Parent stress and autism: an issue that needs a lot more discussion

Two paper are brought to the (brief) blogging table today: the first from Nik Aida Nik Adib and colleagues [1] and the second from Elena Pattini and colleagues [2], both focused on the topic of stress and parenting in the context of autism.

Yes, I know to mention the words 'parenting stress' and 'autism' in the same sentence requires some caution. I know some people don't like to talk about this and related topics (see here). But obscuring such important research from view for fear of upsetting people or impacting on any 'positive PR' does little to approach an issue that is seemingly so widespread (see here).

So what are the key points to take away from both papers on this topic?

1. "Caregivers of an ASD [autism spectrum disorder] child perceived significant stress while taking care of their children." Not exactly a novel results I grant you, but important to reiterate.
2. Autism plus learning disability seems to increase the 'perceived' stress.
3. Parental stress may well present as physiological stress. This is particularly important in relation to the measurement of something called cortisol.

OK, there's nothing earth-shattering about such findings. They again imply that as and when a child receives a diagnosis of autism or ASD, parents or primary caregivers might also benefit from some information on what they might expect and what they can do when it comes to coping with stress. Caring for the carers (see here) and offering things like respite care to those who need it (see here) sound like good initiatives. Bear also in mind, that parenting a child with autism is often done alongside parenting other children too, and what effect that can sometimes have on them (see here)...

----------

[1] Nik Adib NA. et al. Perceived Stress among Caregivers of Children with Autism Spectrum Disorder: A State-Wide Study. Int J Environ Res Public Health. 2019 Apr 25;16(8). pii: E1468.

[2] Pattini E. et al. Psychological characteristics and physiological reactivity to acute stress in mothers of children with Autism Spectrum Disorder. Stress Health. 2019 Apr 26.

----------

Stressed medical students and Lactobacillus casei strain Shirota

"Our findings indicate that the daily consumption of probiotics such as LcS [Lactobacillus casei strain Shirota] preserves the diversity of the gut microbiota and may relieve stress-associated responses of abdominal dysfunction in healthy subjects exposed to stressful situations."

So said the findings reported by Akito Kato-Kataoka and colleagues [1] who following the use of a "double-blind, placebo-controlled trial" method were able to potentially offer "healthy medical students undertaking an authorized nationwide examination for promotion" a leg up when it came to minimising / overcoming stress-induced abdominal dysfunction. As many people might have themselves experienced, exam stress can sometimes manifest in various different ways...

With some of the authors working at the Yakult Central Institute (originally called the Shirota Research Institute after one of the most famous men to have a bacterial strain named after them), researchers followed nearly 50 medical students for 8 weeks "until the day before the examination", half consuming "a LcS-fermented milk" and half "a placebo milk daily." Various measures looking at abdominal symptoms, "psychophysical state" and salivary stress compounds were included in the study as well as composition of the gut microbiota "analyzed using DNA microarray and 16S rRNA gene amplicon sequence analyses."

Results: well you already know what conclusion was reached but a bit more on the details: "The administration of LcS, but not placebo, significantly reduced gastrointestinal symptoms." It's also not beyond the realms of possibility that this 'bowel' finding was also linked to a wider diversity of gut bacterial species found in the experimental (LcS) group over the placebo group. It is also reported that the placebo group showed a "significant increase in salivary cortisol levels before the examination." Quite a few potential positive for the LcS-fermented milk and importantly, few, if any side-effects.

I note that this is not the first time that the use of LcS has been reported on with medical students and stress in mind as other peer-reviewed papers demonstrate [2] (open-access here). Indeed, this is the same cohort talked about in today's discussion paper and complement findings with details such as "the LcS group had significantly higher faecal serotonin levels (P<0.05) than the placebo group." And if you want some animal findings too [3] look no futher...

If I were to start being a little more speculative about the Kato-Kataoka data and implications outside of just medical students under exam stress, I might be inclined to suggest that this is good evidence for the possibility of a connection between the trillions of wee beasties that populate our digestive tract (the gut microbiome) and brain and behavioural functions. Y'know, the gut-bacteria-brain axis that is so popular these days (see here for example). If it is at all likely that medical students are not a million miles away from other groups of people in terms of physiology, the idea that stress manifesting as abdominal dysfunction could be to some degree countered by ingestion of a probiotic, I'd say that there are quite a few important studies to be done. In fact [4]...

And perhaps related to today's musings, an interesting discussion about irritable bowel syndrome (IBS) not being 'all in the mind'.

To close, I know I've not posted much music these past few weeks so to make up for it a film showing British community policing at it's very best...

----------

[1] Kato-Kataoka A. et al. Fermented milk containing Lactobacillus casei strain Shirota preserves the diversity of the gut microbiota and relieves abdominal dysfunction in healthy medical students exposed to academic stress. Appl Environ Microbiol. 2016 May 6. pii: AEM.04134-15.

