What do we really know about newborn infant pain?

Increased awareness of pain in the newborn has led to the development of numerous assessment tools for use in neonatal intensive care units. Here, I argue that we still know too little about the neurophysiological basis for infant pain to interpret data from clinical observational measures. With increased understanding of how the neural activity and CNS connections that underlie pain behaviour and perception develop in the newborn will come better measurement and treatment of their pain. This review focuses upon two interconnected nociceptive circuits, the spinal cord dorsal horn and the somatosensory cortex in the brain, to highlight what we know and what we do not know about infant pain. The effectiveness of oral sucrose, widely used in clinical practice to relieve infant pain, is discussed as a specific example of what we do not know. This ‘hot topic review’ highlights the importance of new laboratory-based neurophysiological research for the treatment of newborn infant pain

Multimodal characterisation of the infant response to retinopathy of prematurity screening and treatment

Retinopathy of prematurity (ROP) is a condition which affects premature infants and is a cause of childhood blindness. Screening is performed repeatedly during the preterm period, using binocular indirect ophthalmoscopy (BIO), to identify disease at a treatable stage; unfortunately screening and treatment are considered to be painful and stressful for infants. Pain and stress during the preterm period can lead to negative consequences for infant development. Reduction of pain and stress during ROP procedures has therefore been attempted using pharmacological and non-pharmacological strategies. However, it is challenging to evaluate the effectiveness of such interventions due to limitations in the accurate measurement of infant pain and stress. In this thesis, novel approaches to quantifying infant pain and stress evoked by ROP procedures are presented. Infant brain activity was characterised using quantitative electroencephalography (EEG) analysis to test the hypothesis that ROP screening evokes noxious-related changes in infant brain activity. The results of this study suggest BIO ROP screening evokes a significant increase in higher frequency brain activity (12 - 30 Hz), and that increase in relative beta power may be a measure of nociception in preterm infants. Infant cardiac autonomic reactivity was characterised using heart rate variability (HRV) analysis to test the hypothesis that ROP screening evokes stress-related autonomic changes. The results of this study suggest BIO ROP screening evokes significant reduction in HRV measures of parasympathetic nervous system activity, indicating a physiological stress response in preterm infants. An approach to characterising the infant response to non-contact ultra-widefield photography (Optos screening) and ROP treatment was also demonstrated. Recruitment of subjects was curtailed by the outbreak of COVID-19, therefore the investigations are presented as an example of approaches which could be performed in a larger sample size. In summary, the research described in this thesis aims to contribute to understanding of the infant experience of ROP procedures; to characterise changes in noxious-related brain activity and stress-related cardiac reactivity evoked by BIO ROP screening, and to use these measures to investigate the infant response to an alternative screening method and to ROP treatments. Improved understanding of the infant experience of ROP screening and treatment may allow clinicians to better identify and treat infant pain and stress during essential clinical procedures

Cortical pain processing in the infant brain.

Premature infants are exposed to multiple invasive procedures as part of their essential medical care. It is not known, however, if nociceptive information is processed by the cortex at this age. The fundamental question to be addressed by this thesis is whether premature infants display cortical responses to noxious stimulation. This thesis describes a series of studies where the question of cortical pain processing is addressed by directly measuring cortical responses to noxious stimulation using near-infrared spectroscopy (NIRS) and electroencephalography (EEG). The NIRS results show that, following an acute noxious event, the contralateral somatosensory cortex is functionally activated in infants from 25 weeks postmenstrual age (PMA). Awake infants have a larger cortical response than asleep infants and, in the awake group, the size of the response increases with PMA. The magnitude of the haemodynamic response correlates with pain scores calculated using the premature infant pain profile (PIPP), although infants who do not display a change in facial expression can still process noxious stimuli at the cortical level. Latency to response is longest in the youngest infants using either the haemodynamic response or change in facial expression as an output measure. The underlying pain-related neuronal activity in the cortex has been investigated using EEG. Nociceptive-specific event related potentials have been observed in infants from 31-42 weeks PMA, with a recognisable N-P complex visible in the contralateral somatosensory cortex in 82% of studies. Noxious stimulation can evoke specific patterns of neural activity within the cortex of preterm and term infants that can be observed on a single-trial basis. The studies represent the first measurements of cortical activation in the immature preterm cortex following a noxious event. The fact that noxious information is transmitted to higher levels of the central nervous system highlights the importance of developing a systematic approach to reduce pain and improve analgesic strategies in this vulnerable population

