Neonatal pain 'causing' autism? I'm not so sure...

I wasn't actually going to talk about the paper by Jin Hwan Lee and colleagues [1] on this blog and the suggestion that: "severe inflammatory pain in neonates and persistent inflammatory reactions may predispose premature infants to development delays and psychiatric disorders including ASD [autism spectrum disorder]." I changed my mind however when a piece appeared on-line titled: 'New Autism Dispute: Is Circumcision a Factor?' with mention of 'ritual circumcision and autism' being made based on some research a while back (see here) and a possible "pain-autism connection" being introduced.

From the outset I'll admit that I'm pretty unconvinced about sweeping notions that 'pain' in early infancy can later manifest as a complicated condition like autism. My viewpoint is based on the idea that (a) pain (different types of pain) is a fairly regular passenger for nearly all of us over our lifetime and (b) unfortunately, whilst some young infants do experience significant pain during their earliest days, not all go on to develop autism or other behavioural labels as a result of their pain. I'm not saying that pain can't have longer term effects when severe enough, just that plausible evidence of a link specifically with autism is currently quite sparse.

Bearing in mind my view, the Lee paper describes how rats were the participants in question when it came to their study on whether "repeated inflammatory pain experienced by preterm/premature babies could lead to acute and delayed brain damage that might be associated with social and behavioral abnormalities at the juvenile age." Aside from utilising an animal model, you'll note there is mention of the word 'inflammatory' in their hypothesis, which already implies that pain is not the only variable under investigation. I'll come back to this shortly.

Said rat pups whose age modelled the "brain developmental stage to human preterm infants" were rather unpleasantly given an injection of formalin (a fairly standard method of stimulating inflammatory pain) or saline and various measures including behavioural and physiological were assessed. Unfortunately, those physiological measures involved the rat brain so animals were eventually sacrificed.

Results: well, there were quite a few of them. Perhaps unsurprisingly, formalin treated rats "travelled less distance and showed a lower velocity than control rats" as a consequence of receiving their injection in their hindpaw. Behaviourally, the formalin treated group were also subsequently described as showing "more time engaging in repetitive behaviors such as self-grooming, repetitive jumping, and spontaneous muscle twitching" and "showed sleeping disorder, exhibited as marked increases in bouts of awake and sleep activities." Increases in various cytokines - chemical messengers of the immune system - were noted in treated rats: "increased levels of inflammatory cytokines, TNF-α, and IL-1β in the blood as well as in the brain, and increased microglia in the brain." The authors also noted "significant cell death" in parts of the brain in those treated rats. Interestingly however: "an anti-inflammation treatment using indomethacin (10 mg/kg, i.p.) at the time of formalin injections suppressed inflammatory responses and neuronal cell death." Finally: "the inflammatory pain led to long-term regulation of ASD [autism spectrum disorder]-associated genes NRXN1, FMR1, and oxytocin/oxytocin receptor in the brain."

Going back to point made a few paragraphs back about the concept of 'inflammation' or inflammatory processes/responses potentially being more important than 'pain' in these results, you can perhaps see what I was trying to get at. Indeed, in their discussion the authors note: "inflammation and pain are distinct insults although may sometimes reciprocal. The pathogenic effects of pain and inflammation may play distinctive roles in ASD, while this is unclear based on available data." Certainly, there is a growing recognition that inflammation/inflammatory processes do seem to show an important relationship to at least some autism (see here and see here for example) although there are some details that still need to be investigated. As part of a wider scheme of research implicating immune-related processes (see here) I'm tempted to err on the side of inflammatory issues being more pertinent to the Lee and other results over and above any 'memory of pain' having a large effect. I say all that accepting that rats are rats not people and that there is still a degree of not knowing...

In terms of the coverage of the paper by Frisch & Simonsen [2] talking about ritual circumcision potentially being associated with an increased risk for autism and 'a pain-autism connection', I'm gonna again link you back to what I said the last time I covered this work (see here). Namely, that studies of association where only a few variables are analysed together should always be treated with caution; also bearing in mind some important details were missing from their analysis on that occasion: "Unfortunately, we had no data available on analgesics or possible local anaesthetics used during ritual circumcisions in our cohort" so other potentially relevant hypotheses could still exert an effect [3].

Pain can very much be a feature of autism (see here) but on the question of pain 'causing' or leading to autism, I'm yet to be convinced with the currently available evidence...

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[1] Lee J-H. et al. Neonatal inflammatory pain and systemic inflammatory responses as possible environmental factors in the development of autism spectrum disorder of juvenile rats. Journal of Neuroinflammation. 2016; 13: 109.

[2] Frisch M. & Simonsen J. Ritual circumcision and risk of autism spectrum disorder in 0- to 9-year-old boys: national cohort study in Denmark. JRSM. 2015. 8 January.

[3] DiMaggio C. et al. Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort. Anesth Analg. 2011 Nov;113(5):1143-51.

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Lee JH, Espinera AR, Chen D, Choi KE, Caslin AY, Won S, Pecoraro V, Xu GY, Wei L, & Yu SP (2016). Neonatal inflammatory pain and systemic inflammatory responses as possible environmental factors in the development of autism spectrum disorder of juvenile rats. Journal of neuroinflammation, 13 (1) PMID: 27184741