[2] Kato-Kataoka A. et al. Fermented milk containing Lactobacillus casei strain Shirota prevents the onset of physical symptoms in medical students under academic examination stress. Benef Microbes. 2016 Mar 11;7(2):153-6.

[3] Takada M. et al. Probiotic Lactobacillus casei strain Shirota relieves stress-associated symptoms by modulating the gut-brain interaction in human and animal models. Neurogastroenterol Motil. 2016 Feb 20.

[4] Diop L. et al. Probiotic food supplement reduces stress-induced gastrointestinal symptoms in volunteers: a double-blind, placebo-controlled, randomized trial. Nutr Res. 2008 Jan;28(1):1-5.

----------

Kato-Kataoka A, Nishida K, Takada M, Kawai M, Kikuchi-Hayakawa H, Suda K, Ishikawa H, Gondo Y, Shimizu K, Matsuki T, Kushiro A, Hoshi R, Watanabe O, Igarashi T, Miyazaki K, Kuwano Y, & Rokutan K (2016). Fermented milk containing Lactobacillus casei strain Shirota preserves the diversity of the gut microbiota and relieves abdominal dysfunction in healthy medical students exposed to academic stress. Applied and environmental microbiology PMID: 27208120

Cortisol and cytokines: a diagnostic tag-team for autism?

A quote from the paper by Chang-Jiang Yang and colleagues [1] begins today's post: "The results of ROC [receiver operating characteristic] analysis indicated the cortisol VAR, IL-6 and TNF-α were potential biomarkers in diagnosis of ASD [autism spectrum disorder]."

With many thanks to Natasa for providing me with a copy of this paper, I'd like to discuss these 'joined up' findings a little further. A few pointers to begin with:

Boot the grime of this world in
the crotch, dear

• Based on quite a bit of previous research looking at the steroid hormone cortisol in relation to autism (see here) alongside an increasingly important body of work talking about cytokines and autism (see here), the authors embarked on assessing the joint role of these compounds as "potential biomarkers in assisting the diagnosis of ASD."
• Based in China, a small-ish group of participants diagnosed with ASD (n=35) aged around 10 years were recruited alongside an asymptomatic group (n=32) "unrelated to the autistic participants".
• Salivary cortisol levels were measured (8 of them) at various points of the day from waking up to just before going to sleep. A fasting blood sample was also provided from each participant for analysis of cytokines. The Childhood Autism Rating Scale (CARS) served as the measure of autism severity.
• Results: the cortisol VAR - "diurnal variation of cortisol" - did show something of a group difference between those with autism and controls exemplified by "reduced diurnal amplitude in... cortisol concentration". Group cortisol concentrations differed particularly at the time of "just before going to sleep", where the ASD group tended to show higher levels than controls.
• Insofar as those cytokines: "There was a significant difference noted in median plasma concentrations of IL-6 and TNF-α between the ASD and control individuals." Both measures were elevated in the autism samples when taking groups as a whole.
• Then came the ROC analysis, and based on those values for cortisol VAR and those two cytokines, various measures of sensitivity and specificity were put forward individually. "The combination of three factors had a sensitivity of 91.43% and a specificity of 96.87% (AUC = 0.97)". Those are pretty good values in anyone's book
• The authors conclude that their study results "may supply a simple clinical approach for aiding the diagnosis of ASD." Importantly however, they make mention of the small participant groups included in their study.

As always, further independent replication of these findings are warranted before anyone goes and gets too excited about the possible implications. That and the fact that 'biomarkers' mentioned in the context of autism perhaps doesn't mean as much as you might think bearing in mind the heterogeneity of the autism spectrum ('the autisms'?) and those all-important comorbidities which I keep going on about. Whether results also translate to other geographic or ethnic populations is another point to be seen.

What I perhaps like best about the Yang paper and results is however the logical simplicity behind their study. As indicated, both areas of cortisol - as part of the HPA axis - and cytokines have something of an important history in autism research [2] which has thus far been seldom looked at together. I acknowledge the paper by Brian Lovell and colleagues [3] (discussed in this post) looking at pro-inflammatory biomarkers and cortisol levels in parents of children with autism or ADHD (attention-deficit hyperactivity disorder) but that was parents, not children with autism.

The obvious next questions after any independent replication are 'why' and what could this mean for potential interventions (if and when required). The 'why' question is probably going to be rather complicated as per the involvement of genetics (see here), epigenetics (see here) and biochemistry (see here) intersecting when it comes to immune function involvement and autism for example. Despite some headlines talking about elements of immune function as being the next frontier for autism research I'd be minded to say that is has been for at least the past 20 years or so, in some circles at least. Oh, and science is also picking up the idea of "an immune-mediated subtype of autism" too [4] perhaps at the centre of any cytokine biomarkers [5].

