Saturday 30 April 2016

The 'anti-neuroinflammatory activity' of oxytocin

Whilst the package inserts of the various drugs that modern medicine has at its disposal provides important information on potential mode of action, there is a growing realisation that drugs generally have quite a few more molecular targets than are perhaps listed. Take for example the quite commonly used (in some parts of the world anyway) compound called melatonin  that in some instances can provide almost miraculous relief when it comes to sleeping issues under certain circumstances. A derivative of the amino acid tryptophan, melatonin might however be quite the molecular handy-person when it comes to its biological targets including its actions on something called leaky gut for example...

The paper by Lin Yuan and colleagues [1] similarly suggests that everyone's favourite 'cuddle hormone' (oxytocin) might also have a wider range of biological effects than has hitherto been fully appreciated.  Drawing on cell line results and intra-nasal administration of oxytocin (OT) to [artificially] immune-stimulated mice, authors reported that "OT possesses anti-neuroinflammatory activity and might serve as a potential therapeutic agent for treating neuroinflammatory diseases."

One of the primary analytical targets of the Yuan study were microglia, those 'constant gardeners' according to one description, and how administration of OT might have some interesting effects on the activation of microglia under certain circumstances. "BV-2 cells and primary microglia were pre-treated with OT (0.1, 1, and 10 μM) for 2 h followed by LPS [lipopolysaccharides] treatment" we are told, and microglia activation and "pro-inflammatory mediators" subsequently monitored. The results tallied with those 'anti-neuroinflammatory' sentiments previously expressed as authors report on various possible reasons for such an effect: "OT suppressed the expression of TNF-α, IL-1β, COX-2, and iNOS at the mRNA and proteins levels and reduced the elevation of [Ca2+]i in LPS-stimulated microglia cells." If that wasn't enough, researchers also looked at what happened following OT pre-treatment when a certain strain of mouse was 'immune stimulated' again in terms of microglia activation and those pro-inflammatory mediators. We are similarly told that: "pre-treatment with OT showed marked attenuation of microglial activation and pro-inflammatory factor levels." So we have something of a match in the lab and in an animal model.

These are interesting results. Yet again, one has to be a little cautious about the use of mouse models or indeed, cell lines (humans are so much more than a group of cells in a petri dish) and further, independent investigations are indicated. But: "These data suggested that OT would be a potential therapeutic agent for alleviating neuroinflammatory processes in neurodegenerative diseases."

I was inclined to talk about the Yuan paper because of the various 'connections' that have been made between oxytocin and autism (see here). With a growing interest in the oxytocin-autism connection in the peer-reviewed literature, this nonapeptide (9 amino acids long) has attracted quite a few researchers to its cause [2] as a function of the idea that: "Oxytocin increases the salience of social stimuli and promotes parental nurturing and social bonds" [3]. As per my interpretation of the current state of the oxytocin-autism research base, there are some interesting results available but once again, universal 'effects' are nowhere to be seen - Autisms, people. Autisms. The Yuan and other results focusing on the 'anti-neuroinflammatory' activity of oxytocin perhaps add another dimension to the possible hows and whys of efficacy when it comes to a label like autism. That also a growing number of people are coming around to the idea that neuroinflammation might be a facet of 'some' autism (see here) and including some mention of microglia (see here) offers an additional correlate to add into the future research mix. Could those with autism who have more prominent signs of neuroinflammatory issues potentially be 'best responders' to oxytocin for example? I did also wonder whether the idea that inflammation or inflammatory issues might feature in complex behaviours like social cognitive processing (see here) could provide another explanation for some of the reported results observed following use of oxytocin in [some] autism?

Much more research is indicated but again the message is... don't be too dogmatic when it comes to pharmacological targets and actions of medicines indicated for conditions such as autism. You might just end up being surprised...


[1] Yuan L. et al. Oxytocin inhibits lipopolysaccharide-induced inflammation in microglial cells and attenuates microglial activation in lipopolysaccharide-treated mice. Journal of Neuroinflammation. 2016; 13:77.

[2] Okamoto Y. et al. The Potential of Nasal Oxytocin Administration for Remediation of Autism Spectrum Disorders. CNS Neurol Disord Drug Targets. 2016 Apr 13.

[3] Young LJ. & Barrett CE. Neuroscience. Can oxytocin treat autism? Science. 2015 Feb 20;347(6224):825-6.

---------- Yuan L, Liu S, Bai X, Gao Y, Liu G, Wang X, Liu D, Li T, Hao A, & Wang Z (2016). Oxytocin inhibits lipopolysaccharide-induced inflammation in microglial cells and attenuates microglial activation in lipopolysaccharide-treated mice. Journal of neuroinflammation, 13 (1) PMID: 27075756

Friday 29 April 2016

Organophosphate exposure and ADHD?

"Children with higher urinary DMP [dimethylphosphate] concentrations may have a twofold to threefold increased risk of being diagnosed with ADHD [attention-deficit hyperactivity disorder]."

So said the results presented in the paper by Yu and colleagues [1] who looking at "97 doctor-diagnosed ADHD cases and 110 non-ADHD controls who were 4-15 years of age" examined urine and blood samples for various factors including "biomarkers of OP [organophosphate] pesticide exposure." They concluded that, adjusting for creatinine, urine levels of DMP but not other dialkylphosphate (DAP) metabolites were higher in the ADHD group compared with the non-ADHD group. Further: "Organophosphate pesticide exposure may have deleterious effects on children's neurodevelopment, particularly the development of ADHD." At the same time, Yu et al also reported nothing very much to see when it came to blood lead levels (BLLs) between the groups.

This is not the first time that examination of urinary metabolites of OPs have turned up something of a potential relationship with behavioural outcomes related to ADHD. The paper by Bouchard and colleagues [2] also reported a possible connection supporting a "hypothesis that organophosphate exposure, at levels common among US children, may contribute to ADHD prevalence." There too urine was the analytical medium and dialkylphosphate concentrations the target compounds. This and other research looking at this issue have led to statements [3] to the effect that: "Children's exposures to pesticides should be limited as much as possible." I don't think many people would disagree with that sentiment.

