Genes 2 Brains 2 Mind 2 Me

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This year, my 5 year-old son and I have passed many afternoons sitting on the living room rug learning to read.  While he ever so gradually learns to decode words, eg. “C-A-T”  sound by sound, letter by letter – I can’t help but marvel at the human brain and wonder what is going on inside.  In case you have forgotten, learning to read is hard – damn hard.  The act of linking sounds with letters and grouping letters into words and then words into meanings requires a lot of effort from the child  (and the parent to keep discomfort-averse child in one place). Recently, I asked him if he could spell words in pairs such as “MOB & MOD”, “CAD & CAB”, “REB & RED” etc., and, as he slowly sounded out each sound/letter, he informed me that “they are the same daddy“.  Hence, I realized that he was having trouble – not with the sound to letter correspondence, or the grouping of the letters, or the meaning, or handwriting – but rather – just hearing and discriminating the -B vs. -D sounds at the end of the word pairs.  Wow, OK, this was a much more basic aspect of literacy – just being able to hear the sounds clearly.  So this is the case, apparently, for many bright and enthusiastic children, who experience difficulty in learning to read.  Without the basic perceptual tools to hear “ba” as different from “da” or “pa” or “ta” – the typical schoolday is for naught.

With this in mind, the recent article, “Genetic determinants of target and novelty-related event-related potentials in the auditory oddball response” [doi:10.1016/j.neuroimage.2009.02.045] caught my eye.  The research team of Jingyu Liu and colleagues asked healthy volunteers just to listen to a soundtrack of meaningless beeps, tones, whistles etc.  The participants typically would hear a long stretch of the same sound eg. “beep, beep, beep, beep” with a rare oddball “boop” interspersed at irregular intervals.  The subjects were instructed to simply press a button each time they heard an oddball stimulus.  Easy, right?  Click here to listen to an example of an “auditory oddball paradigm” (though not one from the Liu et al., paper).  Did you hear the oddball?  What was your brain doing? and what genes might contribute to the development of this perceptual ability?

The researchers sought to answer this question by screening 41 volunteers at 384 single nucleotide polymorphisms (SNPs) in 222 genes selected for their metabolic function in the brain.  The team used electroencephalogram recordings of brain activity to measure differences in activity for “boop” vs. “beep” type stimuli – specifically, at certain times before and after stimulus onset – described by the so-called N1, N2b, P3a, P3b component peaks in the event-related potentials waveforms.  Genotype data (coded as 1,0,-1 for aa, aA, AA) and EEG data were plugged into the team’s home-grown parallel independent components analysis (ICA) pipeline (generously provided freely here) and several positives were then evaluated for their relationships in biochemical signal transduction pathways (using the Ingenuity Pathway Analysis toolkit.  A very novel and sophisticated analytical method for certain!

The results showed that certain waveforms, localized to certain areas of the scalp were significantly associated with the perception of various oddball “boop”-like stimuli.  For example, the early and late P3 ERP components, located over the frontal midline and parieto-occipital areas, respectively, were associated with the perception of oddball stimuli.  Genetic analysis showed that several catecholaminergic SNPs such as rs1800545 and rs521674 (ADRA2A), rs6578993 and rs3842726 (TH) were associated with both the early and late P3 ERP component as well as other aspects of oddball detection.

Both of these genes are important in the synaptic function of noradrenergic and dopaminergic synapses. Tyrosine hydroxylase, in particular, is a rate-limiting enzyme in catecholamine synthesis.  Thus, the team has identified some very specific molecular processes that contribute to individual differences in perceptual ability.  In addition to the several other genes they identified, the team has provided a fantastic new method to begin to crack open the synaptic complexities of attention and learning.  See, I told you learning to read was hard!

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