"Neurodevelopmental effects of prenatal vitamin D in humans"

The results of the systematic review and meta-analysis published by Azahara García-Serna & Eva Morales [1] provide the blogging fodder today.

Their aim was to summarise the collected peer-reviewed research evidence pertinent to "the association between 25-hydroxyvitamin D [25(OH)D] levels in maternal blood in pregnancy or newborn blood at birth and neurodevelopmental outcomes, including cognition, psychomotor performance, language development, behavioral difficulties, attention deficit and hyperactivity disorder (ADHD), and autistic traits." This coming from authors who already have some research 'form' in this area (see here).

Twenty-five studies ("articles") were included in their boiling-down-of-the-relevant-research-literature published up to May 2018. From the combined data, a few *associations* were detected: "Comparing the highest vs. the lowest category of prenatal 25(OH)D levels, the pooled beta coefficients were 0.95... for cognition, and 0.88... for psychomotor development. The pooled relative risk for ADHD was 0.72..., and the pooled odds ratio for autism-related traits was 0.42." What this meant is that measured higher levels of vitamin D in pregnant mums-to-be or in offspring newborn blood correlated with "improved cognitive development and reduced risk of ADHD and autism-related traits later in life" for offspring.

Of course one has to be careful with such data whether it comes from a meta-analysis or not. We're still talking about observational studies where one variable (vitamin D) is being analysed in the context of one or a few others (related to offspring development). Yes, researchers can control for this potential confounder or that potential confounder, but there remains a 101 other variables that likely affect the likelihood of ADHD or 'autism-related traits' appearing, not least biology and genetics.

That being said, the García-Serna / Morales are potentially important. They point to the need for further research into various possibly interlinked areas when it comes to vitamin D levels and their intake. This follows Government guidance (at least here in Blighty) suggesting that many people should be taking a vitamin D supplement already (see here). I'm also minded to suggest that future investigations should also be looking at other related areas around vitamin D such as the various genetic processes that seem to be important to vitamin D levels and the metabolism of the sunshine vitamin (see here).

And if you're still not convinced by the potential effects of vitamin D and offspring outcomes, perhaps the findings - systematic review findings - published by Janet Janbek and colleagues [2] might help sway you a little...

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[1] García-Serna A. & Morales E. Neurodevelopmental effects of prenatal vitamin D in humans: systematic review and meta-analysis. Molecular Psychiatry. 2019. Jan 25.

[2] Janbek J. et al. Associations between vitamin D status in pregnancy and offspring neurodevelopment: a systematic literature review.  Nutr Rev. 2019 Feb 26. pii: nuy071.

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(Subclinical) mania symptoms in kids with autism

Although published a few years ago, PubMed recently brought the paper by Yu Okada and colleagues [1] to my attention and the finding that: "school-aged ASD [autism spectrum disorder] children frequently present subclinical BP [bipolar disorder] symptoms."

As per the authors' idea that "there has been increasing interest in bipolar disorder (BP) in children" and specifically that bipolar disorder might be important to at least some autism (see here and see here), a study idea emerged. That idea merged into a hypothesis: "to identify [the] reliable prevalence of BP and to evaluate a variety of subclinical BP symptoms in children with ASD."

Okada report case-control study results based on "110 referred children aged 6-15 years: 46 with ASD (the case group), 64 without ASD (the control group)" who were first time outpatients at a clinic in Osaka in Japan. As well as the use of a quite comprehensive "diagnostic approach for ASD", researchers also measured various types of cognitive functioning, also looking for the possible presence of the signs and symptoms of a diagnosis of bipolar disorder (via something called the K-SADS-PL-J). Results were collated.

"None of the children were diagnosed with BP in the case [autism] group, although two children were diagnosed with BP in the control group." Various other diagnoses were also recorded in the control (not-autism) group including anxiety disorder (n=28) and depressive disorder (n=16). When however researchers looked at subclinical mania symptoms - "elation/expansive mood, increased goal-directed activity, racing thoughts" - there was something to see for the autism group: "Based on the subclinical BP symptoms, the prevalence of elation/expansive mood and racing thoughts was significantly higher in the case group than in the control group: 26.1% versus 3.1% (p<.001) and 32.6% versus 9.4% (p=0.002), respectively."

There are a couple of ways to take the Okada findings. You could say that bipolar disorder in children with autism, with an average age of about 12 years, is low to non-existent. That's a good thing. But you could also argue that the increased frequency of subclinical mania symptoms noted in those with autism compared to not-autism controls might not be such a good thing. Indeed it could foretell a future greater risk of bipolar disorder in that group or even more pronounced mania in times to come (see here). With specific regard to the possible future diagnosis of bipolar disorder, I'm thinking specifically of the word 'prodrome' to mean early signs and symptoms indicating the onset of future 'disease' (psychopathology). I'll leave you to make the decision as to which option is more important but perhaps further investigation [2] may be indicated...

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[1] Okada Y. et al. Subclinical Manic Symptoms in Children with Autism Spectrum Disorder. Osaka City Med J. 2016 Dec;62(2):103-110.

[2] Van Meter A. et al. Bipolar Prodrome Symptom Scale - Abbreviated Screen for Patients: Description and validation. J Affect Disord. 2019 Feb 12;249:357-365.

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"PEM, cognitive impairment, and orthostatic intolerance as core symptoms of pediatric ME/CFS"

There were a few rather familiar aspects to the study results published by Maria Roma and colleagues [1] investigating health-related quality of life (HRQOL) in relation to myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS).

Familiar because HRQOL was found to be "substantially lower in an ambulatory population of adolescents and young adults with ME/CFS than for healthy controls in North America" in the Roma study, in keeping with other studies looking at this important parameter (see here). Familiar also because PEM - post-exertional malaise - was found to be something really quite important to ME / CFS, again in line with other findings (see here for example). But don't think that the Roma findings aren't important, they are. Indeed, with mention of something called orthostatic intolerance in the context of CFS / ME, they provide some further directions for investigation.

So: "We enrolled 55 consecutive ME/CFS patients (46 F) aged 10–23 years." They all "satisfied the 1994 International Chronic Fatigue Syndrome Study Group criteria" (also called the Fukuda criteria). Importantly too: "Individuals with primary depression who were referred by psychiatrists for evaluation of chronic fatigue were excluded, but those who had developed depression sometime after the onset of ME/CFS were included." See those words 'developed depression... after the onset of ME/CFS'. Control participants (n=55) - asymptomatic and in good health - were also included for study. Quite a large battery of questionnaires and schedules were delivered to participants covering HRQOL and quite a bit more including fatigue and depression. Researchers also asked a few questions about "the type of onset for ME/CFS" as well as items pertinent to the IOM (United States Institute of Medicine) criteria for ME/CFS. Lots to see.