Developing neuroimaging methods for clinical translation and better understanding neonatal brain development

Understanding and measuring pain and brain development in neonates is essential to be able to provide the best care for this vulnerable population. This is particularly important for premature infants, for whom early life is filled with more painful procedures, and earlier exposure to extrauterine stimuli, which can adversely affect development. Infant pain assessments combine behavioural and physiological measures such as facial expression, crying, and heart rate. However, these metrics are not specific to pain experience, nor sensitive enough to provide reliable outcome measures for clinical trials to validate pain treatments in infants. Neuroimaging techniques provide means to study brain health, development and function. EEG and fMRI measurements of noxious-evoked brain activity could be used to develop more objective and specific pain assessment tools. This thesis focusses on using EEG and MRI to measure infant pain and its relation to overall brain development. First, I present tests of the validity of an EEG template measure of noxious response in infants recruited at multiple hospital sites. EEG has been used to quantify noxious-evoked activity and study pain interventions in infants, but a standard generalisable approach needs to be established. I tested whether the EEG template discriminates between noxious and non-noxious stimuli, whether the scale of noxious response is equivalent across different hospital sites, and whether noxious response increases with age in premature infants. I found that noxious-evoked responses are significantly greater than non-noxious responses, but that the scale is not equivalent across study sites, and there was no significant age correlation. This suggests that the EEG template can be reliably used as a surrogate measure of pain, with promise for clinical trials. Additionally, data collection site should be accounted for as a confounding factor as needed. Then, I focus on how MRI can aid our understanding of infant pain and the underlying neurophysiology behind differences in noxious-evoked activity. I present a machine learning model that I developed to predict the magnitude of noxious-evoked responses from resting- state brain activity in infants, using fMRI data. By applying this model to data from the independent Developing Human Connectome Project, I explore how predicted noxious- evoked responses relate to development metrics, including resting-state cortical function and microstructure, as well as prematurity, and assessments of infant cognitive and motor ability at 2-year follow up. I found that prematurity is associated with accelerated development of the nociceptive system, but disrupted neurodevelopment overall. In summary, this thesis demonstrates the potential for neuroimaging techniques to improve our understanding of infant brain development, and improve clinical assessment and treatment of infant pain

Multimodal assessment of neonatal pain

Pain assessment is critical to prevent suffering and harm in infants admitted to the neonatal care unit. As pain is a subjective experience, its assessment in nonverbal infants relies on surrogate measures. Current infant pain assessment tools that are based on behaviour and autonomic nervous system measurements lack face validity — they are unlikely to reflect pain in all its dimensions. In recent years, EEG-derived measures of pain have been developed in late preterm and term infants. Multimodal tools which include these cerebral measurements are conceptually more appropriate to measure pain. Yet, their use is still limited to specific research applications. This thesis focuses on outstanding questions that need to be addressed in order to advance the development of multimodal pain assessment tools that incorporate cerebral measurements. In the first part of this thesis, I focus on the characterisation of preterm infants’ noxious-evoked responses and their development. Across several modalities, premature infants have dampened or altered responsiveness compared to term infants, and it is uncertain if these responses can be reliably discriminated from tactile-evoked responses. In particular, a discriminative pattern of noxious-evoked EEG activity that is present in term infants, is unlikely to be present in preterm infants. In addition, it is unclear how noxious-evoked responses, especially brainderived responses, change with age. In this thesis, I use a classification model to show that infants aged 28–40 weeks postmenstrual age display discriminable multimodal responses to a noxious clinical procedure and a tactile control procedure, and I provide examples of how a such a model could be used in clinical trials of analgesics. I show that noxious-evoked responses change magnitude and morphology across this age range, and that discriminative brain activity emerges in early prematurity. In the second part of this thesis, I focus on improving the neuroscientific validity of a noxious-evoked EEG response measured at the cot-side, as the spatial neural correlates of these responses are still poorly understood. I present an EEG-fMRI pilot study to investigate the spatial neural correlates of inter-individual differences in noxious-evoked EEG responses and provide recommendations for a larger follow-up study. Overall, this thesis provides a characterisation of infants’ noxious-evoked responses and their development across multiple modalities, a crucial next step in improving multimodal neonatal pain assessment

