Hyperemesis gravidarum exposure as a risk factor for autism?

Hyperemesis gravidarum mentioned in the title of this post refers to "prolonged and severe nausea and vomiting" during pregnancy alongside other symptoms. It's thought to affect only a relatively small percentage of pregnant women despite vomiting and nausea being pretty common throughout many pregnancies. Indeed, hyperemesis gravidarum (HG) is much more than just nausea and vomiting.

The findings reported by Marlena Fejzo and colleagues [1] looked at the "neurodevelopmental outcomes of 267 children delivered by 177 mothers with HG were compared to neurodevelopmental outcomes from 93 children delivered by 60 unaffected mothers." The study was undertaken on the basis that previous published research from this study group [2] had identified "neurodevelopmental delay" as a possible *correlate* tied to HG exposure during pregnancy. That being said, on that last occasion researchers also described finding "no evidence for increased risk of 13 emotional, behavioral, and learning disorders, including autism, intellectual impairment, and obsessive-compulsive disorder" in their cohort.

This time around: "Similar to at age 8, the children (now 12) exposed in utero to HG had over 3-fold increase in odds of neurodevelopmental disorders including attention, anxiety, sensory, sleep difficulty, and social development delay/social anxiety." With a longer follow-up period, researchers also reversed their 'no evidence for increased risk' sentiments with regards to a diagnosis of autism in their cohort. So: "there was also a significant increase in Autism Spectrum Disorder (ASD), reported in 22/267 (8%) of children exposed to HG in utero and no unexposed children."

Let me be clear on this: these latest results on their own don't necessarily mean that HG *causes* offspring autism. Although 8% of the HG exposed group reporting autism or ASD seems quite high, it has to be seen in light of an increasing (estimated) prevalence of autism more generally (see here and see here). I'd also suggest that as with many other pregnancy/gestational factors put forward as potentially influencing offspring autism risk, one needs to be mindful of the issues involved in teasing out which is the important variable from potentially many (see here and see here).

But... further investigation is indicated in this area. Indeed, I hark back to the findings reported by Andrew Whitehouse and colleagues [3] who observed a "strong, positive association between increasing frequency and severity of NVP [nausea and vomiting during pregnancy] and ASD severity in offspring." No, not necessarily HG, but an implication that some of the overt features of HG might hold some *connection* to offspring autism risk for whatever reasons...

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[1] Fejzo M. et al. Analysis of neurodevelopmental delay in children exposed in utero to hyperemesis gravidarum reveals increased reporting of autism spectrum disorder. Reprod Toxicol. 2018 Dec 27. pii: S0890-6238(18)30558-6.

[2] Fejzo MS. et al. Neurodevelopmental delay in children exposed in utero to hyperemesis gravidarum. Eur J Obstet Gynecol Reprod Biol. 2015 Jun;189:79-84.

[3] Whitehouse AJO. et al. Symptom severity in autism spectrum disorder is related to the frequency and severity of nausea and vomiting during pregnancy: a retrospective case-control study. Mol Autism. 2018 Jun 19;9:37.

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"Systemisers are better at maths". But be careful of sweeping generalisations...

The title of this post - "systemisers are better at maths" - comes from the findings reported by Paola Bressan [1], an author not unfamiliar to this blog (see here). This time around, the author has opted for a topic a little less 'controversial' [2] than last time, in the form of an analysis of the 'empathising-systemising theory'. In particular, the notion that mathematics is typically a systemising activity (based on rules and laws) and so those who lean more towards being systemisers should be better at maths. That's the theory anyway...

The word 'autism' is mentioned in the Bressan paper because of the *connection* made between systemising and autism by some big names in the autism research field. As far as I can see however, the Bressan study did not include anyone diagnosed with autism or an autism spectrum disorder (ASD) but rather relied on data from mostly university students studying "mainly psychology and engineering." Said student participants (N=201) were given a couple of measures to test maths skills (including a 'how good are you at maths?' self-report measure) alongside tests for non-mathematical intelligence and 'systemising tendencies' in the form of the Italian version of the Systemising Quotient (SQ-Short).

Results: the data for the study are freely available to anyone and everyone (see here). Bressan observed a few details. So: "Systemising was predicted by sex, with men scoring on average higher than women." Occupation, I assume meaning what participants were studying, also showed a potential relationship with systemising scores too. Then to the main event: "In a sample of students of a diverse range of disciplines, the systemising score predicted both self-assessed mathematical skills (201 participants) and mathematical intelligence (151 participants). This remained true after controlling for nonmathematical intelligence, for occupation (social vs biological/physical careers), and for sex."

These are interesting results. They offer some support for the idea that cognitive style *might* be an important factor when it comes to 'success' or not in certain types of discipline, and require further study. But...

