Wednesday, 16 January 2019

Subclinical autistic traits affecting adolescent sleep patterns?

There was something rather intriguing about the results published by Liisa Salmela and colleagues [1] (open-access available here) observing that: "Elevated levels of autistic traits were significantly associated with shorter weekday sleep duration" in a cohort of adolescents from Helsinki in Finland. The fact that researchers also concluded that "autistic traits remained an independent predictor of short sleep duration when comorbid psychiatric symptoms were controlled for" added to the intrigue.

I was impressed with some elements of the Salmela study; notably the use of actigraphy as an objective measure of sleep accompanying self-report data derived from the Pittsburgh Sleep Quality Index (PSQI). The fact that actigraphs were worn "continuously for an average of 8.36 nights (SD = 1.76; range 4–17)" also meant that researchers had access to quite a bit of data from their 150+ participant study group when it came to activity cycles covering sleep.

What was the measure of autistic traits used I hear you ask? Well, we are told that: "Autistic traits were assessed using the Autism Spectrum Quotient (AQ)" which is an OK measure I suppose, although not without some shortcomings in terms of what is being specifically measured (see here). I should also mention that for the most part, the Salmela study was a study of non-autistic adolescents (two participants were reported to have "scored at or above the clinical cut-off score of 32" on the AQ).

"Continuous autistic traits significantly predicted weekday total sleep time" and "having elevated autistic traits as measured by AQ (Autism Spectrum Quotient) increased the risk for short sleep duration." Mindful that correlation is not necessarily the same as causation, details were important to the Salmela findings as we are also told that (a) as a group, boys tended to score higher on the AQ and (b) again as a group "boys had significantly shorter weekday total sleep time" than girls. It's perhaps no surprise therefore that: "Sex had a statistically significant main effect (p = 0.032) on total sleep time."

Next question: why? Why should autistic traits potentially "increase the risk for short sleep duration in a general adolescent population"? Is there something about the presentation of autistic traits that affects sleep either through psychological/cognitive processes or more physiological processes? Well, those are questions that still need answering. And alongside we seem to have yet another example where core autistic features may very well impact on so-called comorbid issues to add to the collection (see here and see here). This also has potential implications for intervention too...

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[1] Salmela L. et al. Autistic traits and sleep in typically developing adolescents. Sleep Med. 2018 Oct 29;54:164-171.

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Tuesday, 15 January 2019

Breastfeeding and ADHD meta-analysed

Readers are asked to consider this post discussing the findings from Ping-Tao Tseng and colleagues [1] concerning breastfeeding and offspring attention-deficit hyperactivity disorder (ADHD) risk, an extension of other blogging chatter on the topic of breastfeeding and other offspring developmental outcomes (see here). The connections? Well, yes, both posts emphasise a possible *association* between breastfeeding and offspring development, but perhaps just as important, both posts will also emphasise how correlation is not necessarily the same as causation and how one has to be careful about making sweeping assumptions when it comes to breastfeeding *choice*...

Same as on the previous paper by Tseng and colleagues [2] I'll mention having a minor part to play in authoring the latest Tseng paper, and how such participation will in no way interfere with my hopefully critical musings on this latest publication.

The name of the research game this time around was to 'meta-analyse' the currently available collected peer-reviewed research literature into some sort of coherent 'where we're at' statement on the topic of breastfeeding practices and offspring ADHD risk. This wasn't about 'making' any new data; just synthesising what is already there on some specific topics: "(1) the difference in the duration of maternal breastfeeding between children with and without ADHD, and (2) the association between maternal breastfeeding and ADHD in children." A total of 11 articles pertinent to those research questions were identified and information was 'boiled down'.

Results: "an association was found between non-breastfeeding and ADHD children (adjusted OR = 3.71, 95% CI = 1.94 to 7.11, p < 0.001)." At first glance this looks like a pretty impressive *relationship* between 'non-breastfeeding' and the presence of a diagnosis of ADHD in offspring. It is, but it might not necessarily mean what you first think. Authors do mention how the early presentation of certain ADHD or possibly related traits might not have been conducive to successful breastfeeding behaviour to the point where a lack of 'cooperation' could have led to less breastfeeding. I'm not saying this is THE reason for the results we reported; merely that it is one possibility to entertain. There may also be other factors to take into consideration too (see here for example) minus any sweeping generalisations.

