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

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

Abstract

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.

Technical Summary

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.

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.
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.
 
Description Council member of British Pain Society
Geographic Reach National 
Policy Influence Type Participation in advisory committee
Impact The British Pain Society represents all professionals and patients involved in improving pain. Influences Government , NHS and NICE.
URL http://www.britishpainsociety.org/
 
Description Member of Council of International Association for the Study of Pain (IASP) Special Interest Group in Pain in Children
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
Impact Pain relief is a human right, yet pain in children is an under-recognized problem around the world. The Special Interest Group on Pain in Childhood of the International Association for the Study of Pain is dedicated to improving pain prevention and treatment for children everywhere.
URL http://childpain.org/
 
Description Musculoskeletal Pain Strategy Group for Arthritis Research UK
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact To advise Arthritis Research UK in defining research priorities in musculoskeletal pain for their support, submission for external funding and subsequent adoption to run through the clinical group.
URL http://www.arthritisresearchuk.org/research/research-funding-and-policy/our-clinical-study-groups/mu...
 
Description Arthritis Research UK award
Amount £237,183 (GBP)
Funding ID 21322 
Organisation Versus Arthritis 
Start 01/2017 
End 01/2020
 
Description IASP Collaborative Research Grants
Amount $15,000 (USD)
Organisation International Association for the Study of Pain (IASP) 
Sector Learned Society
Country United States
Start 11/2017 
End 09/2018
 
Description Nociception and pain in the developing rodent cortex
Amount £663,664 (GBP)
Funding ID BB/R00823X/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 02/2018 
End 01/2021
 
Description The developing human pain connectome and brain dynamics of infant pain: sex differences, pain history and skin-to-skin care
Amount £968,734 (GBP)
Funding ID MR/S003207/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 11/2018 
End 10/2022
 
Description Travel award to Dr Laura Jones
Amount £800 (GBP)
Organisation Guarantors of Brain 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2016 
End 10/2016
 
Description UCL Wellcome Trust Neuroscience PhD programme
Amount £184,757 (GBP)
Funding ID 109006/Z/15/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2016 
End 09/2019
 
Title Novel NIRS analysis 
Description A better methods of quantifying NIRS data from human infants 
Type Of Material Model of mechanisms or symptoms - human 
Provided To Others? No  
Impact Submitted manuscript awaiting review. Then will be available to other research groups. 
 
Title Open source data base of human infant pain related EEG 
Description An open access dataset of cortical, behavioural, and physiological responses following a single, clinically required noxious stimulus in a neonatal sample. Cortical activity was recorded from 112 neonates (29-47 weeks gestational age at study) using a 20-channel electroencephalogram (EEG), which was time-locked to a heel lance. This data is linked to pain-related behaviour (facial expression), physiology (heart rate, oxygenation) and a composite clinical score (Premature Infant Pain Profile, PIPP). The dataset includes responses to non-noxious sham and auditory controls. Jones L, Laudiano-Dray MP, Whitehead K, Verriotis M, Meek J, Fitzgerald M, Fabrizi L. EEG, behavioural and physiological recordings following a painful procedure in human neonates. Sci Data. 2018 Nov 13;5:180248. doi: 10.1038/sdata.2018.248 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
Impact Other groups have contacted us for the data. 
URL https://www.nature.com/articles/sdata2018248
 
Title ipsi database 
Description A preterm and term infant database with anonymised infant participants, their demographics, clinical history and EEG pain responses 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact Will form the basis of our research questions. Will make it available upon request when it has all the data in it. 
 
Description Adolescent Centre for Rheumatology UCL 
Organisation Versus Arthritis
PI Contribution Knowledge of neurobiology of pediatric pain. Scientific expertise
Collaborator Contribution Expertise in adolescent inflammatory joint pain. Access to patient networks
Impact Successful Arthritis Research UK award, based on results from MRC grant
Start Year 2015
 
Description Collaboration with Professor Pillai-Riddell, Dept Psychology, York University, Canada 
Organisation York University Toronto
Country Canada 
Sector Academic/University 
PI Contribution Hosting Prof Pillai-Riddell for a sabbatical, 2017-18. Recording pain related activity in the human infant brain.
Collaborator Contribution Visiting the lab for a sabbatical 2017-18. Measuring maternal infant interactions during a clinically required painful stimulus.
Impact Multi-disciplinary: neuroscience and psychology. Prof Pillai-Riddell's travel expenses have been supported by a UCL Global Engagement Award
Start Year 2017
 
Description Dept Statistics, UCL 
Organisation University College London
Department Department of Statistical Science
Country United Kingdom 
Sector Academic/University 
PI Contribution Collabration with academic statistician at UCL who has provided new statistical analysis of our complex EEG data
Collaborator Contribution Whole new way of analysing the results. LF, a postdoc on this grant has learned a lot of sophisticated analytic and statistical techniques as a result of this work
Impact New methods of analysis that were included in: 20438855 and 20817247
Start Year 2008
 
Description Neonatology, Institute Womens Health, UCLH 
Organisation University College London Hospitals NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution Expertise in infant pain processing. Collaboration for MRC grant.
Collaborator Contribution Expertise in brain structure and MRI of premature infants. Access to neonated in NICU
Impact MRC DTA studentship, MRC grants
Start Year 2009
 
Description UCL ICH paediatric pain research 
Organisation University College London
Department Developmental Neurosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution expertise in neurobiology of pedaitric pain research, electrophysiology training
Collaborator Contribution clinical perspective
Impact Clinical/scientific meetings and discussion groups. Research projects
 
Description Annual FEPS lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Annual lecture for the Federation of Physiological Sciences - across Europe
Year(s) Of Engagement Activity 2015
URL http://www.feps.org/feps-lecturers
 
Description Annual Mabel Fitzgerald Lecture, Anatomy, Physiology & Genetics, Oxford University 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Athean Swan programme. Mabel FitzGerald (1872-1973) has been all but forgotten in the study of human acclimatisation to high altitude. Her great scientific accomplishment was to demonstrate, over the long term, that it is oxygen, and not carbon dioxide, that determines how hard we breathe and sets the haemoglobin concentration in our blood. This she did by travelling around Colorado in 1911 making detailed physiological measurements of the populations living at different altitudes throughout the state.