Allowing for my 'no sweeping generalisations are required' sentiments that are typically included with my analysis of research on this blog, I'm still a little reserved on this topic. I'm reserved because on the previous occasion that I've covered maths achievement and systemising (see here), the results were a little different. The paper by Escovar and colleagues [2] for example, reported that social skills seemed to be more important to maths ability. They also observed that "mathematical achievement was not related to systemizing or the discrepancy between systemizing and empathizing" in their study. Bressan criticised this study for a potential lack of statistical power, but I'm slightly less critical of those results, particularly because Escovar et al utilised a wider range of study instruments covering a wider range of potentially important variables. I'm also inclined to mention how maths ability can sometimes be clouded by other factors. Take for example another post I wrote on maths problem solving ability and autism (see here) and how issues like attention and anxiety can play a role on performance. That and also the fact that not everyone on the autism spectrum is some sort of maths genius...

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[1] Bressan P. Systemisers are better at maths. Sci Rep. 2018 Aug 2;8(1):11636.

[2] Escovar E. et al. The Empathizing-Systemizing Theory, Social Abilities, and Mathematical Achievement in Children. Sci Rep. 2016 Mar 14;6:23011.

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The links between autism and ADHD: sibling study adds a new layer

'A diagnosis of autism or autism spectrum disorder (ASD) does not typically appear in a diagnostic vacuum'. I've said that sentence several times on this blog (see here for example) in line with how science has shown that many different labels (both behavioural and somatic) are over-represented when it comes to a diagnosis of autism. All very ESSENCE like (see here)...

Of the various over-represented comorbidity, attention-deficit hyperactivity disorder (ADHD) - either in symptoms or in diagnosis - is one of the more common ones (see here); something that has implications for screening (see here) and also management. The findings reported by Yi-Ling Chien and colleagues [1] (open-access) add something to the research looking at the possible hows-and-whys of ADHD appearing alongside autism with their focus on "unaffected siblings of probands with autism and Asperger syndrome (AS)." Such work ties into that observing 'unaffected by autism' does not necessarily mean 'symptom or trait-free' in the context of ideas such as the broader autism phenotype (BAP) (see here).

With the aim to "investigate the ADHD-related traits and attention performance in unaffected siblings of probands with autism and Asperger syndrome (AS), as well as the clinical correlates of ADHD-related traits" researchers concluded that generally, unaffected siblings (unaffected by autism) of those diagnosed with an ASD "were more hyperactive/impulsive and oppositional" than those so-called typically developing controls. The finding was based on the use of various questionnaires/schedules pertinent to both the "the core symptoms of DSM-IV ADHD" and also tests to "assess attention performance."

Of particular note was the observation of "more ADHD and oppositional traits in unaffected siblings of AS probands" when looking at subgroups on the autism spectrum. With caution, the authors suggest that such a finding may be evidence "that these traits might be a broader phenotype for AS." They also posit that "more severe ADHD-related symptoms in AS probands rather than autism probands suggest that these two subtypes may not be the same in their clinical expression regarding ADHD symptoms." In these days of plural autisms (see here), things seemingly get even more complicated when diagnostic subgroup x comorbidity is also thrown into the mix.

Although quite a bit more investigation is required in this area, there is at least one important point to take from the Chien work: unaffected siblings of those diagnosed with autism - particularly Asperger syndrome - may benefit from preferential clinical assessment for something like ADHD. I say that with the understanding that a diagnosis of ADHD has been linked to a heightened risk of various 'adverse' outcomes in the longer term (see here and see here) and again, minus any sweeping generalisations, specific interventions for ADHD can seemingly mitigate quite a bit of that excess risk (see here) and onward improve quality of life and more.

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[1] Chien Y-L. et al. ADHD-related symptoms and attention profiles in the unaffected siblings of probands with autism spectrum disorder: focus on the subtypes of autism and Asperger’s disorder. Molecular Autism. 2017; 8: 3.

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Early pregnancy vitamin D levels and later offspring 'behavioral difficulties'?

Drawing on data derived from the Rhea mother-child cohort based in Crete, Greece, the findings reported by Vasiliki Daraki and colleagues [1] provide some food for thought; specifically the observation that "high maternal vitamin D levels in early pregnancy may protect against [offspring] behavioral difficulties, especially ADHD [attention-deficit hyperactivity disorder]-like symptoms at preschool age."

Including nearly 500 mother-child pairs, researchers set about looking at whether pregnancy levels of vitamin D - "serum 25(OH) D concentrations were measured at the first prenatal visit (13 ± 2.4 weeks)" - correlated with cognitive functions and/or behavioural 'difficulties' in offspring at 4 years of age.

Results: as per the headline titling this post, there did seem to be some potentially important *associations* between maternal pregnancy levels of vitamin D and offspring outcomes. So: "children of women in the high 25(OH) D tertile (>50.7 nmol/l) had 37% decreased number of hyperactivity-impulsivity symptoms... and 40% decreased number of total ADHD-like symptoms... at 4 years of age, compared to children of women in the low 25(OH) D tertile (<38.4 nmol/l), after adjustment for several confounders." Investigations looking at pregnancy vitamin D levels and various cognitive functions of offspring children revealed nothing too significant.