I've talked about OPs quite a bit on this blog (see here and see here) and how various conditions/labels might be 'associated' with this class of compounds either when used as insecticides or as something rather more ominous. I've tried not to be too alarmist about the possibility of a connection with health because OPs do serve an important purpose (as an insecticide) and have probably saved quite a few lives as a result. But it is getting increasingly difficult to ignore the possibility that this and other classes of pesticides either alone or in combination with other factors, seem to be implicated in various conditions/labels and more needs to be done looking at the hows and whys. This can however be done without scaremongering.

The Yu results whilst interesting are not however without some cautions. DAP metabolites as markers for OP exposure still requires further investigations [4], not least from which specific OP they are derived from. That other factors such as exposure to second-hand tobacco smoke might also link into the presentation of specific metabolites such as DMP [5] is another consideration. Continuing the theme that combinatorial exposures might also exert an effect [6] other research illustrates how difficult it might be to pin one specific type of exposure to specific behavioural outcomes. And then also we have the added layer of complexity that is the genetics of xenobiotic metabolism with specific focus on OPs. Relationships are likely to be pretty complicated as a result.

Having said all that does not however mean that results like the ones from Yu et al can be just brushed under the carpet...

Music to close, and having watched Guardians of the Galaxy for the Nth time last evening, all I can say is the film soundtrack is kinda cool...


[1] Yu CJ. et al. Increased risk of attention-deficit/hyperactivity disorder associated with exposure to organophosphate pesticide in Taiwanese children. Andrology. 2016 Apr 12.

[2] Bouchard MF. et al. Attention-deficit/hyperactivity disorder and urinary metabolites of organophosphate pesticides. Pediatrics. 2010 Jun;125(6):e1270-7.

[3] Roberts JR. et al. Pesticide exposure in children. Pediatrics. 2012 Dec;130(6):e1765-88.

[4] Sudakin DL. & Stone DL. Dialkyl phosphates as biomarkers of organophosphates: the current divide between epidemiology and clinical toxicology. Clin Toxicol (Phila). 2011 Nov;49(9):771-81.

[5] Jain RB. Levels of dialkylphosphate metabolites in urine among general U.S. population. Environ Toxicol Pharmacol. 2016 Feb 26;43:74-82.

[6] Osaka A. et al. Exposure characterization of three major insecticide lines in urine of young children in Japan-neonicotinoids, organophosphates, and pyrethroids. Environ Res. 2016 May;147:89-96.

---------- Yu CJ, Du JC, Chiou HC, Chung MY, Yang W, Chen YS, Fuh MR, Chien LC, Hwang B, & Chen ML (2016). Increased risk of attention-deficit/hyperactivity disorder associated with exposure to organophosphate pesticide in Taiwanese children. Andrology PMID: 27070915

Thursday 28 April 2016

What parents of children with autism expect from their child's therapists

"Parents ultimately wanted therapists to produce positive outcomes for their children and were willing to sacrifice other desired qualities, as long as the therapy program was effective."


"The SLPs [Speech-Language Pathologists] expressed strong support for evidence-based practice (EBP) and indicated that they thought parents expected their children would be provided with evidence-based interventions."

Those quotes come from two papers recently published in the same journal; the first by Amelia Edwards and colleagues [1] attempting to identify "the qualities parents seek in therapists who work with their children with ASD [autism spectrum disorder]" and the second from David Trembath and colleagues [2] titled: 'What do speech-language pathologists think parents expect when treating their children with autism spectrum disorder?'

Providing what is a quite fascinating (albeit small scale) insight into the expectations of therapists and parents who use therapists for their children when it comes to autism, these papers put some science to what many people might already have suspected. The Edwards paper also carried an important sentence in the paper title - "More than blowing bubbles" - implying how positive real world outcomes are always going to be the most important elements of any intervention program when it comes to autism or indeed, any other label. The idea that avenues towards those positive outcomes should be 'evidence-based' is perhaps a sentiment noted in the views and opinions of [many of] those professionals delivering intervention but might not necessarily be first and foremost for parents whose natural instinct is to want the best for 'their child'.

The link between the concept of 'evidence-based' and autism is particularly interesting. A few years back I covered a paper by Gary Mesibov & Victoria Shea [3] (see here) carrying the idea that there may be both "benefits and limitations" when it came to the application of evidence-based policy and autism intervention. The sorts of variables that made evidence-based policy difficult when applied to autism ranged from the vast heterogeneity present under the label (or labels) to the idea that the gold-standard 'randomised controlled trial' (RCT) might not be all that suitable when assessing comprehensive intervention programs that for example, contain multiple elements. In subsequent years we've also learned that autism rarely appears in some sort of diagnostic vacuum (see here), something that might also impact on evidence-based policy with regards to intervention (see here). For scientific puritans, the Mesibov-Shea discussions could be construed as heresy. For me, there was some substance in their arguments and some lessons on how autism research in particular, needs to adapt and change away from the notion that 'autism' universally covers everyone with autism in terms of similar aetiology and pathology. Endophenotypes and 'snowflakes' people...

It should of course be recognised that quite a lot of the 'not-knowing' when it comes to the autism spectrum has set the field of autism intervention up for a variety of 'unusual' proposals for interventions, many of which have not been suitably scientifically tested (see here). Some are even downright unsafe but are still pursued for one reason or another, probably pertinent to that opening sentence on 'effectiveness' and no doubt playing into other emotions as and when a child presents with autism [4]. Feelings run high on this topic as I once again refer you to the post by Tom Insel on the 'kingdoms of autism' (see here) with a suggestion that different views be respected but at the same time, safety should be paramount.

Acknowledging that there is no 'one-size-fits-all- approach when it comes to autism intervention and that for some, mention of the words 'therapy' and 'intervention' are not necessarily high on their list of priorities, the Edwards and Trembath papers invite quite a bit more investigation. The possibility of a 'disconnect' between what parents want for their children and what therapists are currently able to deliver for their children represents something that could potentially impact on the delivery of intervention and the importance of the parent-professional relationship in this context. I'm also going to throw the paper by Paynter and colleagues [5] into this mix too...

To close, I feel old. Jossy's Giants is 30 years old (although I'm more inclined to the Red and White)...