Insofar as the intervention side of things, well this is where things can get a little more contentious. Accepting that concepts like inflammation are starting to be more readily used in the context of psychiatry (see here), the idea that treating said inflammation might impact on behavioural measures is still something squarely in the research domain at least for now.

But this kind of work does represent an interesting area ripe for further study...

Music to close... and I am the only one transfixed with this 'how to play Heart and Soul' on the piano?

----------

[1] Yang C-J. et al. The roles of cortisol and pro-inflammatory cytokines in assisting the diagnosis of autism spectrum disorder. Research in Autism Spectrum Disorders. 2015; 9: 174-181.

[2] Ashwood P. et al. Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav Immun. 2011 Jan;25(1):40-5.

[3] Lovell B. et al. The psychosocial, endocrine and immune consequences of caring for a child with autism or ADHD. Psychoneuroendocrinology. 2012 Apr;37(4):534-42.

[4] McDougle CJ. et al. Toward an immune-mediated subtype of autism spectrum disorder. Brain Research. 2014. November 13.

[5] Rose D. & Ashwood P. Potential cytokine biomarkers in autism spectrum disorders. Biomark Med. 2014 Oct;8(9):1171-1181.

----------

Yang, C., Tan, H., Yang, F., Liu, C., Sang, B., Zhu, X., & Du, Y. (2015). The roles of cortisol and pro-inflammatory cytokines in assisting the diagnosis of autism spectrum disorder Research in Autism Spectrum Disorders, 9, 174-181 DOI: 10.1016/j.rasd.2014.10.012

Elevated amniotic fluid steroid hormones and autism risk

"These results provide the first direct evidence of elevated fetal steroidogenic activity in autism". Such were the sentiments of the paper by Simon Baron-Cohen and colleagues [1] (open-access) looking at amniotic fluid samples for the presence of various sex steroid levels: Progesterone, 17α-Hydroxy-progesterone, Androstenedione, Testosterone and Cortisol. Most compounds are found in the Δ4 pathway. Suffice to say that the media kinda liked the press release for this study (see here) and the study findings have been reported by quite a few outlets (see here and see here).

The paper is open-access but as always, I'd like to give a brief overview:

• Based on amniotic samples collected in Denmark (yet again those Scandinavian registries are proving their scientific worth), "all amniotic fluid samples of males born between 1993 and 1999 who later received ICD-10 (International Classification of Diseases, 10th Revision) diagnoses of autism, Asperger syndrome or PDD-NOS (pervasive developmental disorder not otherwise specified) (n=128)" were compared with 217 asymptomatic controls. Note the focus on males only.
• Samples were in storage for quite a few years (average of 14 years) but were eventually thawed and prepared for analysis by a favourite technique of mine: liquid chromatography tandem mass spectrometry. If you're really interested, the mass spec used was a triple quadrupole system operated in positive ion mode relying on chemical ionisation.
• Results: rather than any one of the sex steroids being singled out as a biomarker for the autism samples, "a latent steroidogenic factor is elevated, which includes all hormones in the Δ4 pathway, as well as cortisol". Further: "This observation suggests dysregulation of pathways mediated by cytochrome P450-containing enzymes that catalyze the conversion of hormones along the Δ4 and glucocorticoid pathways". One of the figures included in the paper provides a good overview on the extent of the group elevations noted in the study (see here).
• "The source of elevated steroidogenic activity in the fetal development of autism was not tested in the current study, and more research will be needed to understand how different sources such as the fetus, mother, placenta or other environmental factors might contribute to such elevations". In other words, researchers were only recording sex steroid values in samples not looking at the hows and whys of such elevations.

Those who are familiar with the autism research scene will probably know about Prof SBC and his work going back some years (see here). In more recent times, I note that quite a bit more of his work is focusing on the sex hormones and how they may relate to cognitive phenotypes such as systemisers and empathisers (see here and see here) potentially overlapping with facets of the autism and other spectrums. Perhaps more interesting to me has been some shift away from grand sweeping psychological theories of autism to other disciplines pertinent to autism research such as those similar to his analytical chemistry work shown in this post [2]. 

I note in the current paper mention of the words "epigenetic fetal programming" as being one suggestion for how being 'bathed' in elevated levels of these 'male' hormones might potentially explain why a child goes on to develop autism. I know this is a trendy area to talk about these days; David Barker (RIP) must be casting a smile over how far and wide his writings are now seemingly reaching. That being said, I'd be interested to see how subsequent research fares in this area particularly when taking into account other placental-related autism findings and the rise and rise of epigenetics in autism research (see here). The authors also for example write: "The current results may also be relevant to the literature on prenatal stress and autism. We found that cortisol, a biomarker typically associated with stress, is elevated early in the fetal development of autism". Knowing what we think we know about cortisol and autism (see here) again, it will be interesting to see where this research leads. Interestingly too, the authors also talk about GABA and cytokines in their discussion of results hinting at the multitude of possible effects that may stem from their findings.