Of course you would be right to point out that this was a study pitting one variable - pregnancy vitamin D levels - against a multitude of different offspring cognitive/behavioural outcomes some four years later. It's not entirely inconceivable that despite 'adjustment for several confounders' the authors might be in error in linking vitamin D to offspring outcomes and that some (more than one?) other variable(s) might account for the results. I should also point out that Greece is not exactly sunshine deficient; sunshine being a primary pathway pertinent to the biological synthesis of vitamin D.

But this is not the first time that pregnancy vitamin D levels have been *associated* with offspring ADHD or ADHD-like behaviours (see here) and I doubt it will be the last. Added to work looking at the possibility of an *association* between pregnancy vitamin D levels and offspring risk of autism (see here for example), bearing in mind autism and ADHD are not totally unconnected, there is an interesting theme developing on this topic. Perhaps Government (English at least) policy on recommending vitamin D supplementation for large swathes of the population (see here) may have a multitude of onward effects outside of just reducing the risk of bone manifestations of vitamin D deficiency/insufficiency?

And just before you go, even ALSPAC has something further to say on this matter [2]...

To close, 'Are you Tony Stank?'

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[1] Daraki V. et al. High maternal vitamin D levels in early pregnancy may protect against behavioral difficulties at preschool age: the Rhea mother-child cohort, Crete, Greece. Eur Child Adolesc Psychiatry. 2017 Jul 6.

[2] Darling AL. et al. Association between maternal vitamin D status in pregnancy and neurodevelopmental outcomes in childhood: results from the Avon Longitudinal Study of Parents and Children (ALSPAC). Br J Nutr. 2017 Jul 12:1-11.

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High frequency of (self-reported) ADHD symptoms in eating disorders

"There is a high frequency of ADHD [attention-deficit hyperactivity disorder] symptoms in patients with binge eating/purging eating disorders that motivates further studies."

That was the conclusion reached in the study by Nils Erik Svedlund and colleagues [1] (open-access) who, among other things, set out to "explore the prevalence and types of self-reported ADHD symptoms in a large, unselected group of ED [eating disorder] patients assessed in a specialized ED clinic." Participants (over 1100 of them) were "seeking help at the Stockholm Centre for Eating Disorders (SCED) from 4 February 2013 through 18 September 2015" and as well as being confirmed to have an eating disorder were also screened for ADHD-type behaviours using the WHO ADHD Self-Rating Scale for Adults (ASRS-screener). Notice the 'self-rated' part of that last sentence...

Based on a ASRS screener score of 14 or above, researchers reported that some 30% of females (N=1094) self-reported 'issues' associated with a diagnosis of ADHD. Some 34% of men included for study (N=47) reported similar ADHD traits (31.3% of the total group including those diagnosed with 'Eating Disorder Not Otherwise Specified (EDNOS) type 5' were on or above the ASRS screener score of 14).

Bearing in mind the presence of various types of different eating disorders in their cohort, researchers also looked at how those self-reported ADHD traits might correlate with sub-groupings. They report that: "The highest frequency of possible ADHD was found in BN [Bulimia Nervosa] and in AN-BP [Anorexia Nervosa bingeing/purging subtype], respectively." They also noted that specific symptoms of ED correlated with the ASRS-screener scores: binge eating, purging, loss of control over the eating and BMI [body mass index] > 17.5. I might add that based on responses to another schedule - the Comprehensive Psychiatric [Psychopathological] Rating Scale (CPRS) - included as part of the study, authors noted something of a link between the ASRS trait scores and "the CPRS scales for depression..., anxiety... and obsession-compulsion." But: "Psychiatric comorbidity correlated to ADHD symptoms without explaining the differences between eating disorder diagnoses."

Keeping in mind that answering 6 questions on a screener questionnaire does not an ADHD diagnosis make, I am rather interested in these and other findings. I am by no means an expert on eating disorder but I have previously been interested in the suggestion that autistic traits may be 'over-represented' when it comes to ED (see here). Combined with the idea that autism and [diagnosed] ADHD might not also be unstrange diagnostic bedfellows (see here) and you can perhaps see that there is potentially more research to do in this area in these times of overlap and ESSENCE. And speaking of ESSENCE [2]...

With a word or two of caution, I note the authors also talked about potential 'treatment' options given the overlap between ADHD traits (self-reported) and ED. So: "This motivates further randomized trials with stimulant treatment for bingeing/purging ED-patients with and without a concomitant ADHD diagnosis." Certain stimulants have quite a good track record when it comes to ADHD (see here) but the authors rightly note that 'appetite suppression' is a potential side-effect of such pharmacotherapy and something perhaps not ideal if someone is already underweight. More studies are indicated to disentangle what is linked to what.

And while I'm on the topic, the link between autism traits and anorexia nervosa might actually be a little more tenuous that you perhaps think [3]...

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[1] Svedlund NE. et al. Symptoms of Attention Deficit Hyperactivity Disorder (ADHD) among adult eating disorder patients. BMC Psychiatry. 2017; 17: 19.

[2] Karjalainen L. et al. Eating disorders and eating pathology in young adult and adult patients with ESSENCE. Compr Psychiatry. 2016 Apr;66:79-86.