And indeed, the results were pretty revealing. Yes, HRQOL was lower - significantly lower - in the ME/CFS group, as talk about a percentage of those with ME/CFS having to change from regular schooling "to part-time schooling... [or] home tutoring" tells you everything you need to know (yet again). Also: "A novel finding of this study is the correlation of impairment in HRQOL with the frequency of PEM, at least for an ambulatory population with ME/CFS." PEM, or 'payback' as another study categorised it as (see here), is starting to get the clinical and research attention that it truly deserves. Researchers specifically mention how "as the frequency of PEM increased, the mean PedsQL [Pediatric Quality of Life Inventory] score fell and the mean FDI [Functional Disability Inventory] score increased, consistent with a significant association of PEM with worse overall function." Need I say anymore?

And then back to orthostatic intolerance (i.e. the "development of symptoms when standing upright which are relieved when reclining"). Researchers considered this present in participants if "(a) self-reported lightheadedness occurred at least several times per week, (b) there was a history of recurrent syncope in the presence of a structurally normal heart, considered consistent with NMH [neurally mediated hypotension]... or (c) previous upright tilt testing or a passive standing testing (performed in patients not being treated with medications for orthostatic intolerance) had confirmed the presence of NMH or POTS [postural tachycardia syndrome]." And present it was in 96% of participants. So much so that authors decided that with orthostatic intolerance being one of the core diagnostic criteria for the IOM diagnostic criteria for ME/CFS, 85% of their participants hit the diagnostic thresholds based on that scheme. Important stuff.

This takes us neatly back to the quote titling this post: "PEM, cognitive impairment, and orthostatic intolerance as core symptoms of pediatric ME/CFS." And perhaps a change is coming to research and clinical practice in this area. Having said that, change is going to be quite difficult for some groups it seems [2] as words like: "Parental representations could contribute to fatigue maintenance" still appear in the peer-reviewed science literature with CFS/ME in mind...

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[1] Roma M. et al. Impaired Health-Related Quality of Life in Adolescent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Impact of Core Symptoms. Front. Pediatr. 2019. Feb 15.

[2] Loades ME. et al. Perfectionism and beliefs about emotions in adolescents with chronic fatigue syndrome and their parents: a preliminary investigation in a case control study nested within a cohort. Psychol Health. 2019 Mar 1:1-17.

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Autistic traits carrying a 'cognitive cost' into old age?

I don't think anyone should be too alarmed at the findings reported by Gavin Stewart and colleagues [1]. But their observation that "autism traits as measured by the BAPQ [Broad Autism Phenotype Questionnaire] may confer additional risk of cognitive decline in aging" represents something that requires quite a bit of further investigation.

Some twenty 'older' adults who were questioned and deemed to have met criteria for the broader autism phenotype (BAP) were tested on skills related to executive function alongside episodic memory. Their results were compared with twenty 'older' adults who did not reach criteria for the BAP. Authors reported that: "Despite no differences in age, sex ratio, educational history or IQ, the BAP group demonstrated poorer performance on measures of executive function and episodic memory compared to the COA [control older adults] group." They interpret this in the context of that 'additional risk of cognitive decline in aging'.

The numbers of participants in the Stewart study were low and imply that one has to be quite careful about making any sweeping generalisations as a result. Bear also in mind that the BAP does not necessarily equal autism or autism spectrum disorder (ASD) as a function of it describing sub-threshold autistic traits (sub-threshold for a diagnosis). Traits, I might add, that are seemingly not just potentially representative of autism (see here for one example).

But set within a 'gap' in the research base looking at autism in older adults (see here), there is a scheme of work to follow. If for example, the Stewart 'trend' does overlap with the experiences of older adults on the autism spectrum in terms of 'cognitive decline', there is a whole barrage of potentially important implications to consider. More so when one considers that the autism prevalence data continues to head in only one direction (see here) and what this means for societal financial and resource planning.

Just before I go, one more detail was revealed in the Stewart paper: "Older adults who met the BAP criteria also reported higher levels of depression and anxiety." Continuing a theme on this blog that various over-represented issues/diagnoses in relation to autism might not be best described as just being 'comorbid' (see here and see here and see here), I believe that this finding adds further weight to the notion that autistic traits (clinical and sub-clinical) might have some important 'direct' relationships with other psychopathology. Not necessarily a welcome opinion in some quarters, but something that also requires a lot more investigation.

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[1] Stewart GR. et al. Aging with elevated autistic traits: Cognitive functioning among older adults with the broad autism phenotype. Research in Autism Spectrum Disorders. 2018; 54: 27-36.

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PET scanning as a biomarker for ketogenic diet response in autism? Not quite...

The case report findings reported by Iwona Żarnowska and colleagues [1] provide the blogging fodder today and an interesting idea: could PET imaging - "non-invasive positron emission tomography (PET) with 18 fluoro-deoxyglucose (18FDG PET) of the resting brain" - serve as "a biomarker in identifying individuals with autism who might benefit from the KD [ketogenic diet] due to underlying abnormalities related to glucose hypometabolism"?

'We need more research' is the conclusion reached by authors, who describe a case report of a 6-year old boy who seemed to regress into autism (yes, he regressed - "At the age of 2, he was developmentally on target in motor and cognitive skills, used language for communication, and displayed normal interests, social activities, and behaviours that were appropriate for his age") and was subsequently introduced to a ketogenic diet. The ketogenic diet (KD) has been discussed before on this blog in relation to autism (see here and see here for examples), and how "a very strict, high-fat, low-carbohydrate, adequate-protein and vitamin-supplemented diet with meals distributed evenly throughout the day" seems to have some important effects on behaviour for some.

Indeed, we are told that use of the KD diet for this young man diagnosed with autism and ADHD (attention-deficit hyperactivity disorder) seemed to *correlate* with some important changes to his behavioural presentation. So: "improvements in clinical outcomes were observed as early as 1 month after the classic KD initiation." The sorts of things reported included less hyperactive and aggressive behaviours and some important differences in his scores on schedules such as the CARS (Childhood Autism Rating Scale) focusing on autistic behaviours. Cognitively, there were also some positive changes reported too: "The intellectual development of the patient, as measured by the WISC-R at the age of 7 years and 5 months, also improved his Full Scale IQ increased from 82 to 99..., Verbal Scale IQ increased from 102 to 113..., and Performance Scale IQ increased from 62 to 83." All of this bearing in mind the 'case report' status of this study.