[1] Edwards A. et al. "More than blowing bubbles": What parents want from therapists working with children with autism spectrum disorder. Int J Speech Lang Pathol. 2016 Apr 4:1-13.

[2] Trembath D. et al. What do speech-language pathologists think parents expect when treating their children with autism spectrum disorder? Int J Speech Lang Pathol. 2016 Mar 10:1-9.

[3] Mesibov GB. & Shea V. Evidence-based practices and autism. Autism. 2011 Jan;15(1):114-33.

[4] Ooi KL. et al. A meta-synthesis on parenting a child with autism. Neuropsychiatric Disease and Treatment. 2016; 12: 745-762.

[5] Paynter JM. et al. Utilisation of evidence-based practices by ASD early intervention service providers. Autism. 2016. April 18.

---------- Edwards, A., Brebner, C., Mccormack, P., & Macdougall, C. (2016). “More than blowing bubbles”: What parents want from therapists working with children with autism spectrum disorder International Journal of Speech-Language Pathology, 1-13 DOI: 10.3109/17549507.2015.1112835 Trembath, D., Hawtree, R., Arciuli, J., & Caithness, T. (2016). What do speech-language pathologists think parents expect when treating their children with autism spectrum disorder? International Journal of Speech-Language Pathology, 1-9 DOI: 10.3109/17549507.2016.1139625

Wednesday 27 April 2016

The A Word: the science behind...

The A Word
I'm not typically inclined to talk about TV programmes on this blog (well, not usually) but today I'm making an exception based on the conclusion of the BBC drama series 'The A Word' last evening.

For those who might not know, this [fictional] series charts the ups and downs of a family living in the Lake District whose lives are in one way or another touched by autism as a function of a 5-year old boy diagnosed with the condition. The show had a notable addition to the cast with a very straight-talking Christopher Eccleston appearing (yes, one manifestation of Dr Who) but all the actors provided some pretty sterling performances including the child actor Max Vento, who plays Joe 'the 5-year old boy with autism'.

I don't want to go into all the ins-and-outs that the series covered (bearing in mind it was a fictional drama series and not 'real life autism' as per series such as the one by Louis Theroux) but there were a number of themes included that do fall into the peer-reviewed science domain typically covered on this blog. I'd like to briefly cover some of those themes and perhaps provide some short discussion on what they might mean without trying to over-analyse or over-generalise things. I might add that this is my interpretation of the series and readers are also advised to see what others also thought about it.


Every episode of the series opens with Joe happily strolling down a deserted road set against the backdrop of the beautiful Lake District. You'll already note that Joe is a boy and so already we have our first 'stereotype' when it comes to autism. Joe has a 'thing' for music (and some mighty good taste in music I might add) as per his almost constant earphone-wearing, and seems happy on his trails on his own. During most episodes of his wanderings he's met by a friendly couple who know Joe and are happy to return him home. I personally was in two minds about this depiction. As throughout the series, it's obvious that the writers know something about some of the themes in autism (research and practice) and I daresay that this reference is a nod to the idea that autism and wandering has received some much needed research attention. In real-life however, any 5-year old child discovered walking on their own on any road would in all likelihood trigger safeguarding mechanisms should authorities become aware... see episodes 5 & 6.

Parental concerns and diagnosis
The process of going from parental concerns about Joe's behaviour to getting a diagnosis is covered in the series. Again keeping in mind that this is fiction, I think many people (certainly on Twitter) saw the most disconnect in this part of the story given (a) the reluctance of the parents - particularly the mother - to 'accept' something might be 'out of place' with Joe's behaviour and (b) the extremely quick time taken for a diagnosis of autism or autism spectrum disorder (ASD) to be given. Without generalising, diagnosis here in the UK is very rarely a quick thing and many parents can and do feel some relief as and when the 'hurdle' of diagnosis has been eventually overcome. Certainly here in the UK, receipt of a diagnosis normally triggers access to important future plans.

Mainstream schooling vs. home schooling is an important issue covered during the series. We for example, see Alison - Joe's mum - worried about how Joe will cope in his village primary school where his social interaction with other children for example, looks to be minimal at best. The storyline in this area was perhaps one of the most powerful parts of the series as parental worries of 'how will my child cope?' intermixed with the variety of emotions viewers watch the family go through. Interestingly, the series did offer something important to this story as Joe himself voices an opinion about his desire to go to school. Granted things might not always be so easily communicated in real-life but the idea of taking into account the child's wants and wishes when it comes to schooling options is perhaps an important one. Later in the series we also see how Joe does make friends at school. Viewers who've seen the series might have also noticed the opening and closing of school doors during these school segments by Joe reflective of what might be considered a ritual or routine - a core feature of autism.

Speech and language therapy
Again, outside of the dramatic plot line that follows the introduction of a speech and language therapist (SALT) to the series (who it turns out was bullied by the mother of Joe during her school days), it was indeed useful to see how much impact a good SALT can have on a child with autism. As well as emphasising the 'stopping and starting' of developmental progress that accompanies any child irrespective of the presence of autism or not, the series does well to highlight how a range of professionals can make a real difference to the lives of children on the autism spectrum. Personally, I would have liked to have see the archetypal all-rounder that is the occupational therapist (OT) also included in the storyline but there you go...

Joe is seen in pretty much every episode asleep with his night light on followed by a soothing kiss good night from his mother. Again, not one to try and generalise but not every autistic child and their family look forward to such peaceful nights...

Parent and family relationships
Throughout the series, viewers watch how the ups and downs of family life manifest in the relationships between family members. We see for example, how Alison devotes almost her entire existence to Joe in terms of getting a diagnosis and arranging suitable schooling for example, whilst also running a busy household and a business. The stresses and strains tug and pull on important relationships manifesting in various different ways and impacting on various decisions. There are sexual scenes during the series and I know from what some people have written, these were thought of as a distraction to the main storyline. I however think it was important for the writers to include all aspects of parent and family relationships including more intimate moments (bearing in mind the program aired after the watershed). The idea also that autism in the family has the ability to impact on siblings was another important feature of the series. The experiences of Joe's older (half) sister, Rebecca, illustrate how siblings might require additional support when a diagnosis of autism is received in the family but also how they can be very vocal advocates for their brother(s) or sister(s) with autism.