[3] Postorino V. et al. Investigation of Autism Spectrum Disorder and Autistic Traits in an Adolescent Sample with Anorexia Nervosa. J Autism Dev Disord. 2017. Jan 24.

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Svedlund, N., Norring, C., Ginsberg, Y., & von Hausswolff-Juhlin, Y. (2017). Symptoms of Attention Deficit Hyperactivity Disorder (ADHD) among adult eating disorder patients BMC Psychiatry, 17 (1) DOI: 10.1186/s12888-016-1093-1

On fatty acid metabolism and autism and ADHD (again)

"Children with ADHD [attention-deficit hyperactivity disorder] and ASD [autism spectrum disorder] had low levels of EPA [eicosapentaenoic acid], DHA [docosahexaenoic acid] and AA [arachidonic acid] and high ratio of n-6/n-3 PUFAs [polyunsaturated fatty acid] and these correlated significantly with symptoms. Future research should further investigate abnormal fatty acid metabolism in these disorders."

So said the research publication by Natalie Parletta and colleagues [1] (open-access available here) who completed assessments on erythrocytes in blood samples from "565 children aged 3-17 years with ADHD (n = 401), ASD (n = 85) or controls (n = 79)." Alongside fatty acid analyses (undertaken at "a commercial Pathology Laboratory") researchers also included various behavioural measures with their participant group looking at aspects such as attention and impulsivity and also autistic symptoms (via the CARS). Importantly we are told that: "Participants who had taken any nutritional supplement during the previous year were excluded" from the study.

Results:  well as I've mentioned, compared to the asymptomatic (not autism nor ADHD) controls, group values for those with autism or ADHD were lower in terms of EPA and DHA among other things. In fact we are told that: "Children with ASD had lower DHA, EPA and AA and higher n-3/n-6 ratio than children with ADHD" suggesting that fatty acid metabolism might be even more irregular in this group compared to the others. EPA and DHA specifically fall under the banner of omega-3 fatty acids and are generally thought to be the 'good guys' when it comes to all-manner of health effects. I might particularly mention the word 'inflammation' when it comes to this class of fatty acids [2] which could be relevant to quite a bit of the autism spectrum as well (see here). When it however came to the overall ratio between omega 3 and omega 6 fatty acids (sometimes thought of the not-so-good guys), it was ADHD that beat autism that beat controls. The authors make a case for some interesting correlations between fatty acids levels and the various behavioural scores obtained but to be honest, I'm not all that impressed with the figures as they stand.

I've used the word 'again' in the title of this post to denote how this is not the first time that unusual fatty acid metabolism has been described with both autism and ADHD in mind (see here and see here respectively). Minus any sweeping generalisations, the body of peer-reviewed evidence looking at fatty acids and autism or ADHD is pretty consistent in the the findings being reported that one for reason or another, there seems to be 'issues' with fatty acids and screening services should perhaps be preferentially offered as and when a diagnosis (or both) is received."This cross-sectional study is the largest of its kind, supporting previous work that showed low n-3 PUFA levels, particularly DHA, in children with neurodevelopmental disorders." Indeed.

Then comes the question of whether supplementation as and when an atypical fatty acid profile is detected might be useful or not. The jury is still out on this side of things particularly when it comes to autism and the possible effects of supplementation (see here). For ADHD the evidence is a little stronger (see here) and continues to garner research attention [3] as a potentially cost-effective intervention option for some. I was also intrigued to read the authors' reasoning on a possible role for the trillions of wee beasties that call us home (the gut microbiota) and how: "Another explanation could involve the influence of gut microbiota on PUFA uptake and metabolism." In an unrelated post, I've talked about research suggesting a possible role for fatty acids in terms of gut bacteria and something like obesity (see here). One therefore wonders how deep the rabbit hole might go?

For now however, we have more scientific evidence for a potential role for fatty acid metabolism and at least some autism and ADHD...

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[1] Parletta N. et al. Omega-3 and Omega-6 Polyunsaturated Fatty Acid Levels and Correlations with Symptoms in Children with Attention Deficit Hyperactivity Disorder, Autistic Spectrum Disorder and Typically Developing Controls. PLoS One. 2016 May 27;11(5):e0156432.

[2] Simopoulos AP. Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr. 2002 Dec;21(6):495-505.

[3] Gow RV. et al. Current evidence and future directions for research with omega-3 fatty acids and attention deficit hyperactivity disorder. Curr Opin Clin Nutr Metab Care. 2015 Mar;18(2):133-8.

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Parletta N, Niyonsenga T, & Duff J (2016). Omega-3 and Omega-6 Polyunsaturated Fatty Acid Levels and Correlations with Symptoms in Children with Attention Deficit Hyperactivity Disorder, Autistic Spectrum Disorder and Typically Developing Controls. PloS one, 11 (5) PMID: 27232999

Maths problem solving ability and autism: as varied as the label itself

I'm bringing the paper by Tasha Oswald and colleagues [1] to the blogging table today and a reiteration of the important idea that within the vast heterogeneity that surrounds the presentation of autism (or even the autisms) so too there is quite a lot of variability in the presentation of strengths and weaknesses; indeed, not so dissimilar to life in general.