Then to the mention of that word 'biomarker' as PET scanning was conducted "before treatment (baseline study) and 11 months later on the KD (follow-up study)" and results compared. Although no expert on PET (see here for an overview) the aim was to look at glucose and where the glucose-like tracer 'stuck' in terms of parts of the brain. Researchers observed that at baseline, before the KD was put in place, there was evidence of "regional glucose hypometabolism... observed bilaterally in the mesial temporal lobes, basal ganglia, and cerebellum." At follow-up, when the various manifestations of the ketogenic diet had been in place for a year, they reported different findings based on PET scanning: "18F-FDG uptake decreased markedly and diffusely in the whole cerebral cortex with a relatively low reduction in basal ganglia." The authors add that such observations are not a million miles away from similar metabolic changes seen in others when a KD is put in place in relation to the management of epilepsy (a set of conditions where the KD has found a particular usefulness). The shift away from glucose metabolism in those brain areas is thought to represent "a metabolic shift from the utilization of glucose to utilization of ketone bodies as a primary source of energy" a key aim of the ketogenic diet.

Do the Żarnowska live up to their possible 'biomarker' discussions? Erm, I'm afraid not yet they don't. They do make some interesting observations about the use of a ketogenic diet in the context of a single case report including the label autism. They also present some interesting 'brain imaging' data gathered before and after the use of a KD. But as a biomarker? Not on this occasion. Not yet. But don't however discount the potential usefulness of the ketogenic diet in the context of [some] autism however...

To close, of course you know that it's Star Wars Day today. Don't you? 'Penny for your thoughts.'

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[1] Żarnowska I. et al.Therapeutic use of carbohydrate-restricted diets in an autistic child; a case report of clinical and 18FDG PET findings. Metabolic Brain Disease. 2018. April 11.

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"specific microorganisms interact with some ME/CFS symptoms" and intervention could follow?

The quote titling this post: "specific microorganisms interact with some ME/CFS symptoms" and intervention could follow? comes in part from the findings reported by Amy Wallis and colleagues [1]. They reported that, following an open-label study design including 44 eligible patients diagnosed with ME/CFS [myalgic encephalomyelitis/chronic fatigue syndrome], a few potentially important details emerged. Not least that: "antimicrobial and probiotic treatment showed concurrent reduction in enteric Streptococcus counts and improvement in some neurological symptoms." Mmm...

The authors on the Wallis paper have some research form in this area [2] (see here for a previous blogging take on this work) talking about how use of a antibiotic - erythromycin (400 mg) - delivered over a 6-day period seemed to have some important effects on "gram-positive faecal Streptococcus" and also, for some, a positive impact on sleep quality. The caveat being once again, that this was another open-trial so potentially liable to various confounding variables. Still, there was one particularly positive thing to see in this previous trial, the use of actigraphy to collect objective data on sleep-wake cycles (something sadly lacking from various other studies of ME/CFS).

This latest time around it was all about comparing "the treatment response of male and female ME/CFS patients using a combined antibiotic and probiotic intervention aimed at reducing Streptococcus." The trial was registered (see here) and indeed, prospectively registered. The focus was on "sleep, mood and cognitive symptoms" also taking into account sex/gender as a potentially important variable. Alongside the use of an antibiotic, this time researchers also introduced a probiotic into the study protocol on alternate weeks - "Two capsules of Pro4-50 d-lactate free multistrain probiotic." As well as sleep continuing to be a focus for study, a battery of other parameters were also studied over the 4-week period of study covering various aspects of cognition ("word memory, story memory, spatial working memory, visual learning, verbal fluency, processing speed, cognitive flexibility and planning"), fatigue ("General Fatigue subscale from the Multidimensional Fatigue Inventory, MFI-20") and interestingly, 'brain fog'.

Results: the first thing that struck me about the Wallis results was the fact that the attrition (drop-out) rate was zero. Accepting that this was a rather short study, every participant (27 females and 17 males) completed the study protocol and had full results. That's not bad at all. It also makes statistical analyses sooo much easier.

Next, despite the authors reporting that "some sleep" parameters seemed to show some positive changes following the intervention, I'm minded to point out a key statement made in their text: "The primary outcome for sleep, actigraphic sleep efficiency, revealed similar mean scores at baseline... and post... with a small effect estimate... indicating no change in objective measurement of sleep efficiency." Given the 'open trial' nature of the experiment being described combined with the short experimental time, one therefore needs to be cautious about other, more self-report observations included for study. Cautious but not necessarily dismissive.

Then: "Streptococcus count was the only microbial variable that showed a large effect for time... with a reduction from baseline... to post." This is perhaps not unexpected given the use of an antibiotic that targets that specific type of bacteria. That being said, not everyone on the study showed the same 'direction' of effect, as per the statement: "individual variability of treatment response was highlighted by the proportion of participants who increased in Streptococcus counts at post." I guess this might imply that things are complicated when it comes to bacteria and antimicrobial use. Like just about every other medicine in use these days, not everyone will show the same clinical response to the same medicine.

Finally, bearing in mind an important aim of the Wallis study to undertake "sex comparisons", the results pretty much suggested that things are not so clear-cut when it comes to ME/CFS. So: "Analysis of the change in scores from baseline to post for male and female subgroups (sex-time interactions) revealed no large effects and thus did not support a sex-specific response to the treatment."

What we have with the Wallis paper and results is a well-described study, albeit with an inherent issue: the use of an open-label trial. I'm not saying there isn't value in such results; merely that one needs to be cautious about any findings produced (this comes from someone who has used similar trial designs). I might also add that whilst the authors talk about "Change in mean scores for all clinical outcomes (sleep, mood, cognitive and other) [that] were in the direction of improvement at post-intervention" this is not the same as statistically significant findings no matter what your views are on the current system employed. When joined to that open-label study design employed, such 'in the right direction' views needs to be kept to a minimum without further, more controlled investigations, to back them up...

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[1] Wallis A. et al. Open-label pilot for treatment targeting gut dysbiosis in myalgic encephalomyelitis/chronic fatigue syndrome: neuropsychological symptoms and sex comparisons. Journal of Translational Medicine. 2018; 16: 24.

[2] Jackson ML. et al. Sleep quality and the treatment of intestinal microbiota imbalance in Chronic Fatigue Syndrome: A pilot study. Sleep Science. 2015;8(3):124-133.

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Methylphenidate affecting academic performance meta-analysed

When first tweeting about the paper by Anne Fleur Kortekaas-Rijlaarsdam and colleagues [1] I kinda made a mistake. The text of the tweet read something like: "Does methylphenidate improve academic performance? A systematic review and meta-analysis... Pretty much so, but only in relatively small amounts."