Fever and autism (oh and broccoli...)
Episode 4 of the series introduced some interesting research-based concepts into the storyline. We see Joe develop an illness and 'fever' following a planned sleepover with some school friends resulting in some 'changes' to his behaviour. Joe seems more responsive as words like 'empathy' are banded about (bearing in mind no sweeping generalisation are required on this point). Changes to the presentation of autism in 'some' children following fever have been documented in the peer-reviewed literature [1]. It's not by any means a universal phenomenon and so one has to be a little bit cautious about generalisation. It is however something that requires quite a bit more study (allied to related research areas) about how certain 'types' of autism might be sensitive to such physiological changes. In the same episode we also hear mention of the words 'broccoli' and 'research' pointing to another issue that has surfaced on the peer-reviewed autism research radar [2] (see here for even more discussion). Although you might not know it, the commonality between fever and autism and broccoli and autism (aside from autism) is one Andrew Zimmerman and as if to prove a point [3]...

A hat-tip to gluten and casein
I also had to cast a wry smile as the series did include some reference to a topic close to my research heart: diet and autism, and specifically the involvement of gluten and casein. Granted, the reference to gluten and casein (although lactose is mention over casein) comes from one of the other boys sleeping over at Joe's house who has various 'allergies', but again, I think this highlights how the writers had some good insight into the varied autism research scene.

Final thoughts
There is always the risk that films or programmes 'about autism' can present a stereotype of autism and thereby fail to show just how wide and heterogeneous the autism spectrum is. I don't doubt that similar sentiments will be expressed about The A Word paralleling previous artistic presentations such as Rainman. That also important issues such as anxiety and sensory-perceptual issues were only paid lip service during the series is worthwhile mentioning as were the various often life-changing comorbidities that can accompany a diagnosis such as epilepsy or seizure disorders or learning disability. No programme will ever be perfect.

But I do think that quite a few of the important elements that surround childhood autism were included in the series albeit with the hint of drama required for such fictional storytelling. The struggles and strains were balanced with lighter moments and the idea that 'Joe is still Joe' even after receipt of an autism diagnosis came across on multiple occasions particularly from his on-screen sister. I think the writer Peter Bowker probably said it best about The A Word: 'You won't understand autism after watching The A Word – but it will make you want to learn more'. That sounds about as good a sentiment as any when it comes to the series and further expanding the public view about the very heterogeneous autism spectrum...


[1] Curran LK. et al. Behaviors associated with fever in children with autism spectrum disorders. Pediatrics. 2007 Dec;120(6):e1386-92.

[2] Singh K. et al. Sulforaphane treatment of autism spectrum disorder (ASD). Proc Natl Acad Sci U S A. 2014 Oct 28;111(43):15550-5.

[3] Singh K. & Zimmerman AW. Sulforaphane treatment of young men with Autism Spectrum Disorder. CNS Neurol Disord Drug Targets. 2016 Apr 13.

---------- Singh K, & Zimmerman AW (2016). Sulforaphane treatment of young men with Autism Spectrum Disorder. CNS & neurological disorders drug targets PMID: 27071786

Tuesday 26 April 2016

Bacterial origin and transferability of depression?

The paper by Zheng and colleagues [1] caught my eye recently and the interesting ideas that "dysbiosis of the gut microbiome may have a causal role in the development of depressive-like behaviors" and "transplantation of GF [germ-free] mice with ‘depression microbiota’ derived from MDD [major depressive disorder] patients resulted in depression-like behaviors compared with colonization with ‘healthy microbiota’ derived from healthy control individuals."

Bearing in mind the focus on mice not people in these results, it's not necessarily new news that the trillions of bacteria that call our gut home might be doing so much more than just helping to digest food and producing the odd vitamin or two. I've covered the concept a few times on this blog (see here for example) and how the so-called gut-microbiota-brain axis is gaining some scientific ground [2].

Whilst there are still quite a few more investigations to do in this area, this is not the first time that elements of the gut microbiome have been implicated in a complex condition like depression (see here) including how certain routinely available medicines might also show some involvement (see here). Zheng et al elaborate on some of the types of bacteria that might play a role in their results - "the gut microbiotic compositions of MDD patients and healthy controls were significantly different with MDD patients characterized by significant changes in the relative abundance of Firmicutes, Actinobacteria and Bacteroidetes" - but I think we have to be a little cautious about casting 'blame' just yet. The gut houses quite a lot more than just bacteria y'know and it's not outside the realms of possibility that elements of the gut virome for example, might also be able to exert some effect.

The idea of potential 'transferability' or transmission of depression [3] as a function of gut bacteria or other elements also gathers ground based on the Zheng findings. Accepting that familial transmission of depression is not an entirely new concept, the idea that genetic and other non-genetic factors might be complimented by sharing a similar gut microbial profile is a tantalising idea. Not least also because there is the prospect of 'changing' the gut microbiome [4] and potentially impacting on the the presentation of at least some 'types' of depression [5] alongside various other conditions. I say this also with the understanding that depression is a complicated condition and that various other 'biological' factors might also play an important role in presentation (see here and see here)...

But this is interesting work.

Music - and yet again, The Gimme Gimmes with I will survive...


[1] Zheng P. et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Molecular Psychiatry. 2016. April 12.

[2] Rogers GB. et al. From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways. Molecular Psychiatry. 2016. April 19.

[3] Canli T. Reconceptualizing major depressive disorder as an infectious disease. Biology of Mood & Anxiety Disorders. 2014;4:10.

[4] Evrensel A, Ceylan ME. The Gut-Brain Axis: The Missing Link in Depression. Clinical Psychopharmacology and Neuroscience. 2015;13(3):239-244.

[5] Dinan TG. et al. Psychobiotics: a novel class of psychotropic. Biol Psychiatry. 2013 Nov 15;74(10):720-6.

---------- Zheng, P., Zeng, B., Zhou, C., Liu, M., Fang, Z., Xu, X., Zeng, L., Chen, J., Fan, S., Du, X., Zhang, X., Yang, D., Yang, Y., Meng, H., Li, W., Melgiri, N., Licinio, J., Wei, H., & Xie, P. (2016). Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism Molecular Psychiatry DOI: 10.1038/mp.2016.44

Monday 25 April 2016

Parenting a child with autism or ADHD: what the science says...