Mathematics problem-solving was the specific area that Oswald et al have zoomed in on, with the aim of assessing: "the relative proportions of youth with ASD who demonstrate giftedness versus disability on applied math problems."

Researchers reported that of the 27 "high-functioning adolescents with ASD [autism spectrum disorder]" (their words not mine), just over a fifth of participants (22%) "evidenced a mathematics learning disability" whilst only 4% presenting with "mathematical giftedness." These results, by the way, were based on "standardized measures of math problem solving, perceptual reasoning, verbal ability, and test anxiety." When it came to predicting which factors might be relevant to maths problem solving ability, the authors reported a sliding scale: "perceptual reasoning, followed by verbal ability and test anxiety, then diagnosis of ASD" taking into account results from age and cognitively matched controls (n=27) also.

Outside of the idea that not everyone diagnosed with an ASD is Rainman (indeed that whilst autism is over-represented in savant skills, this does not mean that autism = savant [2]), there are some interesting lessons to be potentially learned from the quite preliminary Oswald findings. Not least is the suggestion that results "highlight possible targets of intervention for students with ASD struggling with mathematics" based on those proposed predictors of maths ability and where further educational focus might be directed. Indeed, the specific idea that 'test anxiety' might for example be a factor, ties in well with other peer-reviewed evidence hinting at how the effects of different types of anxiety may be far-reaching when it comes to autism (see here).

I might also forward the idea that whilst autism was the focus on the Oswald data, one should perhaps be mindful of how other comorbidity can similarly affect academic attainment. May and colleagues [3] talked about how aspects of attention could very well affect skills such as mathematics performance with autism in mind and specifically how: "attentional switching difficulties are linked with poorer mathematics outcomes in ASD." Without hopefully confusing attentional switching with something like a diagnosis of attention-deficit hyperactivity disorder (ADHD) (although there is overlap), I will bring in the important data hinting that ADHD difficulties may indeed be over-represented when it comes to autism (see here) and what impact this might have on maths abilities in at least some cases of autism. Further, the question of whether 'tackling' said ADHD might have some interesting effects on areas like maths ability with autism in mind, bearing in mind pharmacotherapy might not be the only suggested avenue?

I'm gonna close with reference to the paper by De Marco and colleagues [4] detailing just how impressive the human mind can be...

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[1] Oswald TM. et al. Clinical and Cognitive Characteristics Associated with Mathematics Problem Solving in Adolescents with Autism Spectrum Disorder. Autism Res. 2015 Sep 29.

[2] Treffert DA. & Rebedew DL. The Savant Syndrome Registry: A Preliminary Report. WMJ. 2015 Aug;114(4):158-62.

[3] May T. et al. The role of attention in the academic attainment of children with autism spectrum disorder. J Autism Dev Disord. 2013 Sep;43(9):2147-58.

[4] De Marco M. et al. Brief Report: Two Day-Date Processing Methods in an Autistic Savant Calendar Calculator.  J Autism Dev Disord. 2015. Oct 17.

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Oswald TM, Beck JS, Iosif AM, McCauley JB, Gilhooly LJ, Matter JC, & Solomon M (2015). Clinical and Cognitive Characteristics Associated with Mathematics Problem Solving in Adolescents with Autism Spectrum Disorder. Autism research : official journal of the International Society for Autism Research PMID: 26418313

Oxytocin moving on: ADHD and inattentiveness

Dare I mention the term 'cuddle hormone' when it comes to oxytocin?

Well, according to a recent news piece in Nature (see here), the 'cuddle hormone' days of oxytocin might well be numbered as science is starting to come to grips with just how complicated a role this hormone might have when it comes to biology and behaviour. Of course we've seen hints of this for quite a while now as autism research in particular comes to grips with the idea that oxytocin may not be the magic 'sociability' bullet that some people thought it might be (see here). That's not to say it might not have it's uses; just not for everyone and not necessarily just exclusively with [parts of] the autism spectrum in mind.

As if to prove a point, today I'm talking about the findings reported by Tsuyoshi Sasaki and colleagues [1] (open-access) and the observation that within a small participant group: "decreased levels of OXT [oxytocin] may play a role in the pathophysiology of patients with ADHD [attention-deficit hyperactivity disorder] and its inherent inattentiveness."

Measuring serum OXT levels in three groups - "drug naive ADHD (n=23), medicated ADHD (n=13), and age- and sex- matched, neurotypical controls (n=22)" - researchers reported that compared with asymptomatic controls, those with a diagnosis of ADHD presented with a significantly lower level as a group. Taking into account the variable of intervention for ADHD (pharmacotherapeutic intervention that is) also seemed to have effects on measured levels of OXT: "serum levels of OXT were significantly higher in medicated ADHD patients than in drug naïve counterparts."

