"abnormally high extra-axial cerebrospinal fluid (CSF) volume" and autism

"Increased extra-axial CSF [cerebrospinal fluid] volume is a reliable brain anomaly that has now been found in three independent cohorts, comprising both high-risk and normal-risk children with autism spectrum disorder."

So concluded the findings reported by Mark Shen and colleagues [1] following their study results - "case-control MRI study" results - enquiring whether "increased extra-axial CSF volume is found in a large, independent sample of children diagnosed with autism spectrum disorder, whether extra-axial CSF remains abnormally increased beyond infancy, and whether it is present in both normal-risk and high-risk children with autism."

This latest study from Shen et al follows a research theme [2], a quite long running research theme [3] by all accounts, observing that extra-axial CSF volume might be important to at least some autism. Increased extra-axial CSF volume is described as a brain anomaly insofar as representing a larger than expected volume of cerebrospinal fluid 'coating' the brain, or at least filling the extra-axial space sitting on top and around the brain. It's perhaps not surprising that this work has also included the words 'brain enlargement' in discussions given the physical effect that such increased volume might have.

This latest chapter in the extra-axial CSF volume research comes from a familiar research initiative - the UC Davis MIND Institute Autism Phenome Project - "a longitudinal analysis of children diagnosed with autism spectrum disorder and age-matched typically developing children." The Autism Phenome Project (APP) has already been discussed a few times on this blog for various research reasons (see here and see here). The APP also has something of an interest in brain enlargement appearing alongside regression too (see here). This time around "159 children with autism spectrum disorder (132 male, 27 female) and 77 with typical development (49 male, 28 female) underwent MRI scans." Researchers were looking at extra-axial CSF volume as well as things like brain volume and head circumference. Alongside, various other behavioural measures and questionnaires on things like sleep were included.

"The autism spectrum disorder group had an average of 15·1% more extra-axial CSF than controls after accounting for differences in brain volume, weight, age, and sex." Further: "Both extra-axial CSF volume... and brain volume... uniquely contributed to enlarged head circumference in the autism spectrum disorder group." Authors also reported that: "Increased extra-axial CSF volume was associated with greater sleep disturbances... and lower non-verbal ability."

As per the opening quote to this post, this is not the first time that some of those findings have been reported in the science arena and I very much doubt that it will be the last time either. The authors also talk about such MRI findings in light of "normal risk (ie, from simplex families) or high risk (ie, from multiplex families)" for autism and applying "a previously validated machine learning algorithm based on extra-axial CSF volume, brain volume, age, and sex" but I'd like to see a lot more data before venturing further into these aspects. Not least, data covering the question of 'why?'. From the previous studies in this area, some hypotheses have been put forward, for example: "[as] CSF circulates through the developing brain, it removes inflammatory cytokines and proteins secreted by neurons that can otherwise accumulate and have a pathological effect on brain development." Such a hypothesis needs further research but is perhaps complementary to other discussions about 'neuroinflammation' in the context of autism (see here).

We await further investigations.

----------

[1] Shen MD. et al. Extra-axial cerebrospinal fluid in high-risk and normal-risk children with autism aged 2-4 years: a case-control study. Lancet Psychiatry. 2018 Sep 27. pii: S2215-0366(18)30294-3.

[2] Shen MD. et al. Increased Extra-axial Cerebrospinal Fluid in High-Risk Infants Who Later Develop Autism. Biol Psychiatry. 2017 Aug 1;82(3):186-193.

[3] Shen MD. et al. Early brain enlargement and elevated extra-axial fluid in infants who develop autism spectrum disorder. Brain. 2013;136(9):2825-2835.

----------

"a low prevalence of definite pathology in children with autism spectrum disorder undergoing brain MRI"

The quote: "a low prevalence of definite pathology in children with autism spectrum disorder undergoing brain MRI [magnetic resonance imaging]" heading up today's post is taken from the paper by Alison Cooper and colleagues [1] who among other things, examined whether MRI picked up anything 'useful' when it came to autism / autism spectrum disorder (ASD) in their cohort. MRI, by the way, refers to the fantastic imaging technology that provides those rather detailed pictures of our inner body workings including that related to the brain.

