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

Lead Research Organisation: University College London
Department Name: Neuroscience Physiology and Pharmacology

Abstract

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.

Technical Summary

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.

Planned Impact

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.
 
Description Collaborative Health Research Project, Co-Is Prof Fitzgerald and Dr Fabrizi
Amount $1,484,330 (CAD)
Organisation Canadian Institutes of Health Research 
Sector Public
Country Canada
Start 08/2019 
End 08/2022
 
Description Dr L Jones IASP travel grant
Amount $1,000 (USD)
Organisation International Association for the Study of Pain (IASP) 
Sector Academic/University
Country United States
Start 09/2018 
End 09/2018
 
Description Dr L Jones travel grant
Amount £500 (GBP)
Organisation Physiological Society 
Sector Charity/Non Profit
Country Global
Start 09/2018 
End 09/2018
 
Description travel grant
Amount £740 (GBP)
Organisation Guarantors of Brain 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2018 
End 09/2018
 
Description EPFL - Prof Olhede 
Organisation Swiss Federal Institute of Technology in Lausanne (EPFL)
Country Switzerland 
Sector Public 
PI Contribution Description: This is a long-standing collaboration with Professor Sofia Olhede which is still active thanks to the support received by the Medical Research Council. Main purpose of this collaboration: application of advanced statistical and signal processing techniques to neonatal electroencephalographic recordings. My contributions to this partnership are: - Intellectual input: formulation of clinical and neuroscientific questions - access to EEG data - Expertise in neonatal EEG - Study design - Preparation of manuscripts and conference abstracts - Management fo the overall projects
Collaborator Contribution The contributions made by Sofia Olhede are: - Financial (part fuding a postdoc) - Expertise in statistical analysis - Expertise in advanced signal processing - Design of ad-hoc statistical and signal processing techniques - Training of postdoc in signal processing
Impact This collaboration is multi-disciplinary and involves: statistical sciences, electrophysiology (EEG), neonatology, neuroscience, signal processing.
Start Year 2019
 
Description KCL - developing pain connectome with MRI 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We have established a close collaboration with Dr Tomoki Arichi and Prof David Edwards from the Centre for the Developing Brain at King's College London. We are using MRI data aquired at KCL to characterise the development of the connections between pain related areas in premature neonates. Our contributions are: - Intellectual input: this project is based on our design - Experties in pain neurobiology - Data collection: the research nurse employed on this award is collecting the clinical data of the subjects in this study across different hospitals - Data analysis: a postdoc employed on this award is conducting the data analysis - Publications and conference abstracts preparation - Management of the overall project
Collaborator Contribution The Centre for the Developing Brain lead by Prof Edwards is the only centre in the UK to have an MR scanner on the neonatal intensive care unit. Here we have access to data and subjects. Contributions made our partners are: - Intellectual input - Data - Expertise in MRI/fMRI data processing and MRI images interpretation - Training in MRI/fMRI skills of our postdoc and myself
Impact This collaboration is multi-disciplinary and involves: brain imaging (MRI/fMRI), neonatology, neuroscience and signal processing.
Start Year 2019
 
Description York University (Toronto, Canada) - Prof Pillai-Riddell 
Organisation York University Toronto
Country Canada 
Sector Academic/University 
PI Contribution We have established a close collaboration with Prof Rebecca Pillai-Riddell from York University (Toronto, Canada). We are conducting collaborative experiments using electrophysiology (EEG), behaviour and physiological recordings to improve pain assessment in neonates using machine learning. Our contributions are: - Intellectual input - Data collection - Expertise in EEG recording - Expertise in EEG data processing - Training in EEG skills of the team in Canada - Publications and conference abstracts preparation
Collaborator Contribution This collaboration is funded by a Canadian Institutes of Health Research Collaborative Health Research Project of which Prof Pillai-Riddell is Principal Investigator. Prof Pillai-Riddell contributions are: - Financial (this collaboration pays for a full-time clinical physiology research assistant to join our group) - Intellectual input - Data collection - Expertise in neonatal behaviour - Publications and conference abstracts preparation - Overall project management
Impact This collaboration is multi-disciplinary and involves: electrophysiology (EEG), psychology, neonatology, neuroscience and signal processing. This collaboration led to: - The award of a Canadian Institutes of Health Research Collaborative Health Research Project of 1,484,330 CAD. This project will fund a full-time clinical physiologist to join our team for 3 years. - One publication in Pain (Laudiano-Dray M.P., et al. (2020))
Start Year 2019
 
Description Hilda Tracy Lecture - Institute Translational Medicine, Liverpool University 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other audiences
Results and Impact University public lecture
Year(s) Of Engagement Activity 2019
URL https://lng.org.uk/event/itm-hilda-tracy-lecture-pain-a-lifelong-journey/
 
Description Dr Fabrizi attended a Patient and Public Involvement meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact Dr Fabrizi partecipated to a Patient and Public Involvement meeting to discuss research priorities. Parents identified basic science as important as direct medical research.
Year(s) Of Engagement Activity 2020
 
Description Dr Jones - Trainee poster prize presentation at the 12th International Symposium on Pediatric Pain (Basel, Switzerland) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Dr L Jones was invited to give a prize lecture at the 12th International Symposium on Pediatric Pain
Year(s) Of Engagement Activity 2019
 
Description Dr L Jones - Chair and speaker of workshop at the 12th International Symposium on Pediatric Pain (Basel, Switzerland) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Dr L Jones organised, chaired and talked at a workshop at the 12th International Symposium on Pediatric Pain (Basel, Switzerland)
Year(s) Of Engagement Activity 2019
 
Description Dr L Jones - UCL Biosciences Postgraduate seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Dr L Jones gave a seminar as part of the UCL Biosciences Postgraduate seminar series
Year(s) Of Engagement Activity 2019
 
Description Dr L Jones and Ms M Laudiano-Dray 5-days training to Mount Sinai Hospital Canada 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Dr L Jones and Ms M Laudiano-Dray organised and delivered a 5-days training course to research and clinical staff at Mount Sinai Hospital, Canada. The training was paid for by our CIHR collaborative grant.
Year(s) Of Engagement Activity 2019
 
Description Invited lecture - Montreal international conference on recent advances of nociceptive neuronal circuit function 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Increased international interest in our research
Year(s) Of Engagement Activity 2019
URL https://montrealpaincircuits.com/
 
Description Miss Laudiano-Dray attended a Patient and Public Involvement meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact Miss Laudiano-Dray attended a Patient and Public Involvement meeting to discuss the information sheet for our study recruitment. The information sheet was modified according to the feedback received.
Year(s) Of Engagement Activity 2019