To complete their study researchers also looked at the possibility of any correlation between levels of serum OXT and behavioural measures with ADHD in mind. They reported something of a possible relationship (negative correlation) between severity symptom scores globally on the ADHD-Rating Scale IV Japanese parents' version (ADHD-RS) (a favourite instrument of mine) and those specific to inattention sub-scores as a function of serum OXT. And with that comes the required call for further research in this area on the basis of their small participant size.

The authors appear to be a little incorrect in detailing their study as: "the first report demonstrating decreased serum levels of oxytocin in ADHD patients." Taurines and colleagues [2] had previously reported that: "Patients with ADHD differed from healthy control children by significantly decreased OT [oxytocin] concentrations." Most of the other research interest in OXT and ADHD seems to have been rooted in the idea that oxytocin as a "medical augmentation of labor" does not seemed to be linked to the later onset of offspring ADHD [3].

Back to the Sasaki study, and the authors try to make some sense of why they got the results that they did. First comes the idea that OXT might play a role in "the human limbic system, including the amygdala" complete with evidence of limbic system involvement potentially linked to ADHD and ADHD-type behaviours. Whilst interesting, I personally am a little sceptical about such a simplistic link. That researchers only looked at OXT levels on one day and during childhood tells us little about any previous levels of OXT during birth or infancy and how they may or may not have affected brain architecture. The fact also that no brain imaging was used as part of the current study means few conclusions can be drawn on this hypothesis at this time.

Next up is some discussion about OXT levels being linked to a variety of other conditions, some of which might overlap with ADHD. Of course this leads us back to autism / autism spectrum and the idea that ADHD and autism appearing comorbid is no stranger to clinical research and practice (see here). Just think ESSENCE. I do think that Sasaki et al are 'on the money' when they suggest "using larger sample sizes of ASD [autism spectrum disorder] cohorts" alongside the ADHD slant as the next step in the evolution of this research area. This might tell us a little more about the nature of any OXT overlap and indeed, which combination of autistic and ADHD traits might further guide OXT research. Needless to say that oxytocin is getting a whole lot more complicated and likely to see even further interest under the wide, wide remit of psychiatry [4]...

Music: Gnarls Barkley - Crazy.

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[1] Sasaki T. et al. Decreased levels of serum oxytocin in pediatric Patients with attention deficit / hyperactivity disorder. Psychiatry Research. 2015. June 15.

[2] Taurines R. et al. Oxytocin plasma concentrations in children and adolescents with autism spectrum disorder: correlation with autistic symptomatology. Atten Defic Hyperact Disord. 2014 Sep;6(3):231-9.

[3] Henriksen L. et al. Medical augmentation of labor and the risk of ADHD in offspring: a population-based study. Pediatrics. 2015 Mar;135(3):e672-7.

[4] Rich ME. & Caldwell HK. A Role for Oxytocin in the Etiology and Treatment of Schizophrenia. Front Endocrinol (Lausanne). 2015 Jun 3;6:90.

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Sasaki, T., Hashimoto, K., Oda, Y., Ishima, T., Kurata, T., Takahashi, J., Kamata, Y., Kimura, H., Niitsu, T., Komatsu, H., Ishikawa, M., Hasegawa, T., Shiina, A., Hashimoto, T., Kanahara, N., Shiraishi, T., & Iyo, M. (2015). Decreased levels of serum oxytocin in pediatric Patients with attention deficit / hyperactivity disorder Psychiatry Research DOI: 10.1016/j.psychres.2015.05.029

Ginkgo biloba for ADHD?

I approach the paper by Fereshteh Shakibaei and colleagues [1] with some degree of caution save any suggestions that I am somehow 'promoting' the herb Ginkgo biloba for attention-deficit hyperactivity disorder (ADHD) or anything else. I'm not, but I am interested in the results of their placebo-controlled trial suggesting that "The G. biloba is an effective complementary treatment for ADHD" and their subsequent calls for further research into this potentially promising intervention.

As per the Medline Plus entry for Ginko biloba, irrespective of your views on herbal remedies and health (have you never heard of pharmacognosy?), there is a growing evidence base suggesting that such a preparation might have a place in the management of quite a few conditions/diagnoses. The caveat being that (a) quite a bit more research is needed, and (b) much like more mainstream pharmaceutics, such herbs are not without their contraindications when it comes to their use alongside other medicines. Treat your herbs et al like you would your typical medicines is the best advice, bearing in mind I don't give medical or clinical advice on this blog.

Shakibaei et al reported results looking at a group of children/adolescents over 6 weeks already in receipt of pharmacotherapy for their ADHD symptoms - "methylphenidate (20-30 mg/day" - to which either G. biloba was added - "80-120 mg/day" - or a placebo. They report that based on responses to the "Parent and teacher forms of the ADHD Rating Scale-IV (ADHD-RS-IV)" (something I've come across in my own research) compared with the placebo group "more reduction was observed with G. biloba" illustrative of potential positive changes to symptoms. The specific area of 'inattention' seemed to be positively affected by the use of G. biloba. The commonplace 'further studies are required' sentence completes the Shakibaei results.