I'm talking about parenting again today. Two papers are served up for your reading interest today, providing an important 'science-based' perspective on the general experience of parenting a child who is also diagnosed with an autism spectrum disorder (ASD) or attention-deficit hyperactivity disorder (ADHD).

The first paper by Britt Laugesen and colleagues [1] "aimed to identify and synthesize the best available evidence on parenting experiences of living with a child with attention-deficit hyperactivity disorder, including their experiences of healthcare and other services." Their review (whose protocol can be seen here), based on over 20 research articles, was able to boil down various study findings into 15 categories or themes. Without plagiarising, they were: "an emotional roller coaster between hope and hopelessness; mothers as advocates in a battlefield within the system and family; parental experiences in a crossfire of blame, self-blame, and stigmatization; shuttling between supportive and nonsupportive services and professionals; routines, structures and strategies within everyday life; and despite multiple challenges, it is not all bad."

The second paper by Khim Lynn Ooi and colleagues [2] (open-access) sought to do a similar thing but with autism (ASD) in mind; coming up with four common themes centred on: "1) The Parent, 2) Impact on the Family, 3) Social Impact, and 4) Health and Educational Services." Within each of these domains, various discussion points were identified covering areas as diverse as 'coping with autism and the child' to 'experience with health services'. As per the final item included in the Laugesen paper on parenting a child with ADHD, raising a child with autism was also described as "not all doom and gloom."

Combined, these papers provide some important details about what might be further done to improve child and parent outcomes as and when autism or ADHD (or both) are suspected or diagnosed. I appreciate that it is easy for me to say this (sat here just blogging about research) and change is often a very slow process. As I've hinted in previous posts, change also needs to be accompanied by additional resources and money, which in these austere times is not an easy thing to come by.

But if there is a bottom line I do think it should be a sentence from the Ooi paper: "The provision of timely, adequate, and continuous support to parents is therefore important in empowering parents to adapt to the lifetime diagnosis of autism, which can be addressed by improvements in public awareness, policy making, and health care practices." Science doesn't necessarily agree with the whole 'lifetime diagnosis of autism' as being applicable to every case (see here) but in particular, I'd champion the idea that 'health care practices' could be modified when it comes to autism (and ADHD) insofar as ensuring that a diagnosis does not lead to a 'second-class citizen' healthcare experience. Words like 'oh, it's just part of their autism' should be heard less and less (see here) as other research seems to agree on the need to focus on "physical well-being" [3]. As to the ideas about policy making and improvements in public awareness, well policy changes are good ideas but don't always come with a guarantee in the real world (see 'Autism Act'). As for public awareness, yes, that is also something that should be happening (see 'The A Word') but given the huge amount of diversity present in the autism spectrum, one has to be very careful not to portray too generalised an 'image' of what autism is (and isn't). Snowflakes people, snowflakes.

Music: Kennedy by The Wedding Present.


[1] Laugesen B. et al. Living with a child with attention deficit hyperactivity disorder: a systematic review. Int J Evid Based Healthc. 2016 Apr 7.

[2] Ooi KL. et al. A meta-synthesis on parenting a child with autism.  Neuropsychiatric Disease and Treatment. 2016; 12: 745-762.

[3] Egilson ST. et al. Quality of life of high-functioning children and youth with autism spectrum disorder and typically developing peers: Self- and proxy-reports. Autism. 2016. April 5.

---------- Laugesen B, Lauritsen MB, Jørgensen R, Sørensen EE, Rasmussen P, & Grønkjær M (2016). Living with a child with attention deficit hyperactivity disorder: a systematic review. International journal of evidence-based healthcare PMID: 27058250 Khan, T., Ooi, K., Ong, Y., & Jacob, S. (2016). A meta-synthesis on parenting a child with autism Neuropsychiatric Disease and Treatment DOI: 10.2147/NDT.S100634

Saturday 23 April 2016

Parents on the autism spectrum and 'parenting efficacy'

There are some aspects of the autism research landscape that make for uncomfortable reading. I've covered a few of them on this blog (see here and see here for example) simply because of my belief that science should not be afraid to ask about and try and answer difficult questions.

I'd place the paper by Winnie Yu Pow Lau and colleagues [1] in that uncomfortable reading zone as a consequence of their findings related to parenting efficacy as a function of parents who themselves have been diagnosed with an autism spectrum disorder (ASD) among other groupings. With one Tony Attwood on the authorship list, results are reported suggesting that whilst "mothers with ASD had comparable levels of parental efficacy to parents without ASD in the family" fathers with an ASD "had the lowest parental efficacy." The authors recommend that further screening and provisions should be put in place "to build fathers parental efficacy" minus any sweeping generalisations from this data. Parenting efficacy by the way, is thought to be a strong predictor of parenting behaviours potentially onwards being related to various offspring outcomes.

As I've mentioned before on this blog, parenting is already a tough job even before any additional issues related to offspring behaviours or diagnoses are added to the mix (see here). Most parents do a good job navigating the various stages of child rearing and would probably have little or no regrets about the way that they eventually did the job. For many parents, to be told about any perceived weaknesses or 'failings' of parenting ability is generally not likely to be taken well considering the amount of time and effort that is devoted to raising a brood. Blood, sweat and tears people...

It is with that sentiment in mind that I tread carefully with the Lau findings whilst at the same time acknowledging that parenting efficacy does perhaps need to be further researched under such circumstances. With the ever-increasing numbers of people being diagnosed on the autism spectrum, it is, by mass action, inevitable that more and more adults with an ASD are going to be raising families of their own. There are some quite high profile examples of parents on the spectrum raising children on or off the spectrum and doing it very well, but one should not assume that every family is fortunate to be the same, particularly when one takes into account individual family circumstances (lone parents, more than one child) and factors such as income and housing among others. The emphasis should rightly be on supporting those families when support is needed [2] whilst not coming across as too 'nanny state' or condescending; keeping in mind that the welfare of children is central to all this.

