The development of human cortical networks: effects of early life stress and injury

Many infants are born too young or too small or with serious medical conditions. As a result, these infants will need to spend time in hospital and undergo numerous clinical procedures, many of which are painful. While even the youngest preterm infant can show behavioural reactions to pain, we do not know how much the pain is processed in their brain. This is important because the brain is responsible for the actual feeling of pain: how much it hurts, where it is and how unpleasant it is. Our research aims to discover this so that infant pain can be prevented or adequately treated. Too much injury and stress in early life, when the brain is still forming connections, is thought to alter normal development of pain pathways in the brain, but this process is poorly understood. We intend to clarify this by measuring brain activity, tissue injury and physiological stress independently and analysing how they influence each other in intensive care. Finally, since each infant is an individual, we need to know how pain pathways in the brain differ between infants and what factors are responsible for these differences. Our work will help ensure that each hospitalised infant receives appropriate pain relief.

Little is known about how and when noxious information is processed in the human infant brain and whether the immature brain can distinguish the effects of clinical injury and physiological stress. This proposal focuses upon the functional maturation of brain networks responsible for discriminating noxious events and creating a state of pain in human infants aged 28 weeks (gestational age) to one year old. The project will be carried out by a group of scientists and clinical investigators who have proven skills, expertise and track record in human infant pain neurophysiology. Using a combination of electroencephalography (EEG) and multi-channel near infrared spectroscopy (NIRS) together with physiological measurements of stress and behaviour we plan to (i) map the developmental trajectory of somatosensory and nociceptive cortical activity patterns and their topographic organisation (ii) discover central brain processes of clinically important, pain hypersensitivity states in preterm infants (iii) measure the interaction between physiological stress and central pain processing in infants, which is an especially important problem in an intensive care environment (iv) investigate the development of individual pain phenotypes in infants at birth and to what extent they are shaped by postnatal experience. These experiments will provide us with novel information about the development of cortical networks in the human infant brain that process nociceptive pain and hyperalgesic pain states and new insights into the developmental regulation of pain and stress and the emergence of individual pain phenotypes in infancy. This data is of fundamental biological importance and will impact substantially upon the treatment of infants in intensive care.

The primary beneficiaries will be preterm and term infants that suffer from painful conditions or who require painful procedures as part of their clinical care.
The UK has the highest rate of low birthweight babies in Western Europe; 12% of all newborns need some level of special care at birth (~80,000 per annum) and 2.5% need neonatal intensive care (~17,000 per annum). In intensive care, each neonate is subjected to an average of 14 noxious procedures per day but clinical use of pain control measures remains sporadic and suboptimal. As these infants are unable to communicate their pain, we cannot easily measure or treat it. One problem is that we do not have a sufficient understanding of how pain is processed in the developing infant brain and how to distinguish the levels and time course of their pain experience. This project will provide new insight into pain processing in this group of individuals and provide a platform for studies of different pharmacological and non-pharmacological methods of pain relief and better patient care.

Clinicians responsible for the care of these infants will also benefit from this research: neonatologists, paediatricians, paediatric anaesthetists and all health professionals involved in the management and treatment of pain in infants will have a better scientific basis upon which to treat infant pain.

Families of affected infants will benefit from an increased understanding and interest in what their babies are experiencing and the drive towards better clinical management of their pain.

In the longer term, there will be economic benefits for society in general. Increasing evidence suggests that pain and stress in early life has long term consequences on brain development and on future pain experience in later life. Preterm infants who have experienced the most tissue breaking procedures in intensive care show the most severely decreased brain growth. Furthermore, early life trauma is associated with chronic pain problems in later life. Infants who are born too young or too small and who have to spend time in intensive care undergoing numerous tissue damaging procedures will therefore benefit from this research, not only at the time but also in later life. The increased understanding of how the brain processes pain in early life in individual infants will not only lead to better treatment and management of pain in this vulnerable group, but also have long term benefits in terms of better health and therefore quality of life over their whole lifespan. Considering that pain is a huge financial burden on society in terms of lost working days and the provision of care, better health outcomes for a growing subset of the population will also potentially have a large impact on society as a whole, helping to relieve this burden.