This is not the first times that G. biloba has been discussed in the peer-reviewed domain with ADHD in mind (see here). As per the 2009 review from Rucklidge and colleagues [2] (someone who knows a thing or two about supplements and ADHD) the jury is still out about G. biloba and it's possible effect with ADHD mind. Certainly, there are quite a few other candidate 'nutrient supplements' which seem to be performing quite a bit better than this herb (see here and see here for example).

That being said, I'd be interested to see what future research has to say about the usefulness of G. biloba with ADHD in mind, specifically from the angle of an adjuvant (add-on) treatment alongside more traditional pharmacotherapy. Again, I say this without in any way, shape or form 'promoting' such use at the current time and with the understanding that management of ADHD is likely to require quite a holistic approach.

Music: The Foo Fighters (who should be at the SoL anytime.... now).

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[1] Shakibaei F. et al. Ginkgo biloba in the treatment of attention-deficit/hyperactivity disorder in children and adolescents. A randomized, placebo-controlled, trial. Complement Ther Clin Pract. 2015 Apr 18. pii: S1744-3881(15)00029-8.

[2] Rucklidge JJ. et al. Nutrient supplementation approaches in the treatment of ADHD. Expert Rev Neurother. 2009 Apr;9(4):461-76.

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Shakibaei F, Radmanesh M, Salari E, & Mahaki B (2015). Ginkgo biloba in the treatment of attention-deficit/hyperactivity disorder in children and adolescents. A randomized, placebo-controlled, trial. Complementary therapies in clinical practice PMID: 25925875

Childhood inattention and later academic outcome

"Across the full range of scores at a population level, each 1-point increase in inattention at age 7 years is associated with worse academic outcomes at age 16."

That was one of the conclusions reached in the study by Kapil Sayal and colleagues [1] (open-access) drawing on data derived from the Avon Longitudinal Study of Parents and Children or ALSPAC to those in the know. This initiative has also recently produced some other intriguing results on the potential long-term effects of bullying for example (see here).

"Matching of the ALSPAC database with the administrative National Pupil Database (NPD, the central repository in England for pupil-level educational data) provided details of the children's results in the General Certificate of Secondary Education (GCSE) examinations at age 16 years." For those resident in England, Wales and Northern Ireland, GCSEs are probably a familiar concept (they were the starting point for my own academic achievement record). For everyone else, GCSEs are normally sat at the end of the school journey (16 years) and form the start of the typical educational achievement hierarchy leading into A-levels, university degree and beyond. "In total, GCSE attainment data were available for 11,640 children (83% of the core ALSPAC sample)."

The Development and Well-Being Assessment (DAWBA) was completed by parents and teachers of participating children when aged 7 years old. Similar to other discussions on this blog mentioning the DAWBA (see here) it relates "closely to DSM-IV items and focus on current problems and associated impairment." For the purposes of the Sayal study "the key variables of interest relate to inattention, hyperactivity/impulsivity, and oppositional/defiant behaviors." Various other potential confounders such as child cognitive abilities and parental social class were also measured and taken into account when it came to the final analyses.

Following some number-crunching the authors concluded that their results potentially "highlights the adverse effects of early childhood behavioral difficulties on educational outcomes in adolescence" specifically based on inattention symptoms: "inattention, particularly if noticeable to a parent or teacher, is a stronger predictor than hyperactivity/impulsivity of later academic difficulties." Disruptive behaviour disorder (DBD) and oppositional/defiant symptoms were also independently linked to worse academic outcomes in boys.

I know that such findings are probably not totally unexpected in terms of issues such as inattention potentially impacting on learning ability/capacity/enthusiasm subsequently also being reflected in exam results, but the results do put a peer-reviewed, evidence-based perspective on things. Authors also note that: "teachers and parents should be aware of the academic impact of early behavioral difficulties, and, in particular, the risk associated with subthreshold difficulties." I might add that such results do not rule out other factors as playing a role in academic outcome as per other recent data [2].

Insofar as what can be potentially done to mitigate such symptoms and their potential impact on academic performance, the authors offer a few suggestions including: "strategies that might help to optimize examination performance during teenage years include time management and organization skills (throughout the course of study), prioritization of key work, minimizing distractions, examination revision, and within-examination strategy." All well and good (and discussed by other authors [3]) I say but perhaps one might also look to 'tackling' issues such as inattention in other ways too. Take for example the recent paper from Bos and colleagues [4] (see this post) discussing their results based on supplementation with omega-3 fatty acids specifically on inattention symptoms. Probably not suitable or useful for every child with attentional issues, but certainly worth quite a bit more investigation looking for potential best responders based on the idea that good nutrition might be an important part of good mental health. Oh, and how about looking at sleep and even chess? [5]

Music: Cannonball - The Breeders.

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[1] Sayal K. et al. Childhood behavior problems and academic outcomes in adolescence: longitudinal population-based study. J Am Acad Child Adolesc Psychiatry. 2015 May;54(5):360-368.e2.

[2] Peyrot WJ. et al. The association between lower educational attainment and depression owing to shared genetic effects? Results in ~25 000 subjects. Molecular Psychiatry. 2015. April 28.