Finally, I note the authors do add quite a big caveat to their findings: "From a clinical standpoint, the current results say nothing about the potential for such data as a prospective prenatal test of autism risk". This based on an issue that Prof SBC has talked about before in the lay arena (see here) which heads down a potentially quite uncomfortable path. Treading carefully, I await replication of these results and that all-important focus on the hows and whys of elevated foetal steroidogenic activity potentially associated with elevated autism risk.

----------

[1] Baron-Cohen S. et al. Elevated fetal steroidogenic activity in autism.  Molecular Psychiatry. 2014. June 3.

[2] Steeb H. et al. Serum proteomic analysis identifies sex-specific differences in lipid metabolism and inflammation profiles in adults diagnosed with Asperger syndrome. Mol Autism. 2014 Jan 27;5(1):4.

----------

Baron-Cohen, S., Auyeung, B., Nørgaard-Pedersen, B., Hougaard, D., Abdallah, M., Melgaard, L., Cohen, A., Chakrabarti, B., Ruta, L., & Lombardo, M. (2014). Elevated fetal steroidogenic activity in autism Molecular Psychiatry DOI: 10.1038/mp.2014.48

Parental stress and autism: what's effective at reducing it?

Raising children is an extremely rewarding experience. That's not to say however that every minute of every day is spent with smiles and adoration of your offspring and their various endeavours: "Was that family heirloom that I just dropped on the floor really, really important Daddy?" Generally speaking the majority of parents I imagine though, would look favourably at the experience of going the family-way.

Gathering the light @ Wikipedia  

The rosy picture of having a family is however never truly complete without realising that having children can be quite a stressful experience. Whether as a result of those earliest days of sleep deprivation and almost constant nappy changing duties, through to some of the growing pains as puberty beckons and even onwards into the adult years, stress is a pretty constant companion to the family journey. And the amount of stress parents face in the child rearing odyssey is very much influenced by lots of other external variables such as money, job, relationships et al. Oh and also how many kids you're parenting (see here).

To have a child with additional needs, whether a physical disability or intellectual / developmental disorder, has been suggested to carry it's own unique challenges which can also impact on parental stress levels. I'm not saying that to somehow blame or stigmatise or anything like that, but merely to reflect the quite extensive body of research which has concentrated on that point (see here for example).

There is also quite a large evidence base to suggest that parents report greater levels of stress associated with raising a child with an autism spectrum disorder as per the example article by Koegel and colleagues*. Indeed it is with this area in mind that I stumbled across the paper by Dykens & Lambert** who noted: "Stress-reducing interventions are needed for parents of children with autism" as part of their analysis of cortisol levels in mums raising children, including those raising children with autism.

I've talked about stress and cortisol before on this blog (see here) as per the collected findings in relation to people with autism. The net result of that post was to say that yes, quite a few people on the autism spectrum present with an unusual stress profile (although not necessarily beyond the range seen in not-autism) but importantly, stress - as monitored via cortisol levels - seems to be a rather more continual process for many. Such results have obvious implications in relation to things like the anxiety issues often reported to follow autism.

The highlighted sentence from the Dykens paper on the need for stress reduction interventions for caregivers pinpoints a fairly obvious issue which I'm sure many people would take as read. Indeed with the suggestion from Osborne and colleagues*** that parenting stress might also potentially impact on the effectiveness of early intervention for autism, the questions are: what kinds of stress-reducing interventions are available and importantly, which ones work?

I don't claim to have some special insight into these questions, but a quick trawl of the research literature offers a few potentially important pointers.

(i) Social support. "With a little help from my friends" was a song by the Beatles but also the title of a rather interesting paper by Brian Lovell and colleagues**** on one potential route for tackling caregiver stress. Appreciating that to many this is not new news, it is perhaps little surprise that through the wonders of social media and the Internet, on-line social support groups for parents of children with autism are numerous and easily accessible in our digital age. With all the talk about how such resources might be 'changing our brains' (erm, or not), I'm minded to say that in this example, it might actually be a change for the better.

(ii) Mindfulness. I know, I know. It sounds like psycho-babble mumbo-jumbo to the nth degree when you first hear it. But actually I'm becoming a bit of a fan of mindfulness as per my previous post making mention of the BBC Horizon program 'The Truth About Personality' featuring the ever-intrepid Dr Michael Mosley. The basic idea is to think about the present, nay focus on the present, and manage the thoughts and feelings that are linked to stress. The evidence base for mindfulness for relieving caregiver stress is what might be described as emerging as per the study by Neece***** although with some potential bonuses for offspring too. It's also worth pointing out that mindfulness techniques are seemingly also finding a role in helping some people on the autism spectrum too (see Spek and colleagues******). Relations to mindfulness such as the use of relaxation techniques for caregivers have also been put forward as potentially useful*******. I wonder if something like blogging might also come under the description of 'managing thoughts and feelings'?

