Early Life Pain Experience Changes Adult Functional Pain Connectivity in the Rat Somatosensory and the Medial Prefrontal Cortex.

Early life pain (ELP) experience alters adult pain behavior and increases injury-induced pain hypersensitivity, but the effect of ELP on adult functional brain connectivity is not known. We have performed continuous local field potential (LFP) recording in the awake adult male rats to test the effect of ELP on functional cortical connectivity related to pain behavior. Primary somatosensory cortex (S1) and medial prefrontal cortex (mPFC) LFPs evoked by mechanical hindpaw stimulation were recorded simultaneously with pain reflex behavior for 10 d after adult incision injury. We show that, after adult injury, sensory evoked S1 LFP δ and γ energy and S1 LFP δ/γ frequency coupling are significantly increased in ELP rats compared with controls. Adult injury also induces increases in S1-mPFC functional connectivity, but this is significantly prolonged in ELP rats, lasting 4 d compared with 1 d in controls. Importantly, the increases in LFP energy and connectivity in ELP rats were directly correlated with increased behavioral pain hypersensitivity. Thus, ELP alters adult brain functional connectivity, both within and between cortical areas involved in sensory and affective dimensions of pain. The results reveal altered brain connectivity as a mechanism underlying the effects of ELP on adult pain perception.SIGNIFICANCE STATEMENT Pain and stress in early life has a lasting impact on pain behavior and may increase vulnerability to chronic pain in adults. Here, we record pain-related cortical activity and simultaneous pain behavior in awake adult male rats previously exposed to pain in early life. We show that functional connectivity within and between the somatosensory cortex and the medial prefrontal cortex (mPFC) is increased in these rats and that these increases are correlated with their behavioral pain hypersensitivity. The results reveal that early life pain (ELP) alters adult brain connectivity, which may explain the impact of childhood pain on adult chronic pain vulnerability.

Somatosensory-Evoked Early Sharp Waves in the Neonatal Rat Hippocampus.

The developing entorhinal-hippocampal system is embedded within a large-scale bottom-up network, where spontaneous myoclonic movements, presumably via somatosensory feedback, trigger hippocampal early sharp waves (eSPWs). The hypothesis, that somatosensory feedback links myoclonic movements with eSPWs, implies that direct somatosensory stimulation should also be capable of evoking eSPWs. In this study, we examined hippocampal responses to electrical stimulation of the somatosensory periphery in urethane-anesthetized, immobilized neonatal rat pups using silicone probe recordings. We found that somatosensory stimulation in ~33% of the trials evoked local field potential (LFP) and multiple unit activity (MUA) responses identical to spontaneous eSPWs. The somatosensory-evoked eSPWs were delayed from the stimulus, on average, by 188 ms. Both spontaneous and somatosensory-evoked eSPWs (i) had similar amplitude of ~0.5 mV and half-duration of ~40 ms, (ii) had similar current-source density (CSD) profiles, with current sinks in CA1 strata radiatum, lacunosum-moleculare and DG molecular layer and (iii) were associated with MUA increase in CA1 and DG. Our results indicate that eSPWs can be triggered by direct somatosensory stimulations and support the hypothesis that sensory feedback from movements is involved in the association of eSPWs with myoclonic movements in neonatal rats.

Construction and validation of a database of head models for functional imaging of the neonatal brain.

The neonatal brain undergoes dramatic structural and functional changes over the last trimester of gestation. The accuracy of source localisation of brain activity recorded from the scalp therefore relies on accurate age-specific head models. Although an age-appropriate population-level atlas could be used, detail is lost in the construction of such atlases, in particular with regard to the smoothing of the cortical surface, and so such a model is not representative of anatomy at an individual level. In this work, we describe the construction of a database of individual structural priors of the neonatal head using 215 individual-level datasets at ages 29-44 weeks postmenstrual age from the Developing Human Connectome Project. We have validated a method to segment the extra-cerebral tissue against manual segmentation. We have also conducted a leave-one-out analysis to quantify the expected spatial error incurred with regard to localising functional activation when using a best-matching individual from the database in place of a subject-specific model; the median error was calculated to be 8.3 mm (median absolute deviation 3.8 mm). The database can be applied for any functional neuroimaging modality which requires structural data whereby the physical parameters associated with that modality vary with tissue type and is freely available at www.ucl.ac.uk/dot-hub.

The distribution of pain activity across the human neonatal brain is sex dependent.

In adults, there are differences between male and female structural and functional brain connectivity, specifically for those regions involved in pain processing. This may partly explain the observed sex differences in pain sensitivity, tolerance, and inhibitory control, and in the development of chronic pain. However, it is not known if these differences exist from birth. Cortical activity in response to a painful stimulus can be observed in the human neonatal brain, but this nociceptive activity continues to develop in the postnatal period and is qualitatively different from that of adults, partly due to the considerable cortical maturation during this time. This research aimed to investigate the effects of sex and prematurity on the magnitude and spatial distribution pattern of the long-latency nociceptive event-related potential (nERP) using electroencephalography (EEG). We measured the cortical response time-locked to a clinically required heel lance in 81 neonates born between 29 and 42 weeks gestational age (median postnatal age 4 days). The results show that heel lance results in a spatially widespread nERP response in the majority of newborns. Importantly, a widespread pattern is significantly more likely to occur in females, irrespective of gestational age at birth. This effect is not observed for the short latency somatosensory waveform in the same infants, indicating that it is selective for the nociceptive component of the response. These results suggest the early onset of a greater anatomical and functional connectivity reported in the adult female brain, and indicate the presence of pain-related sex differences from birth.

Functional magnetic resonance imaging can be used to explore tactile and nociceptive processing in the infant brain.