Reading that tweet back to myself I realised that by saying 'but only in relatively small amounts' it's highly likely that any readers might have thought that I was talking about the dose of methylphenidate (MPH) rather than the [intended] effect on things like "math productivity (7.8% increase, p < .001); math accuracy (3.0% increase, p = .001); [and] increased reading speed (SMD .47, p < .001)." I apologise, and once again reiterate my blogging (and social media) caveat about not giving anything that looks, sounds or smells like medical or clinical advice.

I did think it worthwhile to write a short post about the Kortekaas-Rijlaarsdam findings given that (a) ADHD (attention-deficit hyperactivity disorder) is something that turns up quite a bit on this blog (see here for example), and (b) pharmacotherapy 'for ADHD' is an important intervention area which has also, unfortunately under some circumstances, been 'hijacked' for other purposes (see here). On that last point, I specifically refer to the idea that for some people, striving for a diagnosis of ADHD is merely a route to either better academic accommodations or perhaps more worryingly, to gain access to a class of medicines with some potentially significant 'cognitive-enhancing' qualities...

What sets the Kortekaas-Rijlaarsdam findings apart from other reviews of the potential nootropic (cognitive enhancing) abilities of something like MPH is their focus on resolving the issue of "whether there are improvements in core academic skills or just improvements in academic productivity" in the context of "the mediating or moderating effects of symptom improvements, demographic-, design- and disorder-related variables."

From a starting number of 148 full-text research articles, the collected texts were screened for eligibility and some 34 were eventually included for meta-analysis ("quantitative synthesis"). These articles were included because they "provided information about either accuracy or productivity scores for math, reading or spelling, or a combination of these" or could at least be calculated on the basis of their included data. Various mediating and moderating variables were also thrown into the statistical mix - "age, gender, percent diagnosed with ADHD-inattentive subtype, and study characteristics: release system, trial duration, and titration method" - and results reported.

As per previous sentences, various aspects of maths performance showed an improvement that correlated with MPH use, and reading speed but not accuracy also came out as potentially showing a relationship with medicine usage. Important too was the information that: "None of our mediators or moderators influenced MPH effects on math and reading accuracy or productivity."

So, following meta-analytic scrutiny of some 1700 children, it looks like there is a small but potentially relevant effect from MPH use of some academic abilities, at least in the short-term ("between 1 and 7 days"). The authors do well not to stray too much into speculating mode when it comes to the cause of any nootropic effect but instead to include the need for more research "to isolate groups of patients who may benefit more or less from MPH and to reveal its mechanism of action." Can't argue with that.

And going back to the topic of cognitive enahncers, an interesting article from a few years back on what they may or may not be doing to elements of our University student body...

Music to close... Sia and Chandelier. Seemingly always playing outside my dojo....

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[1] Kortekaas-Rijlaarsdam AF. et al. Does methylphenidate improve academic performance? A systematic review and meta-analysis. Eur Child Adolesc Psychiatry. 2018 Jan 20.

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Vitamin D for schizophrenia? No but...

The results published by Amir Krivoy and colleagues [1] talking about "no significant effect of vitamin D on psychotic, depressive or metabolic parameters" in a cohort of people diagnosed with schizophrenia, make for interesting reading.

Interesting, not only because authors reported very little effect of supplementation on the symptoms of schizophrenia, but also because such 'negative' findings kinda follow a theme in vitamin D - psychiatric research circles: low levels of vitamin D (insufficiency and/or deficiency) being associated with a condition (see here) yet little [experimental] evidence that supplementation does anything more than correct the vitamin D availability issues (see here for another example). Certainly the quite significant speculation that vitamin D might have lots and lots of 'extra-bone' related actions do not yet seem to have been borne out by the currently available experimental data in this area...

Krivoy et al describe the methodology and results of their "eight-week, randomized, double-blind, placebo-controlled clinical trial" focused on some 47 patients "age between 18 and 65 years old, diagnosis of schizophrenia according to DSM-IV-TR criteria confirmed by two senior psychiatrists, treated with clozapine for at least 18 weeks and being on a stable clozapine dose for at least four weeks prior to enrollment, serum 25(OH) vitamin D level below 75 nmol/L (30 ng/ml) and total severity of psychopathology score, as measured by the Positive and Negative Symptom Scale (PANSS) total score above 70." Vitamin D supplementation - 14,000 IU [international units] per week - was pitted against a placebo formulation, although I can't seem to find what exactly the placebo contained (N=24 vs. N=23 respectively). Various outcome measures were used to determine any effect or not.

Results: as per the opening line of this post, there was little to see between the vitamin D and placebo receiving groups when compared on the basis of PANSS scores. Both groups showed a trend towards a decreasing total and sub-scale psychopathology scores over the course of the experimental period indicative of some modest improvement in psychiatric symptoms. At the same time, authors report that vitamin D levels did change amongst those in receipt of the vitamin D supplement: "The 25(OH) vitamin D serum levels increased significantly in the drug group... while essentially unchanged in the placebo group" so we can be pretty sure that there was both compliance with the experimental regime and that vitamin levels were increasing in the supplemented group as expected.

There was one small 'ray of hope' when it came to supplementation that has been hinted at in the research literature previously: "A beneficial effect of vitamin D supplementation was noted on cognitive performance, as reflected in an increase in MoCA [Montreal Cognitive Assessment] total score." I say 'hinted at' because although it is a little premature to talk about vitamin D as a nootropic (cognitive enhancer), there is evidence that low levels of the stuff *might* under certain circumstances, negatively affect certain cognitive abilities (see here for example). Whether supplementation with vitamin D is a more general cognitive 'affector' remains to be seen but the Krivoy results suggest further inspection is indicated.

There is more to do in this area before the vitamin D - schizophrenia link is branded completely spurious. The authors mention the relatively small sample sizes included for study and how the nature of schizophrenia as a condition potentially means that "patients with extreme presentation are less likely to consent to participate in a randomized controlled trial due to their paranoid and suspicious attitudes" as being something important. It's also interesting that at least one of the supplemented participants seemed to show little response to vitamin D in a physiological levels sense: "This patient, despite attending all assessments and dosing visits, showed vitamin D level of 22 nmol/L at baseline and 17 nmol/L at endpoint due to unclear reasons." Assuming that vitamin D testing was accurate i.e. using something like mass spectrometric methods over older, potentially less reliable assays (see here) I wonder if there could be other components required in future studies in this area, such as also looking at the genetics of vitamin D metabolism as per other, unrelated research (see here).

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[1] Krivoy A. et al. Vitamin D Supplementation in Chronic Schizophrenia Patients Treated with Clozapine: A Randomized, Double-Blind, Placebo-controlled Clinical Trial. EBioMedicine. 2017. Nov 29.

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Yet more "lost their diagnosis" and autism research. Not for all but...