(iii) Parent training. I must point out that I am in no way trying to say that anyone is in need of "training" just in case anyone thinks I'm harking back to the bad old 'Bettelheim' days or casting aspersions about parenting style. I merely refer to the body of literature which 'suggests'******** that there may be some merit in looking into this option with stress relief in mind. Whether parent training might also fit under the banner of other programs such as RDI or more generic programs like Stepping Stones Triple P and any knock on effects this might have to parent stress levels is something perhaps requiring a little bit more study in order to define things like potential best responder characteristics.

(iv) Respite. I don't think this option really needs much explanation. Harper and colleagues********* said it best: "More respite care was associated with increased uplifts and reduced stress". Indeed, part of that reduction in stress was seemingly getting a little more quality time with your spouse or significant other... break out the Marvin Gaye. Seriously though, I can't stress enough how important respite care can be to some families. And if you happen to live here in Blighty (that's the UK), there are quite a few resources about respite and how to access the care: see here and here.

(v) A hobby or external interest. Although this is supposed to be an evidence-based post, there are a few other stress-relieving options that have been mentioned in a more anecdotal fashion. An interest involving physical exercise as a stress reducer seems to be a common theme. Indeed as I write this post, I'm just watching the preparations for the Great North Run on this slightly soggy Sunday morning and one parent of a child with Asperger syndrome running for the charity Ambitious About Autism. Using her running preparations as a way of getting some down time was mentioned in her interview. Other parents have talked about the use of activities like martial arts as being a stress reducing tool, which did make think back to some other work on the use of martial arts as a self-esteem builder for children with autism (see here). I'm not necessarily saying that every parent has to immediately join their local Jui-jitsu class or anything like that, but one can perhaps see how the process of physical activity might serve more than just a physical purpose.

I've only really scratched the surface with this post on parental stress and autism and how one might go about tackling / reducing it. If you want a perspective from a parent with autism who is also a medical doctor, look no further than these insights (see here) from a physician who's research has previously appeared on this blog (see here).

One might also argue that tackling some of the more 'disruptive' issues associated with autism which have been reported to be linked to greater parental stress (see here) might also be another route to reducing stress. The very interesting paper from McStay and colleagues********** reporting that "child hyperactivity was the only factor significantly related to parenting stress in parents of children with autism" might even tie into some of the observations we've made recently on the use of a GFCF diet (see here) and even explain some of the popularity of this approach. Indeed, I've not really approached the question of whether comorbidity (including ESSENCE) appearing alongside autism might also be a significant source of parental stress, as one might expect from something like epilepsy or seizure-related disorders for example. And then there is the increasingly common scenario of parents (one or both) with autism bringing up children with autism and how that situation might present additional unique parental stresses. Let us also not forget other siblings of the family unit too and how stress can affect them.

What remains apparent is that (a) parenting, as well as very rewarding, can be a stressful activity, (b) parenting a child with additional needs can carry some of its own unique stresses and (c) tackling or reducing that stress has got to be a win-win situation for everyone concerned; importantly not just for the child, but also for parents too (see here) including in relation to related aspects like fatigue.

To close, some music to dance to (dancing is also a very good stress-relieving activity I'm led to believe).... Wham and Wake Me Up Before You Go-Go. And for all you fathers out there who partake of a bit of 'dad dancing', a hypothesis for you to consider...

----------

* Koegel RL. et al. Consistent stress profiles in mothers of children with autism. J Autism Dev Disord. 1992 Jun;22(2):205-16.

** Dykens EM. & Lambert W. Trajectories of Diurnal Cortisol in Mothers of Children with Autism and Other Developmental Disabilities: Relations to Health and Mental Health. J Autism Dev Disord. 2013; 43: 2426-2434.

*** Osborne LA. et al. Parenting stress reduces the effectiveness of early teaching interventions for autistic spectrum disorders. J Autism Dev Disord. 2008 Jul;38(6):1092-103.

**** Lovell B. et al. With a little help from my friends: psychological, endocrine and health corollaries of social support in parental caregivers of children with autism or ADHD. Res Dev Disabil. 2012 Mar-Apr;33(2):682-7. doi: 10.1016/j.ridd.2011.11.014.

***** Neece CL. Mindfulness-Based Stress Reduction for Parents of Young Children with Developmental Delays: Implications for Parental Mental Health and Child Behavior Problems. J Appl Res Intellect Disabil. 2013 Jul 1. doi: 10.1111/jar.12064.