Whilst I am cautious about making too much of the Tseng findings - subsequent individual studies have reported no link [3] - other, more recent meta-analyses have arrived at similar conclusions to Tseng [4]. Yes, the Zeng paper [4] looked specifically at breastfeeding duration, and yes it was a meta-analysis that overlapped with material used in the Tseng study. But the conclusion - "maternal breastfeeding may reduce the risk of ADHD in children" - is similar, and again suggests closer inspection of any possible relationship specifically focused on the hows-and-whys.

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[1] Tseng PT. et al. Maternal breastfeeding and attention-deficit/hyperactivity disorder in children: a meta-analysis. Eur Child Adolesc Psychiatry. 2018 Jun 15.

[2] Tseng PT. et al. Maternal breastfeeding and autism spectrum disorder in children: A systematic review and meta-analysis. Nutr Neurosci. 2017 Oct 18:1-9.

[3] Schwenke E. et al. Predicting attention deficit hyperactivity disorder using pregnancy and birth characteristics. Arch Gynecol Obstet. 2018 Nov;298(5):889-895.

[4] Zeng Y. et al. Association between the different duration of breastfeeding and attention deficit/hyperactivity disorder in children: a systematic review and meta-analysis. Nutr Neurosci. 2018 Dec 21:1-13.

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Monday, 14 January 2019

"Childhood seizures and risk of psychiatric disorders in adolescence and early adulthood"

I want to bring the findings reported by Julie Dreier and colleagues [1] to your attention today and their observation that: "Children with epilepsy and febrile seizures-with and without concomitant epilepsy-are at increased risk of developing a broad range of psychiatric disorders in later life."

Researchers report results based on the examination of one of those ever-so-impressive Scandinavian population registries that have moved science forward in many, many different areas (see here for example). This time around it was the Danish National Patient Register and the inclusion of data from "1 291 679 individuals... born in Denmark and followed up in our population cohort (approximately 15 million person-years)." Over 43,000 individuals showed a history of febrile seizure - "fits that can happen when a child has a fever" - and over 10,000 had epilepsy. Likewise: "83 735 (6%) cohort members were identified with at least one of the psychiatric disorders of interest" including substance abuse disorders, schizophrenia, mood disorder, anxiety, and personality disorder.

Results: "The risk of any psychiatric disorder was raised in individuals with a history of febrile seizures..., epilepsy..., or both disorders." The magnitude of the risk was categorised as statistically significant in terms of elevation but ranged from between a 10-50% increased risk. Further: "Excess risk of psychiatric illness associated with childhood seizures was present across a range of different disorders, most notably schizophrenia but also anxiety and mood disorders." Authors also opine that further research is needed on this topic with regards to mechanisms pertinent to identifying "potential options for prevention."

Although some caution is always required when one variable (epilepsy) is solely correlated with another (history of recorded psychiatric diagnosis), I am interested in the Dreier findings. I'm interested not only because of the *association* being made between a condition that often has life-changing effects on other often life-changing diagnoses but also because this *association* complements other links being made with epilepsy. I speak of the various studies linking epilepsy to diagnostic labels such as autism and attention-deficit hyperactivity disorder (ADHD) of course (see here and see here for examples) whilst pointing out that ADHD and autism are not to be categorised as mental health conditions. Such links between epilepsy and neurodevelopmental diagnoses are all the more interesting because the presence of labels such as autism and ADHD are also known to manifest elevations in other psychiatric diagnoses such as mood disorder, anxiety and schizophrenia (see here and see here and see here for examples). It's not therefore unreasonable to suspect that there may be some 'over-arching' themes when it comes to epilepsy/febrile seizures 'linking' with various developmental and psychiatric diagnoses.

Minus any sweeping generalisations and being careful how I phrase this, one area that requires a lot more investigation is the neurological effect that epilepsy in particular can have. I speak of the idea that seizures can, in some cases, affect the physical nature of the brain [2] and the question of whether such 'damage' might also then affect the presentation of behaviour akin to the signs and symptoms of a neurodevelopmental or psychiatric diagnosis. I know this is not a particularly palatable line of thinking but it does require further scientific exploration. This is also pertinent to the Dreier study focusing in on childhood seizures and by inference, possible effects on the developing brain. Another area of further investigation is whether the presentation of epilepsy or seizures *might* be part-and-parcel of various syndromes also presenting with neurodevelopmental and/or psychiatric features? We do have some examples of this already (see here) and, given that various genetic syndromes are quite regularly being identified day-by-day, it's another area that could yield some important data.