The question posed in the title of the paper by Solomon and colleagues [1] - "What will my child's future hold?" - examining the "phenotypes of autism spectrum disorder (ASD) based on trajectories of intellectual development from early (ages 2-3 ½) to middle (ages 5-8) childhood" - is an interesting one and a question that many parents/caregivers will probably ask or have asked at one point or another.

It's also an important question because throughout all the sweeping statements that have been made about the autism spectrum past and present, the generalisation that ALL autism is 'lifelong' is one of the more popular ones despite [peer-reviewed scientific] evidence pointing to the contrary (see here for example).

By saying all that I'm not trying to minimise the effect(s) that autism has on the lives of many, many people day-in and day-out throughout their lives and the varying requirements for suitable support. Just that, as per the notion 'if you've met one autistic person, you've met one person with autism' (or words to that effect), the experience(s) of continually hitting the diagnostic thresholds across the lifespan is likely to be different for different people as a function of many, many different factors. I say this acknowledging for example, the rise of 'compensation' in the context of autism recently (see here).

Solomon et al drew on data derived from the Autism Phenome Project including over 100 children "initially diagnosed with ASD." Researchers were particularly interested in cognitive trajectories as measured by IQ between 2 and 8 years of age and whether autistic and other related symptoms/traits were also affected by any changes to intellectual functioning. As it happens, they might be...

"A four class model best represented the data" meaning that participants typically fell into one of four 'patterns' with regards to their intellectual functions/trajectories. This included: "High Challenges (25.5%), Stable Low (17.6%), Changers (35.3%), and Lesser Challenges (21.6%) groups." As per the title of this post, I'm particularly interested in those described as 'Changers' or 'Lesser Challenges' who "demonstrated the most significant IQ change that was accompanied by adaptive communication improvement and declining externalizing symptoms" and "showed a significant reduction in ASD symptom severity" respectively. Indeed, within the Lesser Challenges group we are told that "by age 8, 14% of them no longer met ADOS-2 criteria for ASD." In other words, they did not reach cutoffs for the diagnostic criteria for an autism spectrum disorder (ASD) using a gold-standard assessment instrument and so could be considered not autistic by diagnostic standards.

Also important to the Solomon findings was the observation that: "Intervention history was not associated with group status." I'm not going to say too much more about this at the present time, but if replicated, the implications are pretty huge particularly where the current drive towards early intervention in autism is leading us (see here).

Although not always welcomed by everyone, the idea that a diagnosis of autism is permanent and immutable for all does not stand up well to scientific scrutiny. The best guess estimates currently suggest that somewhere between 9 and 12% of children/adults will 'lose their diagnosis' (see here and see here); also potentially affecting the presence of some important over-represented comorbidity too (see here). The old 'they weren't autistic in the first place' argument is a typical response from some nay-sayers on this topic; something which unfortunately contributes to the denigration of some important parts of the autism spectrum. Certainly a part of the autism spectrum that we can learn a lot from as the Solomon results are starting to show.

Indeed, given the other 'biological' focuses of the Autism Phenone Project [2] I'm hoping that we'll eventually see further results from this initiative providing important information on possible biological correlates linked to those who "no longer met ADOS-2 criteria for ASD". If ever there was a research study needed on autism, it is one including a little more biological and genetic information about those who move from autism to not-autism and what it could mean for the wider autism spectrum and particularly the concept of 'the plural autisms'...

To close, 'I want a deep fried turkey'....

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[1] Solomon M. et al. What will my child's future hold? phenotypes of intellectual development in 2-8-year-olds with autism spectrum disorder. Autism Res. 2017 Oct 27.

[2] Onore CE. et al. Levels of soluble platelet endothelial cell adhesion molecule-1 and P-selectin are decreased in children with autism spectrum disorder. Biol Psychiatry. 2012 Dec 15;72(12):1020-5.

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What does 'recovery from myalgic encephalomyelitis / chronic fatigue syndrome' look like?

The title of this post reflects the material included in the paper by Andrew Devendorf and colleagues [1] who sought "an operationalised definition of recovery from myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) for research and practice."

Although perhaps at first sight being a rather simple question to answer - Q: What does recovery look like in relation to ME/CFS? A: Complete remission of symptoms -  there's a lot more behind such a query than you might expect. I'm particularly thinking about how 'recovery' has been a real source of discussion/debate/argument (delete as appropriate) in the context of ME/CFS in recent 'PACE' times (see here and see here).

Ten experts on ME/CFS were quizzed about their views specifically on recovery from the condition(s). As probably expected: "Physicians conceptualised recovery as complete symptom remission and a return to premorbid functioning (adjusted for with age)." No surprises there then. Insofar as the term 'significant improvement', experts also quite sensibly reported that this should be 'operationalised' as "a substantial reduction in symptoms with considerable functional gains, where patients may operate in daily life but still must cope or be treated." Again, not really that earth-shattering to be honest.

'Recovery' in the context of ME/CFS has been discussed in the peer-reviewed domain before [2] with views to "recommend a consistent definition that captures a broad-based return to health with assessments of both fatigue and function as well as the patient's perceptions of his/her recovery status." Although not everyone agreed with all that was said by Adamowicz and colleagues [3], there  is a general consensus that recovery represents an absolute term where 'complete symptom remission' is the important feature. Everything else outside of recovery falls into 'a spectrum of improvement' (substantial, significant, so-so, etc) through to no change or even potential symptom worsening.

The task facing ME/CFS research and practice now: how best to measure the recovery / non-recovery spectrum? I agree that questionnaires about fatigue and (very) important clinical signs like post-exertional malaise (PEM) need to be part and parcel of such measurements. As with any condition that is [currently] diagnosed solely on the basis of presented symptoms with no genetic or biological test yet able to distinguish cases from not-cases, questionnaires and interviews are always going to be important in terms of how symptoms change/evolve over time either naturally or as a result of some specific intervention(s). But research and practice really need more than that; they need some objectivity too...

So, physical activity levels: well, I've often gone on (and on!) about the great potential of actigraphy in the context of several research areas. You want data on rest and activity cycles for a condition characterised by rest and activity cycles? There's plenty of technology out there in the marketplace to measure such cycles and associated measures that could be used in a complementary fashion (see here). How do you define 'recovery' based on such data? Well, typically (at the moment where such tech are still relatively new) there probably won't be 'before and after' data as noted in other examples of such tech use (see here) so a reliance of general population data is the next best thing. Yes, by doing so we're moving from individual data to more generalised data as a comparator, but when such generalised data runs into the thousands or even millions of people (see here for one example) you can start to build up a picture based on 'expected' physical activity levels taking into account sex/gender, age and other important variables. The important point is that one element of recovery in CFS/ME is going to be a restoration of physical activity levels (and perhaps even sleep cycles?) and there are easy ways to measure that minus any subjectivity issues potentially included in questionnaires or interviews. I say all of that acknowledging that levels of typical day-to-day tasks such as work, shopping, socialising and other pastimes/activities which generally require physical exertion can also be to some extent ascertained via a questionnaire.