The main caveat to the observation that MRI probably isn't going to reveal any sort of autism-specific 'structural brain signature' anytime soon is that comorbidity (whether symptoms or conditions) might count: "In children with abnormal neurologic examination or preexisting finding, seizures, or headaches, one may consider performing brain MRI given the higher prevalence of pathology." This is probably not unexpected given the 'effects' that epilepsy can sometimes have on brain structure for example and how epilepsy is not an unstrange diagnostic bedfellow when it comes to quite a proportion of cases of autism (see here).

I don't want to dwell too much on the Cooper findings but rather set them in the context of other research where brain imaging technologies have been talked about with autism in mind. Specifically, I want to mention an important point about how using the label 'autism' to somehow denote some grand homogeneous presentation covering everyone impacts imaging research and practice just as much as it does every other research/clinical aspect of autism: use of the term 'autism' is not a good starting point (see here). The idea that 'functioning' in autism (I know, not a good descriptive term but the only one we have at the moment) might impact brain MRI findings for example, has been discussed on this blog before suggesting that those with so-called high-functioning autism tend to show little in terms of MRI results (see here) whilst those towards the more severe end of the autism spectrum may tend to more frequently show a little more (see here). You might argue that epilepsy for example, is more likely to follow those towards the more severe end of the autism spectrum (who are also significantly more likely to present with learning/intellectual disability) and this could potentially play a role in the pathology detected. One might also see this as yet more evidence for the plurality of autism (see here).

Although not a 'brain man' and hence no expert on brain imaging, I should also bring in the distinction between MRI and fMRI [functional] and how these might relate to autism. fMRI is basically a type of scan that can be performed using an MRI scanner to assess something other than just brain structure - normally blood flow (or at least blood oxygen content). The idea is that changes in blood flow/constitution may indicate changes in brain activity; something which is linked to all that chatter about brain functional connectivity. fMRI is something that is on the 'up' when it comes to autism research and other areas, the idea being that more subtle pathology could be present when it comes to function over structure at least for some on the autism spectrum perhaps mirroring the whole gene expression/function over structural genetics trend that we are also seeing in autism research and beyond.

Personally, I'm still a little cautious about this whole area and the need to avoid sweeping generalisations about how over- or under-connectivity in this brain area or that might be autism-specific. I don't doubt that MRI and fMRI are going to be useful diagnostic tools for some (indeed, useful to rule out identified organic findings that could be contributory to some autism) but I'm not convinced that many generalisable answers are going to be forthcoming very quickly.

To close, and remaining on the topic of brain imaging, a rather concise view of the recent ups-and-downs of fMRI including the words "I need a full length Atlantic Salmon. For science." Stat.

----------

[1] Cooper AS. et al. The Implications of Brain MRI in Autism Spectrum Disorder. J Child Neurol. 2016 Sep 14. pii: 0883073816665548.

----------

Cooper AS, Friedlaender E, Levy SE, Shekdar KV, Bradford AB, Wells KE, & Mollen C (2016). The Implications of Brain MRI in Autism Spectrum Disorder. Journal of child neurology PMID: 27629267

Consider congenital cytomegalovirus infection when it comes to autism

"The finding lends some further support for congenital CMV [cytomegalovirus] being one of the many aetiologies underlying autism spectrum disorder with intellectual disability."

That was the conclusion reached by Mona-Lisa Engman and colleagues [1] from Sweden following their study looking to "evaluate the prevalence of congenital cytomegalovirus infection (CMV) in a representative sample of children with autism spectrum disorder." Carrying some rather distinguished company as part of the authorship list (see here and see here for example), researchers analysed that most important (and under-rated in my opinion) of resources, the newborn dried blood spot (see here), to screen for "CMV DNA using TaqMan-polymerase chain reaction."

