.

That being said, we're potentially back to the old endophenotypes and responder / non-responder suggestions and the growing need for much more research on autisms rather than autism. The fact that response to intervention might be a more suitable 'indicator' for discerning those homogeneous subgroups over the more traditional shotgun approach to multiple targets based on the autism diagnosis alone is another consideration worthy of future discussion.

I digress.

The question of why the highlighted parent-led interventions don't quite seem to be cutting the statistical mustard is an interesting one. I should at this point demonstrate that other results have indicated some success with home-based programs so we're not talking about a universal failure here bearing in mind some important methodological differences and indeed the targets of such interventions. Other than the reasons already mentioned, there are potentially quite a few other factors at play not least some expected variability in the delivery of the interventions and questions about the outcomes and length of time being studied. It could well be that there is a ceiling effect from such education and behavioural interventions already reached where intensive intervention is already running in the background at school for example.

Outside of the bloomers (or even including the bloomers), we know that there are potentially some great gains to be made from behavioural intervention******* for some children on the autism spectrum and beyond - perhaps also even translating into physiological measures******** - allowing for the fact that much more detailed scientific investigations are required on efficacy and best-responder characteristics. The position of such parent-based programs at a scientific level measured by the current data however, cannot be easily ignored in these evidence-based medicine days. Indeed reliant on the evidence currently available, does this not make a good case for specialist-delivered early intervention to be made more widely available above and beyond the more cost-effective (to the state) parent-led intervention strategies?

----------

* Rogers SJ. et al. Effects of a brief Early Start Denver Model (ESDM)-based parent intervention on toddlers at risk for autism spectrum disorders: a randomized controlled trial. J Am Acad Child Adolesc Psychiatry. 2012; 51: 1052-1056.

** Green J. et al. Parent-mediated communication-focused treatment in children with autism (PACT): a randomised controlled trial. Lancet. 2010; 375: 2152-2160.

*** Carter AS. et al. A randomized controlled trial of Hanen's 'More Than Words' in toddlers with early autism symptoms. J Child Psychol Psychiatry. 2011; 52: 741-752.

**** Soloman R. et al. Pilot study of a parent training program for young children with autism. The PLAY Project Home Consultation program. Autism. 2007; 11: 205-224.

***** Müller RA. et al. Underconnected, but how? A survey of functional connectivity MRI studies in autism spectrum disorders. Cereb Cortex. 2011; 21: 2233-2243.

****** Grindle CF. et al. Outcomes of a behavioral education model for children with autism in a mainstream school setting. Behav Modif. 2012; 36: 298-319.

******* Reichow B. et al. Early intensive behavioral intervention (EIBI) for young children with autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2012; 10: CD009260.

******** Gutstein SE. Empowering families through Relationship Development Intervention: an important part of the biopsychosocial management of autism spectrum disorders. Ann Clin Psychiatry. 2009; 21: 174-182.

********* Dawson G. et al. Early behavioral intervention is associated with normalized brain activity in young children With autism. J Am Acad Child Adolesc Psychiatr. 2012; 51: 1150-1159.

----------

Rogers SJ, Estes A, Lord C, Vismara L, Winter J, Fitzpatrick A, Guo M, & Dawson G (2012). Effects of a Brief Early Start Denver Model (ESDM)-Based Parent Intervention on Toddlers at Risk for Autism Spectrum Disorders: A Randomized Controlled Trial. Journal of the American Academy of Child and Adolescent Psychiatry, 51 (10), 1052-65 PMID: 23021480