PEM? I'm not so sure about how to measure this outside of some limited research in this area [4] talking about a "change in complement C4a level and the increase in pain and fatigue 24 h following the self-paced, physiologically limited exercise support the use of C4a as a marker for postexertional malaise in people with ME⁄CFS." Complement C4a by the way, is something of a 'mediator of local inflammatory processes' and has cropped up on this blog before (see here). In light of other work also suggesting that PEM might have cognitive effects [5] too, I'm sure a little more scientific inquiry could bring together a suite of fairly cost-effective ways and means to objectively measure PEM both in terms of biology and also cognitive prowess. Yes, there are details to be worked out but...

Other things to be included in recovery criteria? Well, it depends on whether you're going to go down the sole 'core' symptoms pathway or going to include elements that may potentially be more peripheral [6] yet still impact on notions of recovery in CFS/ME (hyperacuity anyone?). That's not my call I'm afraid, although given what has been discussed with regards to health-related quality of life and ME/CFS (see here), the addition of something like the EQ-5D-3L to any protocol might not also go amiss as part of any measurement of recovery with CFS/ME in mind...

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[1] Devendorf AR. et al. Defining and measuring recovery from myalgic encephalomyelitis and chronic fatigue syndrome: the physician perspective. Disabil Rehabil. 2017 Oct 5:1-8.

[2] Adamowicz JL. et al. Defining recovery in chronic fatigue syndrome: a critical review. Qual Life Res. 2014 Nov;23(9):2407-16.

[3] Twisk FN. A definition of recovery in myalgic encephalomyelitis and chronic fatigue syndrome should be based upon objective measures. Qual Life Res. 2014 Nov;23(9):2417-8.

[4] Nijs J. et al. Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1beta. J Intern Med. 2010 Apr;267(4):418-35.

[5] Cook DB. et al. Neural consequences of post-exertion malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Brain, Behavior, and Immunity. 2017; 62: 87-99.

[6] Whiteley P.  et al. Correlates of Overlapping Fatigue Syndromes. Journal of Nutritional & Environmental Medicine. 2004; 14: 247-259.

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Can a 'disturbed gut microbiota' explain a cognitive performance dip in those born by C-section?

In answer to the question posed in the title of this post - Can a 'disturbed gut microbiota' explain a cognitive performance dip in those born by C-section? - I have to say that I don't know. I was however, rather intrigued by the findings reported by Cain Polidano and colleagues [1] (open-access) who observed that "cesarean-born children perform significantly below vaginally-born children, by up to a tenth of a standard deviation in national numeracy test scores at age 8–9" when allowing for "a large range of confounders."

Based on data derived from the Longitudinal Study of Australian Children (LSAC), a sort of Aussie equivalent to ALSPAC here in Blighty, researchers set about examining whether the growth in Caesarean sections might have some long-term implications for child cognitive development. The question of whether those trillions of wee beasties (bacteria and the like) that call our gastrointestinal (GI) tract home might be implicated in the cognitive findings stems from previous research talking about how, theoretically, said bacteria might be doing so much more than just helping us to digest our food or producing the odd nutrient here and there (see here for example). This also bearing in mind that those born by C-section have been suggested to show a different gut bacteria profile from those not. I say all that acknowledging that gut bacteria doing this, that and t'other is going through something of a period of reflection at the moment (see here).

It is the size of the Polidano participant sample (N=3,666) and the "internationally recognized and widely-used longitudinal" nature of the LSAC that interested me in these findings. The authors provide quite a bit of detail on how the initiative works and what measures have been put in place to potentially rule out mediating and/or confounding variables. Even missing data has been discussed and accounted for: "non-random attrition does not appear to be seriously biasing our results."

What is unfortunately missing from the Polidano paper is any measure of 'gut bacteria' to substantiate the possibility of a connection between C-section birth, gut bacteria and academic outcome(s). I say this bearing in mind that whilst there is extensive literature talking about *associations* between C-section birth and a variety of cognitive and developmental outcomes, the details are still a little scarce insofar as whether any association is tied to a specific family of bacteria or indeed, something like overall bacterial diversity. One also has to bear in mind that other factors also affect newborn gut bacterial make-up such as breastfeeding and seemingly specific components of breastfeeding [2]. I note that other authors are also not sold on the ideas generated from the Polidano paper (see here) and caution that C-sections are not somehow demonised as a result (not everyone is 'too posh to push').

"While the magnitude of our estimated difference in outcomes is not large, up to a tenth of a standard deviation in national test scores in numeracy, they are large enough to warrant action." The authors note that their observations might not seem to show a particularly large contribution to cognitive development, they are nonetheless still potentially important. Indeed: "A tenth of a standard deviation in national test scores is comparable in size to differences related to gender, class size and teacher quality that are the focus of policy effort." In other words, don't discount this potentially important area of investigation just yet...

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[1] Polidano C. et al. The relation between cesarean birth and child cognitive development. Scientific Reports. 2017; 7: 11483.

[2] Toscano M. et al. Impact of delivery mode on the colostrum microbiota composition. BMC Microbiology. 2017; 17: 205.

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On drinking water lithium content and dementia risk

"Lithium in tap water may cut dementia" went the BBC website headline reporting the study results published by Lars Vedel Kessing and colleagues [1]. The authors relied on some of those oh-so important Scandinavian population registries and other data to examine a possible connection between drinking water lithium levels and risk of "diagnosis of dementia in a hospital inpatient or outpatient contact."

Alongside looking at data for some 70,000 people diagnosed with dementia and nearly three-quarters of a million non-diagnosed controls, researchers estimated lithium exposure via drinking water based on data from over 150 waterworks. The relationship they observed between lithium in drinking water and risk of dementia diagnosis was not altogether straight-forward as "higher long-term lithium exposure from drinking water may be associated with a lower incidence of dementia" but the relationship was described as "nonlinear." Nonlinear meant that those with drinking water levels of lithium at moderate levels - between 5.1 and 10 micrograms per litre - actually showed an increased risk of dementia compared to those who had low levels of lithium (below 5 micrograms per litre) in their drinking water. The authors add: "Nonlinear dose-response associations are often found in medicine, with a gradual increase in drug response at the lower doses and gradual leveling off in response at the highest doses."

