Friday, June 7, 2013

Breastfeeding and brain development: the new data



So technically, I am on a blogging/twitter break, to allow me to focus on fieldwork and papers. However, yesterday was such an awesome day for human lactation research, I really had to check back in. Yesterday, MelissaBartick released an awesome piece showing the maternal health consequences and costs of not breastfeeding, following on earlier work looking at the economic side. And, Sean Deoni and colleagues reported differences in the white matter myelin content of specific brain areas between exclusively breastfed, formula fed, and infants receiving both during the first months of life. The paper was reported in Science News and I immediately pulled the actual paper. It started a journey of discovery, and the story is far more detailed – and interesting – than the Science News article reported. There are actually several papers of interest here, each building on the work of the other in addressing the common theme: are the brains of breastfed and formula fed infants different and if so, how permanent are these differences?
Figure 1: A reference map of the brain. Source: http://www.willamette.edu/~gorr/classes/cs449/brain.html
Prior research has demonstrated that breastfeeding infants have increased IQ and cognitive performance compared to formula fed infants; these differences are seen even in low resource populations, where maternal education and household income tend to be inversely associated with breastfeeding duration. It was speculated that certain fatty acids in human milk, specifically the very long chain essential fatty acids Docosahexaenoic acid (DHA) and Arachidonic acid (AA), may contribute to these differences. DHA and AA are preferentially used in neural myelin sheaths. They have excellent neural conductivity. Studies have found that DHA makes up about 20% of the fatty acids in the brain, although this varies by region (Xiao et al., 2005), and probably population as well, although we do not know for certain. However, we do not know if it is the DHA, if it is the cholesterol in milk, as Deoni (2013) also proposed, or hormones in milk (known or unknown) that may be contributing to these differences. So for the moment, we will leave DHA aside, and focus on the brain differences between breastfed and formula fed infants. 

There are a handful of useful papers here: today I will focus on three. These are Deoni et al. 2013 (Deoni, S.C.L., et al., Breastfeeding and early white matter development: A cross-sectional study, NeuroImage (2013),http://dx.doi.org/10.1016/j.neuroimage.2013.05.090), Kafouri et al., 2013 (International Journal of Epidemiology 2013;42:150–159; doi:10.1093/ije/dys172) and Khedr et al., 2004 (Acta Paediatrica 93:734-738).  Infant brains, by the way are amazing! Our fastest rates of brain growth are during gestation and the first two years of life. During this time, the brain consumes a huge amount of energy – and will reach about 80% of adult size by age two. Below is a map of the brain. I found it quite useful to keep track of what was going on where.

The most recent study, by Deoni et al., (2013) looks at white matter structure in the brains of 3 groups of 133 kids. Groups are defined by feeding status at 3 months of age: exclusively breastfed, formula fed, both. At the time of measurement, each group had a mean age of around 775 days – or just over 2 years of age. There were 85 kids in the EBF group, 38 in the combo group, and 51 in the exclusive formula feeding group. The children were scanned for 19-24 minutes using multicomponent relaxation magnetic resonance imaging (mcDESPOT, Figure 1) during natural sleep (no drugging!). McDESPOT allows for the estimation of the white matter content of neural tissue by measuring the amount of myelin associated water fraction. 
Figure 2:
: Graphic illustrating the principles behind mcDESPOT. Image is by Sean Deoni, the study author. 
The major findings were that the breastfed infants had greater white matter growth in late maturing areas of the brain. This suggests that the absence of something in formula that is present in human milk may have delayed the brain growth in the mixed feed and formula feed kids. Key areas with increased VFm were the frontal brain, left temporal lobe, corpus callous, internal capsule, corticospinal tract, cerebellum, and left optic radiation. By comparison, infants receiving formula had increased white matter in the occipital lobe, right optic radiation, and right internal capsule.
Figure 3: How mcDESPOT looks in my mind. Source: http://www.wtfnews.org/general/kid-freaked-out-by-ronald-mcdonald/
Confused yet? Me too. I read this with a map of the brain and a lot of patience. Essentially, what Deoni et al., found was that the areas of the brain that are considering late maturing – and associated with higher order functions (such as performance on IQ tests, social and emotional functioning) had greater amount of white matter in infants exclusively breastfed to three months, and that these differences could be detected at age 2, along with high receptive language scores. There was also an association between breastfeeding duration and white matter content of specific brain regions. The right inferiorfrontal and corticospinal tract had a 30% increase in white matter compared to those same areas in formula fed infants, and longer breastfeeding durations (600 vs 200 days) were associated with greater white matter content of the Brodmann’s area.
The authors speculated that the greater amounts of white matter in the brains of breastfed infants might persist into later life. 