As a last point, I am going to query the use of the Autism Spectrum Quotient (AQ) in the Lau study as a measure of autistic traits. This instrument may well cover elements of the autism spectrum but (and it is an important 'but') the presence of those traits might not necessarily be exclusive to autism (see here). From that point of view, further research needs to perhaps be a little more thorough about what exactly is being investigated, also understanding that a historical diagnosis of autism might not necessarily be set in stone and that the diagnosis rarely appears in a diagnostic vacuum - both factors that might impact on the stability of parenting efficacy. Indeed, with that last point in mind, the findings reported by Samyra Jogaib Bonatto and colleagues [3] on [self-reported] ADHD symptoms in parents of children with autism, are also deserving of quite a bit more allied scrutiny too.

Music to close, and what else but something that Papa's the world over with have probably heard...


[1] Lau WY. et al. Parents on the autism continuum: Links with parenting efficacy. Research in Autism Spectrum Disorders. 2016; 26: 57-64.

[2] Chong WH. & Kua SM. Parenting Self-Efficacy Beliefs in Parents of Children With Autism: Perspectives From Singapore. Am J Orthopsychiatry. 2016 Apr 14.

[3] Bonatto SJ. et al. The prevalence of symptoms of attention-deficit/hyperactivity disorder in parents of children with autism spectrum disorder. Psychiatry Research. 2016. April 5.

---------- Lau, W., Peterson, C., Attwood, T., Garnett, M., & Kelly, A. (2016). Parents on the autism continuum: Links with parenting efficacy Research in Autism Spectrum Disorders, 26, 57-64 DOI: 10.1016/j.rasd.2016.02.007

Friday 22 April 2016

Developmental regression in autism affects screening results

In today's short post I'd like to bring the findings reported by Lotta Höglund Carlsson and colleagues [1] to your attention and a reminder that developmental regression accompanying autism onset is an important feature for quite a few people.

With the aim of looking at the "national, routine 18-month developmental surveillance at Child Healthcare Centres (CHC) on children later diagnosed with autism spectrum disorder (ASD)" in Stockholm County, Sweden, authors reported on the results of said surveillance for those (N=175) diagnosed with autism in terms of those who initially passed this screen and what might be done to increase it's diagnostic utility. Some interesting data emerged.

We are told that over a third of the autism group "did not pass the required number of items" included in the screen and this was particularly prominent in those later diagnosed with autism and learning (intellectual) disability. We are also told that adding in additional variables linked to "regulatory problems - crying, feeding and sleeping" (the sorts of things that Kanner himself talked about) might increase the diagnostic yield of the 18 month surveillance by about 10%. But also... "Of those with ASD and ID who had passed, more than one-third experienced developmental regression after 18 months of age."

There you have it. Regression is very much part and parcel of quite a few cases of autism and all the chatter about autism being [universally] present during the earliest points of infancy is not necessarily accurate and applicable to all cases. Of course this probably won't be a surprise to many as previous examples of later onset or 'acquired autism' litter the peer-reviewed literature (see here and see here for example). Appreciating that many factors might influence the age at which an autism diagnosis is given (see here) and how the Swedish findings might be important for future work coming out of the UK for example (see here), I'd like to think there is more to do in this area. Y'know everyone keeps talking about the more plural 'autisms' for example (see here), well I'd be minded to suggest that those who passed vs. those that didn't pass early developmental screens might be another comparison to throw into the autism research mix with a focus on phenotypes. And given the previous research conducted by some of the authors on the Höglund Carlsson paper (see here and see here), there may be quite a few other variables that could also be included in future work in this area...


[1] Höglund Carlsson L. et al. Autism spectrum disorders before diagnosis: results from routine developmental surveillance at 18 months. Acta Paediatrica. 2016. April 8.

---------- Höglund Carlsson, L., Westerlund, J., Barnevik Olsson, M., Eriksson, M., Hedvall, �., Gillberg, C., & Fernell, E. (2016). Autism spectrum disorders before diagnosis: results from routine developmental surveillance at 18 months Acta Paediatrica DOI: 10.1111/apa.13418

Thursday 21 April 2016

The inter-pregnancy interval and risk of autism reviewed

"Short IPIs [interpregnancy intervals] are associated with a significantly increased risk of ASD [autism spectrum disorder]. Long IPIs also appear to increase the risk of ASD.

So said the results of the systematic review undertaken by Agustín Conde-Agudelo and colleagues [1] into how birth spacing might impact on the risk of a child developing an ASD. Drawing on data from 7 studies that "reported an association between short IPIs and increased risk of ASD" including over 1.1 million children, the authors confirmed what quite a few people already suspected: "children born to women with IPIs of <12 months had a significantly increased risk of any ASD." 'Autistic disorder' a.k.a autism (over other ASDs such as Asperger syndrome) seemed to shoulder the largest risk following a short IPI.

Of course we've been here before on the topic of IPI and autism risk (see here and see here) and as such the latest review results are not a complete surprise. What perhaps science does have to start thinking about are the various ways and means that a short IPI might confer additional risk of offspring autism. Personally, I'd initially go with the issue of a 'depletion of micronutrients' as being a prominent possible factor, as per what other research in this area has speculated on (see here). Combined with the so-called 'foetal programming hypothesis' (see here) drawing on the work of the late David Barker and others, the 'nine months that made us' is indeed an extremely important time from a nutritional point of view and potentially very relevant to at least some autism.

To close: Victoria Wood - Brief Encounter. RIP mince pie in the eye...


[1] Conde-Agudelo A. et al. Birth Spacing and Risk of Autism and Other Neurodevelopmental Disabilities: A Systematic Review. Pediatrics. 2016. April 7.

---------- Conde-Agudelo, A., Rosas-Bermudez, A., & Norton, M. (2016). Birth Spacing and Risk of Autism and Other Neurodevelopmental Disabilities: A Systematic Review PEDIATRICS DOI: 10.1542/peds.2015-3482

Wednesday 20 April 2016

Talking therapies impacting on the epigenetics of panic disorder?

