"a neurodevelopmental abnormality possibly associated with congenital Zika virus infection"

I'm a little late getting to the findings reported by Marion Rice and colleagues [1] (open-access available here) but I did want to cover them because of their current importance and perhaps future implications. The topic in question was the Zika virus and specifically the research efforts of the U.S. Zika Pregnancy and Infant Registry (USZPIR) used to track those infants exposed to the virus during the important nine months than made them. Just in case you didn't follow the hows-and-whys of the Zika virus outbreak and its effects a while back, some background can be found here.

Rice et al report findings for nearly 1500 children "of mothers with laboratory evidence of confirmed or possible Zika virus infection during pregnancy" in terms of their level of care and clinical follow-up and also "to identify Zika-associated birth defects and neurodevelopmental abnormalities possibly associated with congenital Zika virus infection." Aside from reporting that the majority of their cohort had "some follow-up care reported" ('some' that included very basic "length/height, weight, or head circumference measurements and date of measurements" reported back to the USZPIR), a few other observations were also made. This included findings such as: "approximately one in seven (14%) were identified during infancy or early childhood as having either a Zika-associated birth defect, a neurodevelopmental abnormality possibly associated with congenital Zika virus infection, or both."

Although the talk about birth defects is important to Zika virus exposure (microcephaly being only one part of this), I was specifically interested in the 'neurodevelopmental' side of things reported in the Rice paper as affecting 9-10% of the cohort depending on what laboratory testing for Zika virus exposure was carried out. Bearing in mind the age group of the cohort (1 year old and above), and that such neurodevelopmental issues covered a lot of clinical ground (e.g. "hearing abnormalities; congenital contractures; seizures; body tone abnormalities; movement abnormalities; swallowing abnormalities; possible developmental delay; possible visual impairment; and/or postnatal-onset microcephaly") it's important to understand how infections such as Zika might have the ability to affect cognitive and/or neurodevelopmental outcomes. What's also important too is the realisation that given the young age of the cohort, "the full spectrum of adverse outcomes related to congenital Zika virus infection is not yet known." So developmental delay for example, *could* eventually develop into something else, and why appropriate monitoring will continue through initiatives like the USZPIR.

From a cold, objective science perspective and without wishing to diminish the very human effects associated with this event, the 2016 Zika outbreak that struck the Americas provides an ideal opportunity to study our important interaction with the environment around us. It emphasises how facets of our environment can very much influence both physical and psychological health, particularly at critical times of development. A lesson that perhaps is transferable to many different neurodevelopmental labels [2]...

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[1] Rice ME. et al. Vital Signs: Zika-Associated Birth Defects and Neurodevelopmental Abnormalities Possibly Associated with Congenital Zika Virus Infection - U.S. Territories and Freely Associated States, 2018. MMWR Morb Mortal Wkly Rep. 2018 Aug 10;67(31):858-867.

[2] Lydholm CN. et al. Parental infections before, during and after pregnancy as risk factors for mental disorders in childhood and adolescence – a nationwide Danish study. Biological Psychiatry. 2018. Oct 1.

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Head size in autism is complicated

Size and growth are some pretty important concepts related to lots of different features of the human condition. Although universal connections related to health rarely (never?) exist, there are some interesting data linking small birth weight and later childhood intellectual development for example, as well as brain size and the intelligence quotient (at least to a degree). Size and growth tend to be determined by a variable combination of both genes and environment. This meta-analysis for example, showed how the physical environment affects various growth measures, height and weight, but perhaps not as much parameters such as head circumference. This leads me to the subject of this post - head size and autism - and some of the published research and its potential implications.

Macrocephaly is the technical term where head circumference is larger than about 2 standard deviations from the average (mean); the opposite condition being microcephaly, where head circumference is smaller. There are various reasons why a larger head may occur, such as an enlargement of the brain and cases of hydrocephalus (water on the brain). In most cases in infants and children, larger head size is thought to be governed by more genetic factors such as heredity or the presence of one or more various genetic disorders.

Macrocephaly has, down the years, been associated with some cases of autism spectrum conditions. Kanner first noted that some of his original cohort had larger heads (among other things). An observation which has subsequently been reported again and again and again with prevalence estimates of macrocephaly in autism ranging from approximately 10-30%. The data does suggest some degree of heritability linked to macrocephaly, although the relationship is not entirely straight forward and the heritability implications not immediately clear. In more recent years there has been some debate about macrocephaly and autism and how factors such as ethnicity might also show an effect. This study for example first published as an abstract at IMFAR 2009, based on an Israeli cohort found little evidence of elevated rates of macrocephaly in autism in comparison to asymptomatic controls.

Why might macrocephaly be important to autism? Well I mentioned that outside of heritability, generally macrocephaly is tied into one or more genetic conditions. The theory in autism is that such findings might indicate some genetic component and hence help point towards candidate areas of interest. To see this theory in action, readers may wish to have a look at these studies (here and here) on how macrocephaly from both a case study and group study point of view might help untangle a few research strands in such a heterogeneous condition. The 'endophenotypes' way of study is something which really is the future of autism research.

There are perhaps more immediate effects potentially tied into macrocephaly presenting in autism also. This study suggested specific autistic behaviours tend to be more severe in those with larger heads, including delays  in acquiring language; the language side of things however seems to be the source of some speculation. Uta Frith joins a number of other researchers in saying that macrocephaly may imply abnormal neural connectivity. One might also expect that a larger head may indicate a larger brain and hence the maturational issue of brain growth could be implicated. Certainly studies of total brain volume in autism seem to suggest some discrepancy with control populations, driven by things like an increased cortical surface area. Such studies also seem to point to a 'brain overgrowth' as potentially being present, at least during early infancy with lots of different areas of the brain involved. Thinking about this, I was reminded of some work I have heard discussed quite a few years ago about synaptic pruning in relation to autism and the various instruments of such pruning including the MHC and endogenous opioid peptides. Indeed the work of Zagon and McLaughlin is I think absolutely fascinating, particularly their characterisation of the zeta opioid receptor and their various studies on the effects of opioid antagonists such as naltrexone on rat postnatal development. I don't know if and how it might tie into these latest findings on synaptic pruning.

I think it is important also to note that larger head size is not exclusive to autism spectrum conditions. This paper reported similar trends in head size and various other growth parameters from non-autism controls with a psychiatric disorder. Importantly however they indicated that there may be subtle differences in the timing of measurements between autism and controls which might provide some clues for the underlying processes involved.

What we can ascertain from this collected body of work is that larger heads show more than a passing association to autism spectrum conditions, and perhaps tie into some elements of the presented condition including some interesting findings on serotonin. Having said that, the recent meta-analysis of neonatal factors in connection to autism included as part of this post suggesting that the connection to head circumference might not be all it has been cracked up to be, perhaps needs to be taken on board. What I would like to see is more information on is any link to important autism co-morbidities such as epilepsy and if such 'overgrowth' is confined to early infancy, and whether it is controlled by genes or environment (or both)?

Regarding size matters...