****** Spek AA. et al. Mindfulness-based therapy in adults with an autism spectrum disorder: a randomized controlled trial. Res Dev Disabil. 2013 Jan;34(1):246-53. doi: 10.1016/j.ridd.2012.08.009.

******* Gika DM. et al. Use of a relaxation technique by mothers of children with autism: a case-series study. Psychol Rep. 2012 Dec;111(3):797-804.

******** Bendixen RM. et al. Effects of a father-based in-home intervention on perceived stress and family dynamics in parents of children with autism. Am J Occup Ther. 2011 Nov-Dec;65(6):679-87.

********* Harper A. et al. Respite Care, Marital Quality, and Stress in Parents of Children with Autism Spectrum Disorders. J Autism Dev Disord. 2013 Mar 26.

********** McStay RL. et al. Parenting stress and autism: The role of age, autism severity, quality of life and problem behaviour of children and adolescents with autism. Autism. 2013. 8 October.

----------

Dykens EM, & Lambert W (2013). Trajectories of Diurnal Cortisol in Mothers of Children with Autism and Other Developmental Disabilities: Relations to Health and Mental Health. Journal of autism and developmental disorders PMID: 23468069

Autism, stress and cortisol

Stress is something that everyone, young and old, faces on a daily basis. Partnered with anxiety, stress has become part and parcel of the dictionary of modern day living despite the fact that even in times gone by, I'm pretty sure stress and anxiety were just as rife as they are today, if only under a different set of circumstances.

The stress Father @ Wikipedia 

My own personal view of stress is that it can be a double-edged sword. Particularly in these austere times that we all find ourselves living through, stress has generally taken on the most negative of connotations despite the fact that stress can often have a more productive side when linked to things like motivation and indeed in evolutionary terms, the 'fight-or-flight' response; I believe it falls under the term 'eustress'. Indeed some quite recent research suggests that it is the control factor of stress that might be important over the amount of stress and the concept of behavioural immunisation (UK-spelling) against future stress.

In trying to define stress as something tangible, physiological and measurable, one of the more widespread markers is that of cortisol, a primary stress hormone released in response to stress but also tied into our circadian rhythms. Issues with the cortisol response to stress are often associated with disruption of the hypothalamic-pituitary-adrenal (HPA) axis.

Measuring cortisol with autism in mind, has produced some interesting results so far. The earliest paper that I've found which looked at cortisol and autism is surprisingly one that has already been covered on this blog from Mary Goodwin and colleagues* and their introduction to the gut-brain axis as potentially being important in at least some cases of autism. I'm sorry that I can't link to the full-text of the Goodwin paper (which I recently mentioned in another piece on leaky gut and autism) but suffice to say that their initial measurement of plasma cortisol levels in autism vs. siblings was nothing to write home about. That being said, they did report some interesting findings based on supplementation with 1g of gliadin which "markedly decreased blood cortisol levels and abolished the normal circadian cortisol rhythm" in children with autism and their siblings. Food for thought bearing in mind that whole opioid-food-autism research and what opiates might do to cortisol levels.

Other research has reported other results when comparing autism with not-autism (and not siblings of children with autism either) as per papers like this one from Corbett and colleagues** (open-access) and this one from Kidd and colleagues***. These and other results suggesting that the usual patterns of cortisol were perhaps not followed in some cases of autism, alongside a heightened cortisol response as a reaction to novel stressor situations compared to not-autism.

Keeping in line with the autism-cortisol relationship I want to talk a little bit more about that paper from Kidd and colleagues as well as another paper published by Spratt and colleagues**** (open-access). A brief summary of both first:

Kidd paper:

• Comparing 26 children (mean age = 45 months) diagnosed with autism and confirmed by ADOS and ADI with 26 asymptomatic children  (mean age = 39 months), salivary cortisol and alpha-amylase (sAA) were measured 3 times a day over 2 consecutive days at three testing points (baseline, 3 and 6 months).
• Looking at both cortisol and sAA across the day (waking, midday, bedtime), mean levels were higher in the autism group than controls across each period although not significantly so.
• When participants with autism were divided into groups based on 'functional IQ status', those categorised as extremely low functioning children (authors words not mine) consistently presented with an elevated cortisol response across the day (although again, not significantly different from other functioning groupings). 

Spratt paper:

• Comparing 20 children with autism (mean age = 84 months) with 28 asymptomatic controls (mean age = 66 months), various measures of cortisol were analysed based on collection in urine, saliva and plasma (the blood draw for plasma cortisol analysis also serving as a stressor event too).
• Results: first production morning urine samples analysed for cortisol revealed no significant mean difference between the groups, although urinary cortisol levels were higher in the autism group taken as whole.
• Serum concentrations of cortisol were however significantly different between the groups (p=0.014). 
• Salivary cortisol showed some interesting trends in that, although presenting with a higher initial mean level of cortisol, the autism group did not differ significantly from controls at first testing prior to the blood draw stressor. That all changed following the next salivary cortisol test period 20 minutes after the blood draw, where the autism group registered a significantly elevated cortisol reading compared with controls. Indeed with the final salivary cortisol reading taken 40 minutes after the blood draw, the control group had already dipped below their baseline measurement, whereas the autism group as a whole remained elevated compared with their original baseline.
• Gender nor other items based on specific psychometric measures showed any significant correlation to  cortisol levels although there were some suggestions of links between the various testing medium (saliva, plasma, urine) at various periods of testing.

