Differential maturation of the brain networks required for the sensory, emotional and cognitive aspects of pain in human newborns

Pain is multidimensional and complex, including sensory-discriminative, affective-motivational, and cognitive-evaluative components. While the concept of pain is learned through life experience, it is not known when and how the brain networks that are required to encode these different dimensions of pain develop. Using the two largest databases of human brain magnetic resonance (MR) images in the world - the developing Human Connectome Project and the Human Connectome Project - we have mapped the development of the neural pathways required for pain perception in the human brain in infants from <32 weeks to 42 weeks postmenstrual age (n = 372), compared to adults (n = 98). Partial correlation analysis of 15 mins resting BOLD signal between all possible pairwise combinations of 12 pain-related regions of interest showed that overall functional connectivity is significantly weaker in 32-week infants compared to adults. However, over the following weeks, significantly different developmental patterns of connectivity emerge in sensory-discriminative, affective-motivational, and cognitive-evaluative pain networks. The first subnetwork to reach adult levels in strength and proportion of connections is the sensory-discriminative subnetwork (34-36 weeks PMA), followed by the affective-motivational subnetwork (36-38 weeks PMA), while the cognitive-evaluative subnetwork has still not reached adult levels at 42 weeks. This study reveals a previously unknown pattern of postnatal development of connectome subnetworks necessary for mature pain processing. The brain networks that form the infrastructure to encode different components of pain experience, change rapidly in the equivalent of the last gestational trimester but are still immature at the time of normal birth. Newborn neural pathways required for mature pain processing in the brain are incomplete in newborns compared to adults, particularly with respect to the emotional and evaluative aspects of pain. This data suggests that pain-related networks may have distinct periods of vulnerability to untimely noxious procedures during hospitalization, particularly in preterm infants.