This follows on Kafouri et al., (2013), who were also investigating the association between breastfeeding and brain development. However, Kafouri et al., are slightly later in time – specifically, they are looking at brain scans from 571 adolescents (12-18) and testing for differences in the cortical thickness of specific areas of the brain associated with cognitive function and performance on the Wescher Intelligence Scale Test. Key areas were identified from 23 prior studies and 30 analyses and were limited to 328 foci in 36 “IQ related regions” of the brain. All analyses were adjusted for potential confounders: education and income, and prenatal exposures such as maternal or second hand smoking, alcohol use, parity, birth weight, and infant sex. 
Figure 4: The process behind mapping cortisol thickness. Source: http://www.martinos.org/neurorecovery/technology.htm
Among adolescents, exclusive breastfeeding duration (EBF) had a positive association with cortical thickness in the superior and inferior parietal lobes. There were no differences by EBF duration in the front eye field, medial or ventrolateral prefrontal cortex, or occipital cortex. EBF duration was also associated with increased performance on the full IQ test. However, there was no association between cortical thickness in the superior and inferior parietal lobes and performance on the Wescher IQ test. Overall, the main finding was the increased cortical thickness in the parietal lobes with limited evidence for a dose dependent association between breastfeeding duration and cortical thickness. 

Our blast from the past is Khedr et al., 2004, specifically looking at neurological maturation between breastfeed and formula fed infants at age 1. In a sample of 53 infants, 30 breastfed and 23 formula fed, they reported shorter latencies in the breastfed infants compared to the formula fed infants on two parameters: visual and auditory, but not somatosensory. Essentially, the infants who were breastfed had more mature visual and auditory responses. This makes sense, as the somatosensory system is established prior to birth and postnatal feeding may have minimal influences. 

So what does it all mean? Well, it likely means that the absence of something in formula has long term influences on the neurological development of children, and that some of these differences persist at least into adulthood. And for a first few sentences into what this research will become, it is pretty cool stuff. For many years, researchers have argued about what in milk is associated with the decrease in risk of obesity and related metabolic conditions in breastfed infants. Now, we get to argue about what in milk is associated with the increased amount of white matter and cognitive thickness. And maybe it is DHA, but what we know about DHA is also pretty limited. Before we go jumping on the DHA bandwagon, the DHA content of American women’s milk is actually quite low (Figure 5) compared to the rest of the world. 
Figure 5: DHA in the milks of the world.
The DHA content of US women is actually quite low.  Take a supplement. We are also sad that our data for the Philippines is not on here. Source: http://www.dhababy.com/Infants/BreastisBest.aspx

We could all probably use more DHA in our diets, and maybe we should even recommend that reproductive aged women take a DHA supplement (fish oil) like we recommend folic acid. If it is DHA, that is an easy enough fix – the addition of DHA to infant formula a few years ago provides an opportunity to test the hypothesis that it is DHA by doing a similar set of analyses on breastfed, DHA fortified, and non-DHA fortified formula users. If two groups do not look like the others, you have some interesting results. DHA formula and breastfeeding grouping together? Hooray! It is DHA. The two formula groups lumping together – it is something else, or many, many something elses in the milk – or even the act of feeding. And of course, getting the milk would be awesome as well, because then you could look at the brain and the fatty acids and hormones in the milk (Maybe milk sugars are important? Maybe hormones?). And doing a longitudinal study, starting close to birth and following infants through a year or two. Oh yeah, and there are some gene polymorphisms (FADS) that appear to be involved in fatty acid content of milk and infant cognition as well (Steer et al., 2010).

In summary: there is some new evidence suggesting that breastfeeding is associated with improved growth in white matter in early life, and increased cortical thickness that persists at least until adolescents. However, how these factors change longitudinally is unknown, and what it is in milk that may be associated with normal brain maturation (because breastfeeding is the default feeding condition; infants evolved drinking human milk) is also unknown. But there is a lot of material here, and it will be very interesting to see where it goes next. 

References
Brion MJ, Lawlor DA, Matijasevich A, Horta B, Anselmi L, Ara├║jo CL, Menezes AM, Victora CG, Smith GD. 2011. What are the causal effects of breastfeeding on IQ, obesity and blood pressure? Evidence from comparing high-income with middle-income cohorts. Int J Epidemiol. 2011 Jun;40(3):670-80. doi: 10.1093/ije/dyr020.
Deoni SC, Dean DC 3rd, Piryatinksy I, O'Muircheartaigh J, Waskiewicz N, Lehman K, Han M, Dirks H. 2013 Breastfeeding and Early White Matter Development: A Cross Sectional Study. Neuroimage. May 27. doi:pii: S1053-8119(13)00592-2. 10.1016/j.neuroimage.2013.05.090. [Epub ahead of print]
Kafouri S, Kramer M, Leonard G, Perron M, Pike B, Richer L, Toro R, Veillette S, Pausova Z, Paus T. 2013. Breastfeeding and brain structure in adolescence. Int J Epidemiol. 42(1):150-9. doi: 10.1093/ije/dys172. Epub 2012 Nov 21.
Khedr EM, Farghaly WM, Amry S, El-Din, Osman, AA. 2004. Neural maturation of breastfed and formula-fed infants. Acta Paediatrica. 93(6): 734-738.
Steer CD, Davey Smith G, Emmett PM, Hibbeln JR, Golding J. 2010. FADS2 polymorphisms modify the effect of breastfeeding on child IQ. PLoS One. 2010 Jul 13;5(7):e11570. doi: 10.1371/journal.pone.0011570.
Xiao Y, Huang Y, Chen ZY. 2005. Distribution, depletion and recovery of docosahexaenoic acid are region-specific in rat brain. Br J Nutr 94(4):544-50.