The psychologist Oliver James has made some waves recently, coinciding with the publication of his new book, with the suggestion that nurture might be 'outdoing' nature when it comes to various concepts from intelligence to mental health. At times the recent 'debates' in this area have not been pretty as arguments about 'what the science actually says' with regards to [structural] genetics vs. environment have tended to get a little heated, and the word 'blame' being banded around quite a lot. This set in the context of views and opinions of certain relevant disciplines.

With all that in mind the paper by Ziegler and colleagues [1] (open-access) perhaps offers an olive branch between the various camps on whether genes or environment play the more important role in relation to something like mental health. Reporting results on "MAOA [monoamine oxidase A] methylation changes during the course of exposure-based cognitive behavioral therapy (CBT) in PD [panic disorder]" the authors describe how: "In a psychotherapy-epigenetic approach, responders and non-responders to a 6-week standardized CBT as defined by the number of panic attacks showed differential dynamics of MAOA methylation during the course of treatment: response was associated with a significant increase in MAOA methylation up to the level of healthy controls, while non-response rather went along with a further decrease in MAOA methylation."

In a sort of two-stage study, Ziegler et al first compared the methylation status of the MAOA gene in a small-ish sample of female participants diagnosed with PD (n=28) compared with age- and sex-matched 'not PD' controls. Actually, it wasn't just a case of looking at the gene and saying 'yes it's methylated' or not but rather looking at those little islands on a gene where a methyl group can be added and reporting findings (for 13 of them). Authors reported that as a group, the PD participants showed MAOA methylation differences compared to controls - overall hypomethylation of the gene and "at CpGs 3, 6–9, 12 and 13." Hypomethylation normally means something akin to increased gene expression; as the authors note: "As in a functional in vitro assay decreased methylation has been shown to activate MAOA expression... MAOA hypomethylation might result in a decreased availability of monoamines in the synaptic cleft and thereby confer an increased risk for PD." Authors also reported something of an interesting association between baseline PD severity and MAOA methylation levels.

In the second part of the study: "MAOA methylation was furthermore analyzed at baseline (T0) and after a 6-week CBT (T1) in the discovery sample parallelized by a waiting time in healthy controls, as well as in an independent sample of female PD patients (N=20)." The particular type of CBT administered has been detailed in other results [2] as we are also told that: "Pharmacological treatment remained unmodified during the course of CBT" and "patients were instructed to keep smoking behavior constant during the time course of therapy." Researchers reported that: "overall [in the] patient group irrespective of responder/non-responder status, as well as in the control group, MAOA methylation did not change significantly from T0 to T1 for average methylation or at any individual CpG site." When however the CBT group were sub-categorised as 'responders' or 'non-responders' on the basis of 'the number of panic attacks at T1 compared with T0' there was something a little more interesting to see. So: "responders displayed an increase in average methylation after therapy (mean change±s.e., 3.37±2.17%), while non-responders decreased in average methylation (mean change±s.e., −2.00±1.28%; P=0.001)."

Without getting too carried away with the Ziegler results and accepting that furrowed brows still accompany talk about epigenetics, the potential implications of this study could be pretty huge. I'm not completely enthralled by the 'talking therapies' it has to be said, and the 'bigging up' of the idea that they are some sort of panacea when it comes to mental health and wellbeing as a whole despite their usefulness in certain contexts. Plurality people, plurality. I am however interested when an association is made between their use and gene expression as a function of responder status even if only one gene and one condition has so far been examined with little other genetic or biochemical factors taken into account. My stance on the whole 'genes vs environment' bit too is that it is rather too simplistic to say just 'one or the other' when it comes to complicated things like human behaviour and the vast heterogeneity that underlies it. For some people it could be more of a genetic thing [2] underlying certain characteristics of a particular condition, for others it might be more non-genetic factors. The N=1 seems to be an important point.

If indeed it does turn out that the talking therapies (among various other 'environmental' factors) can impact on gene expression, there could be a few implications. The rise and rise of something like mindfulness (minus the hype) might also find a similar effect and could perhaps be [scientifically] pitted against CBT and other similar intervention hopefuls both in terms of behavioural outcomes and methylation status. Same goes for other potential 'methylation-modifiers' such as exercise for example in light of some changing attitudes in this area (see here). There is also the prospect that with some further science to do, the types of modification to gene expression could eventually be translated into a more biological intervention. Y'know, as per other discussions about the methionine cycle as a source of those methyl groups (see here) or the various agents that can affect methylation practices. Perhaps even looking at the various medications that psychiatry already has in its arsenal as having an epigenetic effect too?

More investigation is required.


[1] Ziegler C. et al. MAOA gene hypomethylation in panic disorder-reversibility of an epigenetic risk pattern by psychotherapy. Transl Psychiatry. 2016 Apr 5;6:e773.

[2] Okbay A. et al. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses. Nature Genetics. 2016. April 18.

---------- Ziegler C, Richter J, Mahr M, Gajewska A, Schiele MA, Gehrmann A, Schmidt B, Lesch KP, Lang T, Helbig-Lang S, Pauli P, Kircher T, Reif A, Rief W, Vossbeck-Elsebusch AN, Arolt V, Wittchen HU, Hamm AO, Deckert J, & Domschke K (2016). MAOA gene hypomethylation in panic disorder-reversibility of an epigenetic risk pattern by psychotherapy. Translational psychiatry, 6 PMID: 27045843

Tuesday 19 April 2016

Bumetanide for schizophrenia? A case report

Bumetanide - a medicine known as a diuretic - has appeared before on this blog (see here for example) in relation to some preliminary suggestions that at least some types of autism might be sensitive to intervention using this particular compound [1]. The names Lemonnier (Eric) & Ben-Ari (Yehezkel) are a big part of the research group interested in bumetanide and its use outside of more traditional indications; particularly, the focus on its action on NKCC1 onwards to an effect on GABA.

Whilst there is still interest in the use of bumetanide for 'some' autism [2], today I'd like to briefly bring your attention to an interesting report on the use of this pharmaceutic in an adolescent diagnosed with schizophrenia [3]. The case report by Lemonnier et al details how following the use of bumetanide, there was a corresponding effect on some of the positive symptoms of schizophrenia; in particular: "Long-term treatment reduced hallucinations significantly." The authors conclude that "Further clinical trials and experimental studies are warranted."