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[1] Dreier JW. et al. Childhood seizures and risk of psychiatric disorders in adolescence and early adulthood: a Danish nationwide cohort study. Lancet Child Adolesc Health. 2018 Dec 6. pii: S2352-4642(18)30351-1.

[2] Bronen RA. et al. The Status of Status: Seizures Are Bad for Your Brain's Health. American Journal of Neuroradiology. 2000; 21: 1782-1783.

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Saturday, 12 January 2019

Sex differences in autism presentation continued

The paper by Ligia Antezana and colleagues [1] provides the brief blogging fodder today and some further focus on potential sex/gender differences when it comes to the presentation of autism (see here).

The aim of the study was a relatively simple one: "to identify whether specific RRBI [restricted and repetitive behaviors and interests] (i.e., stereotyped, self-injurious, compulsive, insistence on sameness, ritualistic, and restricted), as measured by item-level data on the Repetitive Behavior Scale-Revised (RBS-R), can distinguish girls from boys with ASD [autism spectrum disorder]." The sample was a pretty good size - "615 individuals with ASD (507 boys; 82.4%)" - and the findings were rather interesting...

So: "Items that best-discriminated gender were heightened stereotyped behaviors and restricted interests items in boys and compulsive, sameness, restricted, and self-injurious behavior items in girls." The authors add that: "This study is the first to find that girls with ASD may have increased compulsive, sameness, and restricted RRBI compared to boys."

Bearing in mind the care required when talking about sweeping generalisations about 'boy autism' and 'girl autism', the Antezana results do point to a need for further study in this area. Not least because the authors rightly mention how: "Future research should disentangle whether elevated rates of RRBI in girls are central to the presentation of ASD in girls or an epiphenomenon of the high rates of co-occurring disorders (e.g., anxiety) noted in girls." This based on the idea that autism rarely exists in some sort of diagnostic vacuum (see here) and some of that *comorbidity* (if that is the right word to use) could very well be part and parcel of such clinical observations.

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[1] Antezana L. et al. Gender differences in restricted and repetitive behaviors and interests in youth with autism. Autism Res. 2018 Dec 17.

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Friday, 11 January 2019

"Are women with autism at an increased risk of adverse pregnancy outcomes?"

The paper by Heléne Sundelin and colleagues [1] provides the blogging fodder today, and research pertinent to the question: "Are women with autism at an increased risk of adverse pregnancy outcomes?" The short answer to the question is yes: "Maternal autism is associated with preterm birth, likely due to an increased frequency of medically indicated preterm births, but also with other adverse pregnancy outcomes, suggesting a need for extra surveillance during prenatal care."

It was refreshing to read the results from Sundelin et al (a research group who are no strangers to autism research) because this was a study devoted to looking at women with autism / autistic women and their pregnancy outcomes. It was distinct from other research on maternal pregnancy outcomes and offspring autism more traditionally seen in the peer-reviewed research literature and covered on this blog (see here and see here for examples).

The source material for the Sundelin study was the Swedish Medical Birth Registry (yes, one of those fantastic Scandinavian population registries again) and records of "2,198 births to 1,382 women with autism and 877,742 births to 503,846 women never diagnosed with autism." When comparing the groups across various different measures including preterm delivery ("defined as <37 completed weeks of gestation"), tobacco smoking during pregnancy and the use of various prescription medicines during pregnancy, some interesting trends were observed.

"Women with autism were at an increased risk of preterm birth..., which after stratification, remained for moderately (32 to <37 weeks) preterm birth." Also: "Maternal autism was also linked with an increased risk of elective cesarean delivery in births to women with autism" and "Preeclampsia was more prevalent in mothers with autism."