Altered cortical processing of somatosensory input in pre-term infants who had high-grade germinal matrix-intraventricular haemorrhage

High-grade (large) germinal matrix-intraventricular haemorrhage (GM-IVH) is one of the most common causes of somatomotor neurodisability in pre-term infants. GM-IVH presents during the first postnatal week and can impinge on somatosensory circuits resulting in aberrant somatosensory cortical events straight after injury. Subsequently, somatosensory circuits undergo significant plastic changes, sometimes allowing the reinstatement of a somatosensory cortical response. However, it is not known whether this restructuring results in a full recovery of somatosensory functions. To investigate this, we compared somatosensory responses to mechanical stimulation measured with 18-channels EEG between infants who had high-grade GM-IVH (with ventricular dilatation and/or intraparenchymal lesion; n = 7 studies from 6 infants; mean corrected gestational age = 33 weeks; mean postnatal age = 56 days) and age-matched controls (n = 9 studies from 8 infants; mean corrected gestational age = 32 weeks; mean postnatal age = 36 days). We showed that infants who had high-grade GM-IVH did not recruit the same cortical source configuration following stimulation of the foot, but their response to stimulation of the hand resembled that of controls. These results show that somatosensory cortical circuits are reinstated in infants who had GM-IVH, during the several weeks after injury, but remain different from those of infants without brain injury. An important next step will be to investigate whether these evidences of neural reorganisation predict neurodevelopmental outcome

Mapping cortical responses to somatosensory stimuli in human infants with simultaneous near-infrared spectroscopy and event-related potential recording

Near-infrared spectroscopy (NIRS) and electroencephalography (EEG) have recently provided fundamental new information about how the newborn brain processes innocuous and noxious somatosensory information. However, results derived independently from these two techniques are not entirely consistent, raising questions about the relationship between hemodynamic and electrophysiological responses in the study of touch and pain processing in the newborn. To address this, we have recorded NIRS and EEG responses simultaneously for the first time in the human infant following noxious (time-locked clinically required heel lances) and innocuous tactile cutaneous stimulation in 30 newborn infants. The results show that both techniques can be used to record quantifiable and distinct innocuous and noxious evoked activity at a group level in the newborn cortex. Noxious stimulation elicits a peak hemodynamic response that is 10-fold larger than that elicited by an innocuous stimulus (HbO2: 2.0 vs 0.3 µm) and a distinct nociceptive-specific N3P3 waveform in electrophysiological recordings. However, a novel single-trial analysis revealed that hemodynamic and electrophysiological responses do not always co-occur at an individual level, although when they do (64% of noxious test occasions), they are significantly correlated in magnitude. These data show that, while hemodynamic and electrophysiological touch and pain brain activity in newborn infants are comparable in group analyses, important individual differences remain. These data indicate that integrated and multimodal brain monitoring is required to understand central touch and pain processing in the newborn

A developmental shift in habituation to pain in human neonates

Habituation to recurrent non-threatening or unavoidable noxious stimuli is an important aspect of adaptation to pain. Neonates, especially if preterm, are exposed to repeated noxious procedures during their clinical care. They can mount strong behavioral, autonomic, spinal, and cortical responses to a single noxious stimulus; however, it is not known whether the developing nervous system can adapt to the recurrence of these inputs. Here, we used electroencephalography to investigate changes in cortical microstates (representing the complex sequential processing of noxious inputs) following two consecutive clinically required heel lances in term and preterm infants. We show that stimulus repetition dampens the engagement of initial microstates and associated behavioral and autonomic responses in term infants, while preterm infants do not show signs of habituation. Nevertheless, both groups engage different longer-latency cortical microstates to each lance, which is likely to reflect changes in higher-level stimulus processing with repeated stimulation. These data suggest that while both age groups are capable of encoding contextual differences in pain, the preterm brain does not regulate the initial cortical, behavioral, and autonomic responses to repeated noxious stimuli. Habituation mechanisms to pain are already in place at term age but mature over the equivalent of the last trimester of gestation and are not fully functional in preterm neonates