Although still early days, I find this to be interesting research if not the first time that NKCC1 has been mentioned with schizophrenia in mind. When one looks at the range of 'effects' potentially linked to the NKCC1 inhibitors such as bumetanide [4] one gets a flavour for what might be potentially linked. As Jaggi et al suggest: "The inhibitors of NKCC1 are shown to produce anxiolytic effects; attenuate cerebral ischemia-induced neuronal injury; produce antiepileptic effects and attenuate neuropathic pain." I'm particularly drawn to the 'antiepileptic effects' bit in particular, as a function of the quite long-standing association between schizophrenia and epilepsy (see here). I'm not putting my eggs in one scientific basket by saying that, but given what is known about NKCC1 and some 'refractory' epilepsy [5] for example, it sounds as good a place to continue investigations as any...

Music: Me First & The Gimme Gimmes with a classic... Top of the World.


[1] Lemonnier E. et al. A randomised controlled trial of bumetanide in the treatment of autism in children. Transl Psychiatry. 2012 Dec 11;2:e202.

[2] 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.

[3] Lemonnier E. et al. Treating Schizophrenia With the Diuretic Bumetanide: A Case Report. Clin Neuropharmacol. 2016 Mar-Apr;39(2):115-117.

[4] Jaggi AS. et al. Expanding Spectrum of Sodium Potassium Chloride Co-transporters in the Pathophysiology of Diseases. Curr Neuropharmacol. 2015;13(3):369-88.

[5] Sen A. et al. Increased NKCC1 expression in refractory human epilepsy. Epilepsy Research. 2007; 74: 220-227.

---------- Lemonnier E, Lazartigues A, & Ben-Ari Y (2016). Treating Schizophrenia With the Diuretic Bumetanide: A Case Report. Clinical neuropharmacology, 39 (2), 115-117 PMID: 26966887

Monday 18 April 2016

'Autism genes' are not just 'genes for autism'

The paper by Ya Wen and colleagues [1] (open-access available here) caught my attention recently with the suggestion that: "ASD [autism spectrum disorder]-associated genes may contribute not only to core features of ASD themselves but also to vulnerability to other chronic and systemic problems potentially including cancer, metabolic conditions and heart diseases." Further: "ASDs may thus arise, or emerge, from underlying vulnerabilities related to pleiotropic genes associated with pervasively important molecular mechanisms, vulnerability to environmental input and multiple systemic co-morbidities."

With a quite well renowned inclusion on the authorship list - Martha Herbert - who along with another notable writer penned a pretty good book not so long ago, Wen et al present data pertinent to "an ASD pathway network" where details of ASD-related genes were downloaded from SFARI (Simons Foundation Autism Research Initiative) and gene set enrichment analysis conducted "with the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Database." The idea was to focus in on some of the specific molecular processes attached to the function of those genes and how [some] autism might be but one 'effect' from structural issues with those genes.

Some 650 genes were included for analysis. They were eventually sorted into a 'top 50 enriched pathways' pointing to some rather interesting biology. "Two pathways stood out most strongly amongst the pathways in which the SFARI ASD-associated genes participated: the MAPK signaling pathway which was the most highly interactive, and the calcium signaling pathway, which was the most highly enriched pathway." Further: "integrated analysis for MAPK and calcium signaling pathways came together in the process “calcium-PKC-Ras-Raf-MAPK/ERK”" something that the authors speculate might 'link' the genetics of autism to various other conditions - "involved in cancer, heart diseases and metabolic problems." But don't be fooled by the focus on just two pathways as the authors present a rather complicated picture of interacting 'disease' and 'functional' pathways (see here for Figure 2) as old favourites such as 'tryptophan metabolism' crop up alongside mention of mTOR  for example.

There is quite a lot to take in with the Wen results and once again, I would encourage readers to have a good read through the data keeping in mind the idea that a diagnosis of autism does not seem to be protective against other comorbidity appearing. The calcium signalling dysregulation noted in particular, is interesting. There is quite a bit of information both in [2] and outside the peer-reviewed domain (see here) on this topic and as per the discussion by Wen et al "if something went wrong with calcium signaling systemically, both cardiac and neural problems might ensue. Although identifying an overlap between neural and cardiac genes ought to make us more attentive to potential comorbidities, the overlap may simply highlight how core molecular functions play roles across diverse systems of the body and brain." Not to try and make connections where none might exist but something like congenital heart disease and autism risk has also been discussed on this blog previously (see here) and one might similarly extend a relationship [3] in light of the Wen findings.

As important as the Wen paper is, it is not by any means perfect in terms of "The tendency to study genes that are related to genes already implicated in ASDs" among other things. Indeed, I note that one of the curators of the SFARI database also has something to say. As I've mentioned quite a few times on this blog, structural genetics is an important area for autism research but does not necessarily encompass the entirety of the genetics of autism or any other label. More and more science is starting to appreciate that gene expression is something also quite important and how, minus any hype, the body has quite a few ways of switching genes on or off in various tissue as per the science of 'epigenetics'. Then there are the other elements that make up our genome (see here) as also being potentially important and the idea that the plural autisms (see here) probably reflect more than one pathway onwards to developing of symptoms.

But don't let any of that detract from the finding from Wen and colleagues and their potential importance...

To close, I can't let today pass without mentioning a certain 'Awakening' film coming to DVD today. My brood and I already have our popcorn ready for this evening and no doubt quite a few more after. Cue the rolling titles...


[1] Wen Y. et al. Pathway Network Analyses for Autism Reveal Multisystem Involvement, Major Overlaps with Other Diseases and Convergence upon MAPK and Calcium Signaling. PLoS One. 2016 Apr 7;11(4):e0153329.

[2] Schmunk G, Gargus JJ. Channelopathy pathogenesis in autism spectrum disorders. Frontiers in Genetics. 2013;4:222.

[3] Splawski I. et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell. 2004 Oct 1;119(1):19-31.

---------- Wen Y, Alshikho MJ, & Herbert MR (2016). Pathway Network Analyses for Autism Reveal Multisystem Involvement, Major Overlaps with Other Diseases and Convergence upon MAPK and Calcium Signaling. PloS one, 11 (4) PMID: 27055244