Although not seemingly affecting many of the 'adverse' pregnancy outcomes examined, researchers also noted that rates of tobacco smoking (light and heavy use) during early pregnancy were elevated in mums with autism, alongside prescription medicine use (antiepileptics, antipsychotics, hypnotics/anxiolytics, antidepressants) being more frequently reported before and during pregnancy compared to non-autistic pregnant mums. Authors reported that "there was no increased risk of adverse pregnancy outcomes except for induction of delivery" but one has to remember that the focus was on pregnancy outcomes - "completed weeks of gestation, mode of delivery, 5-minute Apgar scores, intrauterine growth, stillbirth, and maternal complications (preeclampsia and gestational diabetes)" - and does not say anything about longer term post-pregnancy outcomes. I say this with a few potential 'issues' in mind (see here and see here and see here).

The Sundelin study is by no means perfect - a "limitation is the lack of information on life circumstances" - but does carry the research weight that comes from those extremely well-categorised Scandinavian population registries. The authors conclude that their: "results suggest a need for individual prenatal care for women with autism, weighing pros and cons for continuation of psychotropic medication, with a better understanding of the difficulties related to autism, especially regarding the communication with health care professionals." Who am I to argue with them?

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[1] Sundelin HE. et al. Pregnancy outcomes in women with autism: a nationwide population-based cohort study. Clin Epidemiol. 2018 Nov 30;10:1817-1826.

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Thursday, 10 January 2019

Lactobacillus (L.) reuteri and mouse-modelled autism: spotlight on the vagus nerve?

I am a little late getting to the findings reported by Martina Sgritta and colleagues [1] but I eventually arrived at them. As per the title of this post - "Lactobacillus (L.) reuteri and mouse model autism: spotlight on the vagus nerve?" - there were a number of important elements to this research covering mouse-modelled autism, the "gut-microbiota-brain axis", and something called the vagus nerve. Pretty good fodder for this blog by all accounts, given some past discussions (see here) including mention of previous research from some of the Sgritta paper co-authors (see here).

So, continuing a theme from this research group suggesting that, in mice at least, some pregnancy 'risk factors' for autism might have a microbial connection [2], authors set out to examine whether the inclusion of a specific bacterial species called Lactobacillus reuteri or L. reuteri for short might have some important effect on the social behaviour of a mouse model of autism. L. reuteri has been the source of quite a bit of study down the years [3] as a function of it's antimicrobial activity and connection to inflammatory conditions. Outside of the Baylor College group research, this bacterial species has also been talked about with autism in mind [4] in other studies, as per conclusions like: "This study identifies bacterial species that are sensitive to an autism-related mutation." I'll say no more on that study for now aside from offering a viewpoint from elsewhere on the web.

Alongside their observation that "treatment with L. reuteri selectively rescues social deficits in genetic, environmental, and idiopathic ASD [autism spectrum disorder] models" Sgritta et al also put a little scientific flesh on what underlying mechanism(s) might be pertinent to such 'rescuing' of social issues. You might think it was something to do with the contribution of L. reuteri to the gut microbiome of the [mouse] host? Well, yes and no, as authors highlighted how "L. reuteri acts in a vagus nerve-dependent manner" so bringing in the notion that bacteria in the gut *talk to* the brain (or the wider central nervous system) via the vagus nerve. The paper by Bruno Bonaz and colleagues [5] provides as good an explanation as any of how bacteria talk to the brain and what this means for the "gut-microbiota-brain axis." Interestingly too, authors mention how when the vagus nerve was 'disrupted' in said mouse-modelled autism, so the the gut-microbiota-brain link was also disrupted, and onward that L. reuteri didn't seemingly work as well at rescuing those social issues. They also talk about a role for oxytocin receptors in their findings similar to their last research occasion, but I'm going to leave that for now. All I will say is that oxytocin has also been mentioned in other autism research circles (see here).

Obviously, there are caveats to the Sgritta findings; not least that mouse-modelled autism is just mouse-modelled autism and probably not totally representative of real-life human autism (see here). Generalisations of the social behaviour of mice raised and living under laboratory conditions to people (children and adults) traversing the big, wide real world always require a degree of caution.

But I am interested in this area and would like to see more study done on the "gut-microbiota-brain axis" with autism in mind. Given that L. reuteri is freely available to anyone and everyone and seems to have quite a good safety record, I'd perhaps suggest that a clinical trial could be something that a young, upcoming researcher or research group might possibly want to consider exploring...