"One of the 33 children with autism spectrum disorder and intellectual disability - 3% of that group - had congenital CMV infection." Allowing for the small group included for study and the isolated case of congenital CMV infection detected, the corresponding general population estimate for congenital CMV in Sweden (0.2%) was surpassed leading to the call for "similar studies with much larger samples."

I've talked about congenital CMV infection and autism before on this blog (see here) and how some studies [2] have talked about infection rates quite a bit in excess of that seen in the general population when examining children diagnosed with autism. I've got little more to say on this topic aside from the idea that screening for congenital CMV should perhaps be expanded as and when autism is diagnosed. As per other research from Engman [3] congenital CMV might also carry some specific morphological changes to the brain which could also be included for further inspection, particularly in light of the findings from Erbetta and colleagues [4] covered in a recent post (see here).

And then to mechanisms of effect...

Music: Kate Bush and Army Dreamers. And if you're really interested (as I was), The Kate Bush Story: Running Up That Hill.

----------

[1] Engman ML. et al. Prenatal acquired cytomegalovirus infection should be considered in children with autism. Acta Paediatr. 2015 Apr 21.

[2] Sakamoto A. et al. Retrospective diagnosis of congenital cytomegalovirus infection in children with autism spectrum disorder but no other major neurologic deficit. Brain Dev. 2015 Feb;37(2):200-5.

[3] Engman ML. et al. Congenital cytomegalovirus infection: the impact of cerebral cortical malformations. Acta Paediatr. 2010 Sep;99(9):1344-9.

[4] Erbetta A. et al. Low-Functioning Autism and Nonsyndromic Intellectual Disability: Magnetic Resonance Imaging (MRI) Findings. J Child Neurol. 2015 Apr 20.

----------

Engman ML, Sundin M, Miniscalco C, Westerlund J, Lewensohn-Fuchs I, Gillberg C, & Fernell E (2015). Prenatal acquired cytomegalovirus infection should be considered in children with autism. Acta paediatrica (Oslo, Norway : 1992) PMID: 25900322

Magnetic Resonance Imaging (MRI) findings in severe autism

"The aim of this study was to evaluate the frequency of neuroradiologic abnormalities in low-functioning autistic children compared to Intellectual Quotient and age-matched nonsyndromic children, using the same set of magnetic resonance imaging (MRI) sequences."

Accepting that the term 'low-functioning autism' is not one that I would personally use (indeed I'm not exactly enamoured by the term 'high-functioning' either), the results of the study by Alessandra Erbetta and colleagues [1] are briefly served up for your reading delight today. Mirroring other findings from this group [2], authors reported that: "MRI was rated as abnormal in 44% of autistic and 54% of children with intellectual disability" surveyed. Further: "The main results were mega cisterna magna in autism and hypoplastic corpus callosum in intellectual disability."

I'm not a 'brain man' insofar as having any experience of MRI or the 'neuroradiologic' findings reported by Erbetta on either publication occasion. I do however find the idea that MRI or similar imaging methods might be indicated when someone presents with 'severe' autism (severe as in severely impacting on both clinical presentation and interfering with the acquisition of adaptive skills) as being quite a sensible approach. Mega cisterna magna - significantly enlarged CSF retrocerebellar cisterns in the posterior fossa with normal cerebellar morphology (apparently) - is still the source of some debate as to exactly what such a finding means. Zimmer and colleagues [3], looking through almost 20,000 "consecutive CT/MRI of the brain" found 49 cases of "isolated mega cisterna magna" in their cohort. Despite presenting with "overall normal cognitive functioning" they suggested that such a finding might have some influence on aspects of memory and verbal fluency. I say all this acknowledging that the brain is a mighty complex organ that is also surprisingly flexible in terms of the various duties it performs. A possible link between mega cisterna magna and congential cytomegalovirus (CMV) infection [4] is also intriguing from an autism perspective (see here) as per the recent paper from Engman and colleagues [5].