The authors do caution about their results and the various limitations attached to the findings. Not least is their reliance on a diagnosis of dementia as a starting point and how factors such as "accessibility to health care services that vary geographically" may have influenced such results. Indeed they note: "accessibility to health care services is increased in eastern regions of Denmark, where lithium levels generally are higher, and decreased in western regions, specifically in Jutland, where lithium levels generally are lower." They also found: "a direct inverse association with increasing risk of dementia in rural areas" as part of a sensitivity analysis, and as noted in some other studies [2]. More investigation is definitely required.

But these remain interesting results. Lithium is a treatment of choice when it comes to conditions such as bipolar disorder (see here). I've also talked about this stuff in connection to some other important research looking at suicide reduction too (see here) based on quite a body of research [3] (and growing all the time [4]) but minus simplifying something like suicide ideation, attempts or completion all down to lithium 'deficiency'. In relation to the possible effects on dementia risk, this is not the first time that lithium has been discussed as per findings looking at dementia risk in cases of lithium treated bipolar disorder [5] (something else that has been discussed on this blog - see here).

Questions still however remain. The mechanism of effect(s) is still to be suitably deciphered and one also needs to keep in mind the safety profile of lithium [6] as a balance to any risk-reduction effects on dementia or anything else. This is particularly relevant to those who might be at particular risk for dementia [7]. I'll also add that any focus on lithium intake and dementia also needs to keep in mind other *associations* that have been previously discussed in the peer-reviewed research literature such as that talking about vitamin D deficiency and dementia risk for example (see here) as part of a wider research interest in vitamin D and cognitive functions in the context of ageing (see here).

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[1] Kessing LV. et al. Association of Lithium in Drinking Water With the Incidence of Dementia. JAMA Psychiatry. 2017 Aug 23.

[2] Contador I. et al. Childhood and Adulthood Rural Residence Increases the Risk of Dementia: NEDICES Study. Curr Alzheimer Res. 2015;12(4):350-7.

[3] Cipriani A. et al. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013 Jun 27;346:f3646.

[4] Kanehisa M. et al. Serum lithium levels and suicide attempts: a case-controlled comparison in lithium therapy-naive individuals. Psychopharmacology (Berl). 2017 Aug 28.

[5] Gerhard T. et al. Lithium treatment and risk for dementia in adults with bipolar disorder: population-based cohort study. Br J Psychiatry. 2015 Jul;207(1):46-51.

[6] Albert U. et al. Lithium treatment and potential long-term side effects: a systematic review of the literature. Riv Psichiatr. 2014 Jan-Feb;49(1):12-21.

[7] Holroyd S. & Rabins PV. A Retrospective Chart Review of Lithium Side Effects in a Geriatric Outpatient Population. Am J Geriatr Psychiatry. 1994 Autumn;2(4):346-351.

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Valproate use during pregnancy and/or breastfeeding and "greatest odds of adverse development"

As per other blogging occasions when I've talked about the antiepileptic drug (AED) valproate and its use specifically during pregnancy, I caution that no medical or clinical advice is given or intended on this blog. Anyone in any doubt or seeking an opinion on this other or any other AED should consult their prescribing physician. Don't mess with epilepsy. I repeat: don't mess with epilepsy.

The findings however reported by Areti Angeliki Veroniki and colleagues [1] (open-access) synthesising the available peer-reviewed evidence to compare "the safety of antiepileptic drugs (AEDs) on neurodevelopment of infants/children exposed in utero or during breast feeding" provides an all too familiar picture specifically in relation to valproate use during pregnancy. Namely: "Valproate alone or combined with another AED is associated with the greatest odds of adverse neurodevelopmental outcomes compared with control."

Utilising something called a Bayesian random-effects network meta-analysis (NMA), researchers set about synthesising and ranking various AEDs previously studied in terms of their safety when it comes to *association* with various childhood developmental diagnoses including autism and things like cognitive developmental delay. Based on the results from 29 studies reporting on AED use and 'neurological outcomes' including some 5000 patients, authors made some important observations.

Not to be alarmist but: "results suggest that AEDs generally pose a risk for infants and children exposed in utero or during breast feeding." The authors caution that their results whilst methodologically strong are not without limitations; not least that the studies in this area are observational only and therefore have "inherent biases because of confounding and shortcomings of these studies." That being said, the tide of such observational research cannot be readily ignored. If there is one or more confounding variables that is/are somehow being hidden behind something like valproate use during pregnancy and its potential risks of offspring developmental outcomes, they seem to be very well hidden indeed.

"Valproate was significantly associated with more children experiencing autism/dyspraxia, language, cognitive and psychomotor developmental delays versus children who were not exposed to AEDs." Valproate came 'top of the pops' when it came to those neurological outcomes. Other AEDs also showed associations with specific outcomes - "oxcarbazepine and lamotrigine were associated with increased occurrence of autism" - but the data pointed to valproate as potentially showing greatest risk to offspring. I should point out that there is a mouse model of autism that relies on offspring valproate exposure which, whilst subject to shortcomings (see here), kinda suggested that there may be an important association. Said animal research also reveals some potentially important avenues for perhaps mitigating any deleterious effects of valproate use on offspring too (see here) with the requirement for more experimental study.

"Future studies should assess the genetic contribution from the biological father, maternal seizures during pregnancy, exposure through breast feeding only, types of epilepsy and maternal family history." Of course the authors are right to talk about other factors that are probably important to various childhood developmental outcomes. But unlike a related area talking about medicines taken during pregnancy potentially affecting risk of something like autism and how one might tease apart medicine use from underlying health issue(s) (see here for example), I don't think it too likely that there is going to be a large bank of pregnant mums out there who present with epilepsy or other seizure disorder that is not going to be already managed via AEDs. Indeed, it would be rather unethical as well as unwise to leave epilepsy untreated under any conditions.

To close, where we're up to when it comes to government (UK) advice on AEDS such as valproate and pregnancy use. Again, if it doubt, talk to your prescribing physician.

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[1] Vernoniki AA. et al. Comparative safety of antiepileptic drugs for neurological development in children exposed during pregnancy and breast feeding: a systematic review and network meta-analysis. BMJ Open. 2017; 7: e017248.

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"low vitamin D is related to poorer cognition" but does supplementation help?

The findings reported by Alicia Goodwill & Cassandra Szoeke [1] provided some reading interest recently and the observation that "low vitamin D is related to poorer cognition" following a systematic review and meta-analysis of the peer-reviewed science literature in this area.

Looking at the cumulative data from nearly 30 studies (most observational), researchers picked up something of a potentially important trend in relation to how low levels of measured vitamin D seemed to be *linked to* both "worse cognitive performance... and cognitive decline." This follows a trend that has been touched upon before on this blog (see here for example) and onward how applicable such findings might be to the development of conditions that primarily affect cognitive processes (see here).

