Behavioural discrimination of noxious stimuli in infants is dependent on brain maturation

Abstract

Changes in facial expression are an essential form of social communication and in nonverbal infants are often used to alert care providers to pain-related distress. However, studies of early human brain development suggest that premature infants aged less than 34 weeks' gestation do not display discriminative brain activity patterns to equally salient noxious and innocuous events. Here we examine the development of facial expression in 105 infants, aged between 28 and 42 weeks' gestation. We show that the presence of facial expression change after noxious and innocuous stimulation is age-dependent and that discriminative facial expressions emerge from approximately 33 weeks' gestation. In a subset of 49 infants, we also recorded EEG brain activity and demonstrated that the temporal emergence of facial discrimination mirrors the developmental profile of the brain's ability to generate discriminative responses. Furthermore, within individual infants, the ability to display discriminative facial expressions is significantly related to brain response maturity. These data demonstrate that the emergence of behavioural discrimination in early human life corresponds to our brain's ability to discriminate noxious and innocuous events and raises fundamental questions as to how best to interpret infant behaviours when measuring and treating pain in premature infants.

Figure 1.

Facial expression and brain activity discrimination emerges with increasing gestational age. (A) The proportion of infants who displayed facial expressions after noxious stimulation (red) and innocuous stimulation (blue) according to gestational age. Proportions were calculated in 2-week intervals, with intervals overlapping by 1 week. The fit from a generalised linear model (solid lines) and 90% confidence intervals (dashed lines) are overlaid. The bottom colour bar indicates the P-values for the difference in proportions between the 2 groups calculated using Gaussian process modelling. The proportion of infants younger than 32 weeks' gestation who responded to the noxious stimuli shows substantial overlap with the proportion who responded to innocuous stimulation (P > 0.1), whereas in infants older than 33.9 weeks' gestation, infants are significantly more likely to display facial expressions after noxious stimulation compared with innocuous stimulation (P < 0.01, Gaussian process model). (B) Infants younger than 32 weeks also had no significant difference in the duration of their facial expression after noxious or innocuous stimulation, whereas facial expression responses of infants older than 33.9 weeks' gestation were significantly longer in duration after the noxious stimulation compared with the innocuous stimulation (**P < 0.001). (C) The proportion of infants who exhibited noxious-specific brain activity (blue) or non–modality-specific delta brush responses (red) to the noxious stimulation. (D) The proportion of infants who exhibited a sensory-evoked potential (black) and delta brushes (red) after innocuous stimulation.

Figure 2.

Facial expression discrimination depends on brain response maturity. (A) A decision tree was used to classify infants according to brain response maturity based on their responses to both noxious and innocuous stimuli. Noxious-specific brain activity and sensory-evoked potentials are seen in more mature, older infants. By contrast, delta brush responses are more immature. Therefore, infants classified on the right of the tree have more mature responses compared with infants on the left. The first split of the tree classifies infants dependent on the presence of noxious-specific brain activity; the second split classifies infants dependent on the presence of a sensory-evoked potential; and the final split considers whether delta brush activity was recorded at any electrode. Crosses indicate that a particular type of brain activity was not present, whereas ticks indicate that this type of brain activity was present. The number of infants classified at each split is indicated at the bottom of the branches. (B) Brain response maturity classification determined from the decision tree is plotted against the proportion of infants in each group that display facial expression discrimination (a response to the noxious stimulus but not the innocuous stimulus). The fit from a generalised linear model (solid lines) and 90% confidence intervals (dashed lines) are overlaid.