Mabel FitzGerald had a middle class upbringing, but her life abruptly changed in 1895 when both her parents died. She came to live in Oxford with her four sisters in 1896 in a house in Crick Road, just north of the University Parks. She was fascinated by physiology and the University permitted her to attend classes informally from 1896-1899. She gained top marks in the examinations, but these could not count towards a degree because women could not be officially enrolled.

She was "rediscovered" by accident in the 1960s, still living in her house in Crick Road. With the help of the then Regius Professor of Medicine, Sir Richard Doll, the University of Oxford finally bestowed an honorary Master of Arts degree on her in 1972 - the first centenarian to receive one. Sir Ric

hard wrote that her example first convinced Oxford "that women can do as well as men". On bestowing the degree, the then Vice Chancellor, Alan Bullock, acknowledged that it had come three-quarters of a century too late. Based on her pioneering work in Colorado, Mabel FitzGerald became only the second female member of the American Physiological Society in 1913, but it was not until 1973 that she was made an honorary member of the British Physiological Society. She was then the American Physiological Society's oldest living member.
Year(s) Of Engagement Activity 2016
URL https://www.dpag.ox.ac.uk/seminars/mabel-fitzgerald-lecture-2017-title-tbc
 
Description Celebrating 100 years of Women in Physiology 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Organised by the Physiological Society: Speaker at an event celebrating 100 years of women in physiology.
Contributed to a booklet published to celebrate women physiologists
Year(s) Of Engagement Activity 2015
URL http://www.physoc.org/100years
 
Description Grand rounds: Cincinnati Childrens Hospital, Anesthesiology, Pediatrics, Nursing 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Pediatricians, anesthesiologists and nurses in Cinicinnati childrens hospital learnt about how to measure and understanding how pain is processed in the infant brain
Year(s) Of Engagement Activity 2015
 
Description Guest lecture European Society for Paediatric Anaesthesia, Glasgow 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Guest Lecture entitled 'Neonatal Pain: A Journey'
Year(s) Of Engagement Activity 2017
URL http://www.euroespa.com/wp-content/uploads/2017/02/ESPA2017_ProgA5_web-3.pdf
 
Description Janelia Farm Somatosensation Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Study participants or study members
Results and Impact This meeting brought together molecular geneticists, physiologists, behavioral scientists, and bioengineers using rodent, human, and non-human primates model systems. Presentations and discussions focused on mammalian cutaneous afferents and their associated neural circuits within the spinal cord, brain stem and cortex that underlie tactile perception, object and form recognition, and pruritic behaviors.
Year(s) Of Engagement Activity 2015
URL https://www.janelia.org/you-janelia/conferences/mammalian-circuits-underlying-somatosensation
 
Description Lecture at The Challenge of Chronic Pain 04 - 06 March 2019 Wellcome Genome Campus, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Study participants or study members
Results and Impact Focusing on the translation of basic research insights into new therapies for pain
Year(s) Of Engagement Activity 2019
URL https://coursesandconferences.wellcomegenomecampus.org/our-events/chronic-pain-2019/
 
Description Lecture and Workshop at Pain Mechanisms and Therapeutics Conference 3 - 8 June, 2018, Taormina, Sicily 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Study participants or study members
Results and Impact Joined researchers and clinicians interested in all aspects of pain research and therapeutics. In addition to hearing the latest data from academia and industry, attendees benefitted from informal interactions throughout the conference.
Year(s) Of Engagement Activity 2018
URL http://pain.euroconferences.org/
 
Description Otto Wolff Annual Lecture, Institute of Child Health 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Guest lecture at annual open day
Year(s) Of Engagement Activity 2017
URL http://www.ucl.ac.uk/ich/short-courses-events/short-courses-events-publication/owlnov2017/otto-wolff...
 
Description PICH2GO Unravelling the Puzzle of Paediatric Pain, Calgary 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Pain in Child Health (PICH) research training initiative has transformed Canada into a world-leader in pediatric pain research. PICH2GO has fostered a community of scientists and trainees charged with creating new knowledge to minimize pain and suffering in children around the world.
Year(s) Of Engagement Activity 2016
URL http://www.thepainhubuottawa.com/single-post/2016/12/23/PICH2GO-Calgary
 
Description Plenary Lecture at American Pain Society Scientific Summit, Anaheim 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Communicating the research to the very large US pain research and practice community
Year(s) Of Engagement Activity 2018
URL http://americanpainsociety.org/meetings-and-events/2018-scientific-summit/2018-scientific-summit
 
Description Plenary lecture at ISPP in Kuala Lumpur 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Plenary Lecture - first time that the research was directly communicated in Asia
Year(s) Of Engagement Activity 2017
URL http://www.ispp2017.org/
 
Description Public lecture - Encountering Pain 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Over two days, we explored a range of international and interdisciplinary approaches that can help us better understand encounters with pain both within and beyond the clinic.
The event diverted radically from the traditional academic conference format to encourage exchange between different groups affected by pain.
Year(s) Of Engagement Activity 2016
URL https://www.ucl.ac.uk/encountering-pain