The MRI results of those with severe autism also need to be compared against the data amassed from those perhaps not falling into that 'severe autism' categorisation. I've previously covered the paper by Roma Vasa and colleagues [6] (open-access) (see this post) who concluded that in 90% of cases of 'high-functioning' autism, there was very little too see from a brain imaging perspective. The more recent paper from Koolschijn et al [7] questioning the idea that autistic traits are specifically linked to brain morphometry adds to the idea that looking for a 'brain signature' for 'all autism' is probably not going to yield too many generalisable results, but rather the focus needs to be on endophenotypes.

Music: Daft Punk - Da Funk.

----------

[1] Erbetta A. et al. Low-Functioning Autism and Nonsyndromic Intellectual Disability: Magnetic Resonance Imaging (MRI) Findings. J Child Neurol. 2015 Apr 20. pii: 0883073815578523.

[2] Erbetta A. et al. Neuroimaging findings in 41 low-functioning children with autism spectrum disorder: a single-center experience. J Child Neurol. 2014 Dec;29(12):1626-31.

[3] Zimmer EZ. et al. Clinical significance of isolated mega cisterna magna. Arch Gynecol Obstet. 2007 Nov;276(5):487-90.

[4] Dogan Y. et al. Intracranial ultrasound abnormalities and fetal cytomegalovirus infection: report of 8 cases and review of the literature. Fetal Diagn Ther. 2011;30(2):141-9.

[5] Engman ML. et al. Prenatal acquired cytomegalovirus infection should be considered in children with autism. Acta Paediatr. 2015 Apr 21.

[6] Vasa RA. et al. Normal rates of neuroradiological findings in children with high functioning autism. J Autism Dev Disord. 2012 Aug;42(8):1662-70.

[7] Koolschijn PC. et al. Are Autistic Traits in the General Population Related to Global and Regional Brain Differences? J Autism Dev Disord. 2015 Apr 7.

----------

Erbetta A, Bulgheroni S, Contarino VE, Chiapparini L, Esposito S, Annunziata S, & Riva D (2015). Low-Functioning Autism and Nonsyndromic Intellectual Disability: Magnetic Resonance Imaging (MRI) Findings. Journal of child neurology PMID: 25895913

MRI and (high-functioning) autism

I've nattered before about trends in autism research and how even across a relatively short period of time, the focus of autism research can change as interests and funding priorities change. The concept of an 'autism gene' for example seems like a increasingly distant memory as the heterogeneity of autism and its comorbidities combines with the complexity of the human genome to illustrate that one gene does not equal one condition but rather multiple genes work together over several processes and also show some connection to the environment of their 'user'. We are all a product of our genes and their mutations and we all carry our own individual genetic nuances.

Whilst genetic research into autism and lots of other conditions is still on-going, one of the other big areas of research focus currently is that of the application of imaging technologies to autism spectrum conditions. I assume most people have heard about MRI (Magnetic Resonance Imaging) and seen the pictures of those Star Trek body scanners and the spectacularly clear images they produce of our inner bodily workings. The application of MRI and its counterpart (functional) fMRI to conditions like autism where the brain is an important area of interest is seemingly growing by the day as evidenced by the large numbers of papers being published in this area. If you were to apply all these findings universally, you might well think that autism is absolutely, undoubtedly, 100% linked to structural issues in the brain. Heck, why don't we just diagnose autism by MRI?

Well, hold that thought for a moment.

An interesting paper was recently published by Vasa and colleagues* at the Kennedy Krieger Institute. The paper is open-access until 31st December 2011 (here). The main message from the study is that after reviewing the neuroradiological findings from quite a large proportion of children with autism (high-functioning autism) gathered over a 9 year period, about 90% of children showed no significant brain abnormality. That's right, you heard correctly, roughly 1 in 10 children with high-functioning autism had something picked up on their MRI, which was actually the same ratio for typically developing controls and slightly less than the figure for children with ADHD.