Based on these papers, one could surmise a few things:
(a) children with autism may present with an overall increase in cortisol levels, although not necessarily significantly outside the range seen in asymptomatic children,
(b) the effect of a novel stressor (novel insofar as children don't generally take part in blood draws everyday) seemed to correlate with a greater elevation in cortisol levels in cases of autism, and
(c) the regulation of stress, as in the stressor has passed and so cortisol levels should drop, seems to be affected in cases of autism, leaving a persistence of the stress state as per the findings of another study***** (open-access). Issues with habituation? I dunno.

Such important findings reported on cortisol and autism might potentially [and partially] explain some of the more debilitating aspects to the condition such as issues with responses to new and novel situations outside of those expected (the so-called repetitive behaviours domain) and maybe even the rates of anxiety that often accompany a diagnosis of autism. The implications resulting from an unusual pattern of production of glucocorticoids like cortisol noted in autism might also have some interesting links back to things like immune function too. Dare I even suggest a potential tie-in with findings related to things like hypertension too? How about something similar to that noted in depression with stress affecting neurogenesis?

Assuming some role for stress and the cortisol response to cases of autism, the final question should really be what can be done to mitigate its effects? Many parents and professionals have talked about routines and the various ways of planning for events and functions which might take a person with autism outside of their comfort zone as per things like trips to the doctors or even dentists. There's even been some speculation that dog ownership might positively affect the stress response in cases of autism, highlighting yet another effect from the pets win (prosocial) prizes potentially also following the Jedi massage route. It might also sound a little out of left field but I'm taken back to the work  by Julia Rucklidge and colleagues on micronutrients and stress (after earthquake) and whether or not similar mechanisms and modes of action might also pertain to autism? How about looking to control our bacterial masters too?

To conclude, it is rather quiet here, how about something a little big band from Iceland?

---------

* Goodwin MS. et al. Malabsorption and cerebral dysfunction: a multivariate and comparative study of autistic children. J Autism Child Schizophr. 1971; 1: 48-62.

** Corbett BA. et al. Variable cortisol circadian rhythms in children with autism and anticipatory stress. J Psychiatry Neurosci. 2008; 33: 227–234.

*** Kidd SA. et al. Daytime secretion of salivary cortisol and alpha-amylase in preschool-aged children with autism and typically developing children. J Autism Dev Disord. April 2012.

**** Spratt EG. et al. Enhanced cortisol response to stress in children in autism. J Autism Dev Disord. 2012; 42: 75-81.

****** Corbett BA. et al. Comparing biobehavioral profiles across two social stress paradigms in children with and without autism spectrum disorders. Mol Autism. 2012; 3: 13.

----------

Spratt EG, Nicholas JS, Brady KT, Carpenter LA, Hatcher CR, Meekins KA, Furlanetto RW, & Charles JM (2012). Enhanced cortisol response to stress in children in autism. Journal of autism and developmental disorders, 42 (1), 75-81 PMID: 21424864

Bah Ram Ewe, sheep be true

Babe, the sheep-pig, the hero/heroine of the novel (and films) by Dick King-Smith is always a family favourite. Babe's sheep-herding abilities are based in part on the revelation that there is a secret code among sheep 'Bah Ram Ewe, sheep be true'. As a user of this code, Babe earns a perfect sheep-herding round at the sheepdog trials; to be congratulated by Farmer Hoggett "That'll do Pig. That'll do" and satirised by Peter Griffin, everyone's favourite Family Guy.

Why oh why is he talking about Babe and sheep I thought I heard you ask? The reason is a new piece of research which suggests that even lambs can be picky eaters, and when fed monotonous diets, lambs become more stressed than lambs fed a diverse diet which is also reflected in their physiology and open-field behaviour.

The paper is this one by Villalba and colleagues* published in the journal Physiology & Behaviour. I appreciate that this might be pushing the boundaries of what this blog was originally supposed to do but what this and other research suggests is that we might be able to learn something from our wool-bound friends. Stay with me on this.

I will at this point add that I am in no way suggesting any person, any group of people, or any condition is in anyway related to sheep or any other animal. Some people may have heard that 'All cats have Asperger Syndrome' but not from me.