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[1] Sgritta M. et al. Mechanisms Underlying Microbial-Mediated Changes in Social Behavior in Mouse Models of Autism Spectrum Disorder. Neuron. 2018 Dec 3. pii: S0896-6273(18)31009-2.

[2] Buffington SA. et al. Microbial Reconstitution Reverses Maternal Diet-Induced Social and Synaptic Deficits in Offspring. Cell. 2016 Jun 16;165(7):1762-1775.

[3] Mu Q. et al. Role of Lactobacillus reuteri in Human Health and Diseases. Front Microbiol. 2018;9:757. 

[4] Tabouy L. et al. Dysbiosis of microbiome and probiotic treatment in a genetic model of autism spectrum disorders. Brain Behav Immun. 2018 Oct;73:310-319.

[5] Bonaz B. et al. The Vagus Nerve at the Interface of the Microbiota-Gut-Brain Axis. Front Neurosci. 2018;12:49. 

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Wednesday, 9 January 2019

"by the time ongoing fatigue was established, the immune activation was no longer present"

The quote heading this post - "by the time ongoing fatigue was established, the immune activation was no longer present" - comes from some media coverage of the paper published by Alice Russell and colleagues [1]. Said paper observed some interesting results in relation to the use of interferon-alpha (IFN-α) "used in the treatment of chronic Hepatitis C Virus (HCV) infection" and what this *could* mean in relation to a "proxy model of chronic fatigue syndrome."

The long-and-short of the Russell results and their possible application to chronic fatigue syndrome (CFS) is that for quite a few years now there have been rumblings that at least some cases of CFS (also known as myalgic encephalomyelitis, ME) might be *associated* with a viral hit-and-run encounter. By saying 'hit-and'run' I mean that an initial viral or bacterial infection is experienced which induces the symptoms of CFS. Said infection then eventually disappears for whatever reason(s) but leaves persisting symptoms such as long-term fatigue and more. Further explanation of this hypothesis can be seen in another of my posts on CFS (see here).

So: "Fifty-five patients undergoing IFN-α treatment for chronic HCV were assessed at baseline, during the 6–12 months of IFN-α treatment, and at six-months post-treatment." The use of IFN-α is clinically indicated for HCV infection as part of an antiviral therapeutic regime ("IFN-α and ribavirin"). Various biological parameters were assessed in the 55 participants as well as in separate groups of those diagnosed with CFS and so-called "healthy volunteers."

Treatment with IFN-α induced fatigue in quite a few of those being treated for HCV infection. Most cases of fatigue resolved at 6-months post-treatment but for some, fatigue remained and for about 30%, levels of fatigue were "higher six-months post-treatment than at baseline." The authors looked at the biological results obtained for those with 'persistent fatigue' (PF) and compared them with those with 'resolved fatigue' (RF) to see if they could discern some differences.

They came up with a few important group observations: "Subjects who later develop PF have higher fatigue in response to IFN-α", "Subjects who later develop PF have higher IL-10 levels before treatment, and IL-6 and IL-10 levels in response to IFN-α", and "Psychosocial and clinical risk factors do not distinguish PF from RF subjects." What this all amounts to is that within quite a small participant group: "findings from this study support the hypothesis that abnormal immune mechanisms are important in CFS, but only early in the course of the illness, around the time of the trigger, rather than when the syndrome is established." Further the study: "confirms the importance of the acute fatigue response to the trigger, rather than of the recovery period preceding the illness."

There is more to do in this area bearing in mind that CFS is a pretty heterogeneous condition both in terms of symptom onset and the course of the illness. Researchers also admit that they "can only speculate at this stage on whether or not the mechanisms underlying the persistence of fatigue in CFS and IFN-α induced PF are related" and their suggestion of a proxy model. Others who have covered this study have said similar things (see here). This is also important given other results reported by the authors on those diagnosed with CFS compared with those 'healthy' controls/volunteers.

Still, there are some interesting observations made by Russell et al and once again, such results hopefully move CFS further away from the biopsychosocial (BPS) model of old that has seemingly done considerable damage to those diagnosed (see here and see here). Indeed, such post-infective thinking kinda brings CFS back full circle...

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[1] Russell A. et al. Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome. Psychoneuroendocrinology. 2018 Dec 17.

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