[3] Ciesielski HA. et al. Academic Skills Groups for Middle School Children With ADHD in the Outpatient Mental Health Setting: An Open Trial. J Atten Disord. 2015 Apr 29. pii: 1087054715584055.

[4] Bos DJ. et al. Reduced Symptoms of Inattention after Dietary Omega-3 Fatty Acid Supplementation in Boys with and without Attention Deficit/Hyperactivity Disorder. Neuropsychopharmacology. 2015 Mar 19.

[5] Blasco-Fontecilla H. et al. Efficacy of chess training for the treatment of ADHD: A prospective, open label study. Rev Psiquiatr Salud Ment. 2015 Apr 21. pii: S1888-9891(15)00048-8.

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Sayal K, Washbrook E, & Propper C (2015). Childhood behavior problems and academic outcomes in adolescence: longitudinal population-based study. Journal of the American Academy of Child and Adolescent Psychiatry, 54 (5), 360-36800 PMID: 25901772

Improving inattention in boys with and without ADHD

The [truncated] PubMed listing of the abstract by Dienke Bos and colleagues [1] does little justice to the results reported by this group looking at the effects of omega-3 fatty acid supplementation on the behaviour of boys both diagnosed with ADHD (attention-deficit hyperactivity disorder) and those who are described as 'typically developing'.

Luckily the paper is open-access (see here) and one can get a true flavour of what happened to this cohort of boys with and without a diagnosis of ADHD following consumption of "10 grams of margarine daily, enriched with either 650mg of EPA/DHA [Eicosapentaenoic Acid / Docosahexaenoic Acid] each or placebo." Indeed, the study is also listed on ClinicalTrials.gov too (see here) and has received some press attention too (see here).

So:

• Authors "set out to investigate the effects of omega-3 PUFA [polyunsaturated fatty acid] dietary supplementation on ADHD symptoms in young boys with and without ADHD in a randomized, placebo-controlled trial." Randomised [placebo-controlled] trials are sweet music to science ears.
• As mentioned, researchers did not however limit their analysis of any potential effects from fatty acid supplementation to just boys diagnosed with ADHD. No, instead they "included a typically developing reference group to investigate the specificity of treatment to subjects with ADHD."
• Over 16 weeks of supplementation (or not) and including measures at baseline (before intervention), researchers assessed the strength of any results based on both psychometric and other more physiological measures including buccal (cheek) swabs "for analysis of phospholipid fatty acid levels" and urine samples to "measure the HVA [homovanillic acid] to creatinine ratio, as a proxy for dopamine turnover." They also imaged the brain via fMRI.
• Results: "Omega-3 PUFA dietary supplementation improved symptoms of inattention in boys with and without ADHD in a double blind randomized controlled trial." This was based on scores on the Child Behavior Checklist (CBCL) and in particular, scores around attention. Inattention scores were not unexpectedly higher in boys diagnosed with ADHD but the authors are pretty adamant that "there was an effect of treatment on parent-rated symptoms of ADHD, regardless of diagnosis."
• "The dietary intervention affected omega-3 PUFA levels in cheek cell phospholipids." This gives us some idea that the behavioural changes reported also correlated with a physiological difference over placebo. It doesn't confirm the possible mechanism but is a good start linking behaviour and physiology. Other more physiological variables such as urinary HVA and the fMRI results did not show any specific effects following active intervention.
• The authors conclude: "this study provides new evidence that dietary supplementation using omega-3 PUFAs may be an effective augmentation of pharmacological treatments of ADHD."

These are interesting results which add to a growing body of work suggesting that PUFAs may have some important effects when it comes to behaviour. With ADHD specifically in mind, PUFAs have received a mixed response from science albeit with some more recent meta-analyses now starting to come down on the side of (possible) effect over no effect, at least for some (see here). Outside of just ADHD, there is also a bank of research suggesting that skills such as reading ability might also have some connection to PUFA status (see here) again, for some. I say this with the caveat that there is more research to do in these areas.

As per the discussions by Bos, their study was of a particularly high methodological standard so that must count in favour of strength of their results. They did note that "a small number of participants with ADHD had changes made to their medication during the intervention" but found similar results without including these participants in separate analysis. With those issues in mind, I'd be inclined to say that we should be paying a lot more attention to fatty acids and behaviour...

Music: Bobby Fuller Four - I Fought The Law.

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[1] Bos DJ. et al. Reduced symptoms of inattention after Dietary Omega-3 Fatty Acid Supplementation in boys with and without Attention Deficit/Hyperactivity Disorder. Neuropsychopharmacology. 2015 Mar 19.

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Bos DJ, Oranje B, Veerhoek ES, Van Diepen RM, Weusten JM, Demmelmair H, Koletzko B, de Sain-van der Velden MG, Eilander A, Hoeksma M, & Durston S (2015). Reduced symptoms of inattention after Dietary Omega-3 Fatty Acid Supplementation in boys with and without Attention Deficit/Hyperactivity Disorder. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology PMID: 25790022