Assuming that you either did not want to or could not access the full-text of this paper, here is a summary:

• Structural data from MRI scans for children with autism (n=73) were compared with data from children with ADHD (n=107) and asymptomatic controls (n=144). When I say 'autism' these were children who were either diagnosed with high-functioning autism (32/73) or Asperger syndrome (41/73) and lumped together partly "because of on-going discussions that these two disorders may not exist as separate entities" (their words not mine). I should also add that quite a few comorbidities were also isolated in the autism group including ADHD(?), OCD and things like conduct disorder.
• I can't pretend to be able to give you the authoritative low-down on the MRI methods employed. My Mr Men reading suggests that scans were not necessarily done all on the same instrument but certain protocols on where to look were followed for each case. These included a set of 11 predefined lesion categories taken from the research literature alongside systematic ways to code for these lesions. Going back to the notion of physicians as artists, this also seemingly applies to neuroradiologists in terms of their coding of what may or may not be considered 'normal' and 'abnormal'. Consensus was reached on cases where the findings were a little bit fuzzy.
• Results: when looking at the sample groups as a whole, nearly 90% of participants either showed nothing at all in terms of 'abnormal' features or showed only normal variant findings. For the autism group, 11% showed one or more abnormal finding; for the ADHD group this was 12.1% and the control group, 11.1%. The most frequent finding for the autism group was in the category of focal white matter lesions (n=3, 4.1%). Having said that similar focal white matter lesions were found in 3 children with ADHD (2.8%) and 8 of the control group children (5.6%) also. As per the lack of statistical difference, the results in all areas seemed to be very similar across the groups.

The main strength of this study is that it includes data for quite a large group of children including control samples. Ages were matched but gender once again was more male-skewed in the autism group than the other groups which could potentially be a confounding variable. One should also bear in mind that this was a study looking at children towards the more able end of the autism spectrum so we can't generalise too much to those with a more severe presentation or with learning disability as a comorbidity. Bearing in mind that operational criteria were set for where and what to look for via MRI, there are some interesting points to take from this trial.

First, brain findings from MRI in relation to high-functioning autism don't yet appear to be particularly useful as objective diagnostic markers. That's not to say that they won't in future as the hardware and software get more complex and sensitive, but for now we wait. I was interested to see that focal white matter lesions came up given the link (and my obsession) between such features and coeliac (celiac) disease (CD) and other inflammatory bowel conditions; I wonder how many kids in this study were screened for potential 'dietary' issues particularly with the recent CD-ADHD paper in mind?

Second, much like the old one-gene hypothesis of autism, a picture seems to be emerging whereby no one brain area or MRI findings seems to be tied into the presentation of autism - all cases of autism. Yes, I take your point about the recent profrontal cortex study by Eric Courchesne and that deserves further work given that it was based on a very small participant sample. As far as I am aware however MRI scans cannot currently count neurons(?) so we are perhaps looking at different things in relation to brain findings in autism. Again with the biological phenotypes study fresh in my mind, it is not inconceivable that various brain areas might be involved in certain types of autism or at least contributory to certain presented features.

Finally, the brain is a pretty remarkable piece of kit. One of the best things about the brain is its adaptability; so when one part of it malfunctions for whatever reason, other parts of it are often able to take up the reins. Potential examples of this process are abound in the literature. What this might imply is that even though there may be structural issues detected, that does not necessarily translate into aberrant functioning. The recent remarkable comeback shown by Congresswoman Giffords is probably the best example of just how resilient the brain can be. Combined also with the fact that brain biochemistry might be an important feature to look at, we perhaps need to take a more holistic look at the brain with imaging technologies as part of the repertoire for autism research but not necessarily the sole agent of this important area of investigation.

To finish, a link to a band who just got a worthy entry into the Brit pop hall of fame.. Blur.

* Vasa RA. et al. Normal rates of neuroradiological findings in children with high functioning autism. JADD. November 2011.