The developing human pain connectome and brain dynamics of infant pain: sex differences, pain history and skin-to-skin care

Many infants need neonatal care at birth, either because they have been born prematurely or because they are unwell. Some of the most premature and unwell babies can spend months in hospital where they undergo numerous clinical procedures, many of which are tissue breaking and likely to be painful. Despite efforts to reduce the number of procedures and handling, the burden to these vulnerable individuals is considerable, particularly as they occur at a critical phase of brain development, when connections are forming between different brain regions. The developing brain requires sensory stimulation to develop normally, but if this stimulation is exaggerated or applied at inappropriate developmental stages, it can cause permanent harm. Indeed, repeated early exposure to painful procedures is associated with lasting adverse changes to the brain. The aim of this project is to understand how pain is processed in the human infant brain. We will map the structural and functional development of the brain circuits that are necessary to process pain and investigate how these are affected by the repeated tissue-damaging procedures of hospital stay. We will establish whether these circuits develop differently in males and females. Moreover, as the experience of pain is highly dependent upon what is already going on in the brain and what happens around us, we will explore how ongoing brain activity influences the response to a painful stimulus and how we can manipulate these processes with non-pharmacological interventions, such as caregiver skin-to-skin care, to reduce the pain experienced. This research project will provide the knowledge we need to alleviate infant pain and reduce any long-term adverse effects of neonatal intensive care procedures.

This proposal aims to study the structural and functional development of pain networks in the human infant brain, focussing upon the dynamic interactions between brain oscillations and pain. We will record resting and noxious evoked activity in the brains of premature and term infants of 28-42 weeks corrected gestational age in the neonatal units at UCLH and St Thomas' Hospital, using electrophysiology and magnetic resonance imaging. We will: (i) map the developing human pain structural and functional networks using existing data and our own acquired diffusion weight (DWI), structural (MRI) and functional (fMRI) brain images and (ii) record brain oscillations and nociceptive event related potentials (nERPs) using non-invasive electroencephalography (EEG) to analyse the dynamics of these networks. Data will be entered into a unique open access database and will be used to test these hypotheses: 1. The pain connectome matures over the last trimester of gestation. 2. Functional pain dynamics (the interaction between brain dynamics and an incoming noxious stimulus) undergo distinct developmental changes over the perinatal period. 3. Sex differences in the developing pain connectome and functional pain dynamics are apparent from birth. 4.Pain history, that is the frequency, intensity and timing of painful events, alters the development of the pain connectome and functional pain dynamics in the newborn brain. 5. Care-giver skin-to-skin contact diminishes or alters the functional pain dynamics. The data will provide novel insights into the development of pain processing in the human brain, how these interact with ongoing brain oscillations and how they may be modified by intrinsic and contextual factors. The results will provide a brain-based rationale for designing effective methods of pain control in neonatal 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.
Rates of preterm birth have globally increased accounting for approximately 11% of live births worldwide. In the UK alone about 60,000 infants are born before 37 weeks of gestation every year, and over 95,000 are cared for in neonatal units around the country because they have either been born prematurely, or full term, but sick. During 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. Pain is not only related to the incoming stimulus, but also depends on what is already going on in the brain and around us. By monitoring the status of the brain, we will potentially be able to time a painful intervention to a moment when the brain is less receptive and therefore reduce the impact. We will also be able to test the effect that holding a newborn in skin-to-skin contact has on the brain dynamics and consequently on the pain perception. This project will also 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, therefore enhancing their quality of life.
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. Neuroimaging protocols, especially combining multimodal imaging techniques, could ultimately identify biomarkers to be targeted therapeutically. Moreover, neuroimaging will have an invaluable screening scope in identifying those individuals at higher risk of abnormal neurodevelopment.
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 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 which has implications for their cognitive and behavioural outcomes. 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 terms of better health and therefore quality of life over their whole lifespan. Rates of preterm birth are highest in low-income countries where access to care is most limited. In this context, skin-to-skin has already proved to reduce mortality and morbidity at discharge from the intensive care unit. Understanding the impact that skin-to-skin care has on the immediate and long-term processing of pain will add a new dimension to this no-cost intervention and help to roll it out worldwide. Considering that pain and disability are both 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.