The Impact of Neonatal Inflammatory Insult on Adult Somatosensory Processing: The Role of the Descending Nociceptive Circuit

The neonatal period represents a critical window of increased neurodevelopmental plasticity in the immature nervous system. Unlike other sensory modalities, which require appropriate stimulation for proper development, maturation of nociceptive circuitry in neonates typically occurs in the absence of noxious stimulation. Premature infants, however, are routinely exposed to multiple invasive medical procedures during neonatal intensive care treatment, which are largely performed in the absence of anesthetics or analgesics. To date, it is largely unknown how exposure to early noxious insult during this time of increased plasticity alters the development of the CNS and influences future nociceptive responses. As previous studies examining the impact of neonatal inflammatory insult on adult nociceptive responses have been conducted primarily in males, the potential adverse effects in females are unknown. Furthermore, the biological mechanisms underlying neonatal insult-induced deficits in nociceptive processing have yet to be elucidated. Therefore, this dissertation addressed the following questions: (1) Does neonatal inflammatory insult differentially alter male and female baseline somatosensory thresholds and response to re-inflammation in adulthood?; (2) Are neonatal inflammation-induced deficits in nociceptive responsiveness mediated by a potentiation in endogenous opioid tone?; and (3) Does pre-emptive morphine analgesia attenuate the behavioral consequences of neonatal inflammatory insult? Collectively, these studies will provide valuable information about the long-term consequences of neonatal noxious stimulation in males and females, which may lead to improved understanding and prevention of the lasting effects of repeated invasive interventions in premature infants in the NICU

Individual contextual factors in the validation of the Bernese pain scale for neonates: protocol for a prospective observational study

Background: The Bernese Pain Scale for Neonates (BPSN) is a multidimensional pain assessment tool that is already widely used in clinical settings in the German speaking areas of Europe. Recent findings indicate that pain responses in preterm neonates are influenced by individual contextual factors, such as gestational age (GA), gender and the number of painful procedures experienced. Currently, the BPSN does not consider individual contextual factors. Therefore, the aim of this study is the validation of the BPSN using a large sample of neonates with different GAs. Furthermore, the influence of individual contextual factors on the variability in pain reactions across GA groups will be explored. The results will be used for a modification of the BPSN to account for individual contextual factors in future clinical pain assessment in neonates. Methods and design: This prospective multisite validation study with a repeated measures design will take place in three university hospital neonatal intensive care units (NICUs) in Switzerland (Bern, Basel and Zurich). To examine the impact of GA on pain responses and their variability, the infants will be stratified into six GA groups ranging from 24 0/7 to 42 0/7. Among preterm infants, 2–5 routine capillary heel sticks within the first 14 days of life, and among full-term infants, two heel sticks during the first days of life will be documented. For each heel stick, measurements will be video recorded for each of three phases: baseline, heel stick, and recovery. The infants’ pain responses will be rated according to the BPSN by five nurses who are blinded as to the number of each heel stick and as to the measurement phases. Individual contextual factors of interest will be extracted from patient charts. Discussion: Understanding and considering the influence of individual contextual factors on pain responses in a revised version of the BPSN will help the clinical staff to more appropriately assess pain in neonates, particularly preterm neonates hospitalized in NICUs. Pain assessment is a first step toward appropriate and efficient pain management, which itself is an important factor in later motor and cognitive development in this vulnerable patient population. Trial registration: The study is registered in the database of Clinical Trial gov. Study ID-number: NCT 02749461. Registration date: 12 April 2016. Keywords: Pain assessment, Premature infants, Contextual factors, Diagnosti