Back to sheep. The Villalba study looked at 3 diets: (i) a monotonous yet suitably nutritious diet, (ii) a diverse diet changing at set periods with various combinations of foods, (iii) a diverse diet similar to group (ii) also including supplementary phytochemicals. The results. When shown a more diverse diet, the monotonous diet sheep group got more stressed than the other groups as demonstrated by increased plasma cortisol levels and changes to rectal temperature when exposed to the open field test. Stress can be a learned response.

Whilst making generalisations from sheep behaviour to human behaviour is fraught with difficulties, I do feel as though there could be something in such research as this. The implication is that early dietary restrictiveness as a 'norm' might invoke a heightened stress response when a greater number of foods is presented to a person. So when a toddler who eats only pizza and chips (link to BBC3 programme 'Fast food baby') is presented with vegetables or fruit not normally included in the diet, the refusal side of things might not just bring about a tantrum but also some learned physiological stress? The flipside to such observations is that reducing the physiological stress response might make for a more varied diet, as per the recent presentation at the BPS conference on carrot not stick to get children to eat new foods.

Studying mammals like sheep perhaps removes some of the various social and cultural 'baggage' which would accompany similar human research. That and the fact that most human volunteers probably would not like their rectal temperature taken for any kind of experimental study; at least not without some significant reward. I will perhaps return to our mammalian friends at later points in this blog and how, as models of humans, they may offer some special insights into our very human behaviours e.g. autistic mice**?

* Villalba JJ.et al. Relationships between early experience to dietary diversity, acceptance of novel flavors, and open field behavior in sheep. Physiology & Behaviour. August 2011.

** Penagarikano O. et al. Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell. September 2011.

The inflammatory consequences of caring?

Another quickie post (yeah right!) this one based on a study which just entered my Twitter radar. Published in the journal Psychoneuroendocrinology, Brian Lovell and colleagues* from Northumbria University based here in the bracing North-East of England ask whether there might be any psychosocial, endocrine or immune consequences as a result of caring for a child with autism or ADHD. Their answer: yes but not necessarily as straight-forward as you might expect.

Lovell and colleagues compared 56 caregivers of children with autism or ADHD and 22 control parents on various psychometric measures of stress, social support, etc. Patterns of cortisol, a hormone released in response to stress were measured at various points throughout two weekdays, I assume to capture daily life when kids need to be woken, taken to school, brought home, catered for, bathed and put to bed (and all the things in-between). The proinflammatory markers of interleukin-6 (IL-6) and C-reactive protein (CRP) were also measured. IL-6 in particular has some history with autism.

The results. Caregivers of children with autism or ADHD reported more stress than controls. Nothing particularly novel there in light of other similar findings. Caregivers of children with autism or ADHD also reported less social support. No Nobel prize there either. When it came to cortisol levels though, no significant difference between the groups was found. So being a young or middle-aged parent of a child with autism or ADHD is physiologically about as stressful as raising any child according to this study. This might make some sense given that raising children, whether with autism or ADHD or not, delivers stress, period. Searching the literature however, other studies have reported differences in maternal cortisol levels associated with caring for an adolescent or adult with autism, indeed with many disabilties. Does this mean that parental stress increases as a child gets older? Or as parents age they are more likely to show the effects of stress? Who knows.

Looking also at measures of CRP, there was some reported difference in levels of this inflammatory marker between the groups; greater CRP levels in parents of children with autism or ADHD and more frequent episodes of physical ill-health.

There are two ways you can take a study like this. Perhaps the more negative way is the implication that raising children with autism or ADHD is such a stressful thing to do that parents are doomed to a life of a greater risk of inflammatory-based diseases. The other way of looking at the study and its results is to say yes, parents might be more susceptible to problems caused by a 'disinhibition of the inflammatory response', but to question whether this is because of raising a child with autism or ADHD, or something that was always present either coincidentally or potentially tied into some of the inflammatory findings comorbid to autism?

OK this is a relatively small study in terms of participants and requires larger replication before we get too ahead of ourselves. The CRP findings however are interesting, and as per the Medline Plus link here, potentially tie into lots of things including those related to the bowel and other connective tissue disorders. The elevated risk of some of these conditions associated with parents of children with autism has been discussed previously in the literature. I was also drawn to this article which suggests that rather than just being a marker for inflammation, CRP could [speculatively] also have the capacity to 'protect' against certain autoimmune diseases. I can't say more than that really.

As per the mantra of this blog in terms of fostering a welcoming society with appropriate support and opportunities for people with autism, papers like this one also suggest that society should be doing a little more for parents of children/adults with autism also. Within the multitude of guidance for autism, for identifying autism, for 'managing' autism, for enabling people with autism, how much guidance do we offer that the physical and psychological health of parents should also be catered for?

* Lovell B et al. The psychosocial, endocrine and immune consequences of caring for a child with autism or ADHD. Psychoneuroendocrinology. September 2011