But just before anyone reaches for the vitamin D as some sort of nootropic of choice, there is a cautionary tale of 'evidence currently lacking' when it comes to the use of vitamin D in an effort to try and improve cognitive performance: "Vitamin D supplementation showed no significant benefit on cognition compared with control." Indeed, such a lack of evidence kinda mirrors what has been talked about in other areas of vitamin D discussion, where for example, some types/cases of depression seem to be *associated* with vitamin D deficiency/insufficiency (see here) but oral supplementation to correct said deficiency does not always lead to improvements in the presentation of symptoms [2] despite impacting on measured biological vitamin D levels.

One might speculate as the authors did that "there is likely a therapeutic age window relevant to the development of disease and therefore vitamin D therapy" as being important. I'd also put forward the idea that further investigations taking into account the genetics of vitamin D metabolism might be similarly useful, both in the context of any vitamin D-cognition link and the proposed value of supplementation for certain groups of people.

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[1] Goodwill AM. & Szoeke C. A Systematic Review and Meta-Analysis of The Effect of Low Vitamin D on Cognition. J Am Geriatr Soc. 2017 Jul 31.

[2] Kjærgaard M. et al. Effect of vitamin D supplement on depression scores in people with low levels of serum 25-hydroxyvitamin D: nested case-control study and randomised clinical trial. Br J Psychiatry. 2012 Nov;201(5):360-8.

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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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Physical exercise as a nootropic of choice

Nootropic, defined as a 'smart drug' or cognitive enhancer, is generally taken to mean a substance/compound/medicine that has some positive effect(s) on aspects of cognition. I've talked about the possibility that various compounds might fit this bill on this blog (see here for example) but today I'm discussing another quite important potential nootropic: exercise.

It was the paper by Joseph Michael Northery and colleagues [1] (open-access) that added exercise to the nootropic categorisation on the premise of their meta-analysis results suggesting that "physical exercise interventions are effective in improving cognitive function in adults aged >50 years, regardless of cognitive status." As you can imagine, findings such as that tend to generate news headlines as per this one.

Including the results of some 39 studies where exercise and cognition were included as watchwords and trials were of the randomised-controlled design, researchers set about analysing the collected data covering various types of exercise and various cognitive outcomes. Aside from some issues with various forms of bias, most prominently with regards to blinding(!), they concluded that various types of exercise seemed to positively impact on cognitive functions. Particularly notable were the positive effects on executive functions: "a set of cognitive processes responsible for the initiation and monitoring of goal-orientated behaviours" and aspects of memory via the use of resistance training (i.e. using weights). Other more aerobic exercise regimes also seemed to have positive effects on other aspects of cognition too. It seems some combination of aerobic and resistance exercise regimes might provide the best generalised advice according to the authors "of at least moderate intensity and at least 45 min per session, on as many days of the week as possible." Just going back to that resistance training - executive functioning link being proposed, I wonder whether there may be other investigations to be carried out here with specific labels in mind [2].

Added to other research talking about 'exercise as medicine' (see here) and more particularly that exercise *might* have some important effects for aspects of psychological health and wellbeing (see here and see here for examples) there is a peer-reviewed, evidence-based picture emerging. It suggests that messages about moving more (see here) as being important for weight and BMI might be only the tip of iceberg.

And although not for everyone, I'm minded to yet again extol the virtues of the martial arts which also might have some "positive effect on some aspects of cognition" [3] (even for those under 50 years old with middle-aged hips like mine)...

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[1] Northey JM. et al. Exercise interventions for cognitive function in adults older than 50: a systematic review with meta-analysis. Br J Sports Med. 2017. April 24.

[2] Demetriou EA. et al. Autism spectrum disorders: a meta-analysis of executive function. Molecular Psychiatry. 2017. April 25.

[3] Fabio RA. & Towey GE. Cognitive and personality factors in the regular practice of martial arts. J Sports Med Phys Fitness. 2017 May 5.

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Northey, J., Cherbuin, N., Pumpa, K., Smee, D., & Rattray, B. (2017). Exercise interventions for cognitive function in adults older than 50: a systematic review with meta-analysis British Journal of Sports Medicine DOI: 10.1136/bjsports-2016-096587

ADHD, obesity and bariatric surgery?

"The findings suggest that a considerable number of patients before and after bariatric surgery screened positive for ADHD [attention-deficit hyperactivity disorder]. It can be hypothesized that some core ADHD symptoms improve after surgery."

Bariatric surgery, where several surgical options are available to aid weight loss in those who present with 'dangerous' obesity, was the topic of the paper by Nielsen and colleagues [1] (open-access available here) who set out to compare "pre- and post-bariatric surgery patients using the internationally used Conners' Adult ADHD Rating Scale (CAARS™) to screen for ADHD" among other measures. The authors came up with some interesting details. They reported that the rate of 'probably ADHD' (defined using the CAARS and also the Wender Utah Rating Scale Short Version (WURS-k) cut-off scores) were 8.3% in their pre-surgery sample (n=120) and 6.3% in their post-surgery sample (n=128).

When looking at the behavioural profiles of those pre- and post-surgery, there were some not entirely unexpected differences when it came to items related to depression and eating-related psychopathology - both scoring lower in the post-surgery participants. But also those post-surgery reported some potentially important information in relation to generally better attention and memory compared to pre-surgery participants. I was intrigued by the authors explanation of this: "The finding of a better attention and memory function in the post-surgery sample is in line with the results of longitudinal studies demonstrating improvements in cognitive functioning following bariatric surgery." Further: "It is reasonable to assume that postoperative cognitive improvement in attention and memory might have impacted the self-report on the respective CAARS subscale." Does this imply that bariatric surgery might act as some kind of nootropic for [some of] those with obesity?

In these days of ADHD being 'linked' to obesity (see here), the Nielsen results fit nicely. Alongside the idea that weight loss surgery might link into improved cognitive functioning and onwards, impacting on facets of ADHD I'd have to question what the biological mechanism(s) might be. Does the restriction of food intake as a consequence of surgery indicate a role for food in some cognitive processes? Does such surgery potentially impact on the trillions of wee beasties that populate our gut and then onwards exert an effect of cognitive processes? There are several questions that still need answering...

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[1] Nielsen F. et al. Attention Deficit Hyperactivity Disorder Prevalence and Correlates Pre- and Post-Bariatric Surgery: A Comparative Cross-Sectional Study. Obes Facts. 2017 Jan 20;10(1):1-11.

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Nielsen F, Georgiadou E, Bartsch M, Langenberg S, Müller A, & de Zwaan M (2017). Attention Deficit Hyperactivity Disorder Prevalence and Correlates Pre- and Post-Bariatric Surgery: A Comparative Cross-Sectional Study. Obesity facts, 10 (1), 1-11 PMID: 28103594