AIM: Despite the importance of neonatal skin stimulation, little is known about activation of the newborn human infant brain by sensory stimulation of the skin. We carried out functional magnetic resonance imaging (fMRI) to assess the feasibility of measuring brain activation to a range of mechanical stimuli applied to the skin of neonatal infants. METHODS: We studied 19 term infants with a mean age of 13 days. Brain activation was measured in response to brushing, von Frey hair (vFh) punctate stimulation and, in one case, nontissue damaging pinprick stimulation of the plantar surface of the foot. Initial whole brain analysis was followed by region of interest analysis of specific brain areas. RESULTS: Distinct patterns of functional brain activation were evoked by brush and vFh punctate stimulation, which were reduced, but still present, under chloral hydrate sedation. Brain activation increased with increasing stimulus intensity. The feasibility of using pinprick stimulation in fMRI studies was established in one unsedated healthy full-term infant. CONCLUSION: Distinct brain activity patterns can be measured in response to different modalities and intensities of skin sensory stimulation in term infants. This indicates the potential for fMRI studies in exploring tactile and nociceptive processing in the infant brain.

Health Care Professionals' and Parents' Perspectives on the Use of AI for Pain Monitoring in the Neonatal Intensive Care Unit: Multisite Qualitative Study.

BACKGROUND: The use of artificial intelligence (AI) for pain assessment has the potential to address historical challenges in infant pain assessment. There is a dearth of information on the perceived benefits and barriers to the implementation of AI for neonatal pain monitoring in the neonatal intensive care unit (NICU) from the perspective of health care professionals (HCPs) and parents. This qualitative analysis provides novel data obtained from 2 large tertiary care hospitals in Canada and the United Kingdom. OBJECTIVE: The aim of the study is to explore the perspectives of HCPs and parents regarding the use of AI for pain assessment in the NICU. METHODS: In total, 20 HCPs and 20 parents of preterm infants were recruited and consented to participate from February 2020 to October 2022 in interviews asking about AI use for pain assessment in the NICU, potential benefits of the technology, and potential barriers to use. RESULTS: The 40 participants included 20 HCPs (17 women and 3 men) with an average of 19.4 (SD 10.69) years of experience in the NICU and 20 parents (mean age 34.4, SD 5.42 years) of preterm infants who were on average 43 (SD 30.34) days old. Six themes from the perspective of HCPs were identified: regular use of technology in the NICU, concerns with regard to AI integration, the potential to improve patient care, requirements for implementation, AI as a tool for pain assessment, and ethical considerations. Seven parent themes included the potential for improved care, increased parental distress, support for parents regarding AI, the impact on parent engagement, the importance of human care, requirements for integration, and the desire for choice in its use. A consistent theme was the importance of AI as a tool to inform clinical decision-making and not replace it. CONCLUSIONS: HCPs and parents expressed generally positive sentiments about the potential use of AI for pain assessment in the NICU, with HCPs highlighting important ethical considerations. This study identifies critical methodological and ethical perspectives from key stakeholders that should be noted by any team considering the creation and implementation of AI for pain monitoring in the NICU.

Cortical activity evoked by an acute painful tissue-damaging stimulus in healthy adult volunteers.

Everyday painful experiences are usually single events accompanied by tissue damage, and yet most experimental studies of cutaneous nociceptive processing in the brain use repeated laser, thermal, or electrical stimulations that do not damage the skin. In this study the nociceptive activity in the brain evoked by tissue-damaging skin lance was analyzed with electroencephalography (EEG) in 20 healthy adult volunteers (13 men and 7 women) aged 21-40 yr. Time-frequency analysis of the evoked activity revealed a distinct late event-related vertex potential (lance event-related potential, LERP) at 100-300 ms consisting of a phase-locked energy increase between 1 and 20 Hz (delta-beta bands). A pairwise comparison between lance and sham control stimulation also revealed a period of ultralate stronger desynchronization after lance in the delta band (1-5 Hz). Skin application of mustard oil before lancing, which sensitizes a subpopulation of nociceptors expressing the cation channel TRPA1, did not affect the ultralate desynchronization but reduced the phase-locked energy increase in delta and beta bands, suggesting a central interaction between different modalities of nociceptive inputs. Verbal descriptor screening of individual pain experience revealed that lance pain is predominantly due to Aδ fiber activation, but when individuals describe lances as C fiber mediated, an ultralate delta band event-related desynchronization occurs in the brain-evoked activity. We conclude that pain evoked by acute tissue damage is associated with distinct Aδ and C fiber-mediated patterns of synchronization and desynchronization of EEG oscillations in the brain.

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.

Clinical thresholds in pain-related facial activity linked to differences in cortical network activation in neonates.

ABSTRACT: In neonates, a noxious stimulus elicits pain-related facial expression changes and distinct brain activity as measured by electroencephalography, but past research has revealed an inconsistent relationship between these responses. Facial activity is the most commonly used index of neonatal pain in clinical settings, with clinical thresholds determining if analgesia should be provided; however, we do not know if these thresholds are associated with differences in how the neonatal brain processes a noxious stimulus. The objective of this study was to examine whether subclinical vs clinically significant levels of pain-related facial activity are related to differences in the pattern of nociceptive brain activity in preterm and term neonates. We recorded whole-head electroencephalography and video in 78 neonates (0-14 days postnatal age) after a clinically required heel lance. Using an optimal constellation of Neonatal Facial Coding System actions (brow bulge, eye squeeze, and nasolabial furrow), we compared the serial network engagement (microstates) between neonates with and without clinically significant pain behaviour. Results revealed a sequence of nociceptive cortical network activation that was independent of pain-related behavior; however, a separate but interleaved sequence of early activity was related to the magnitude of the immediate behavioural response. Importantly, the degree of pain-related behavior is related to how the brain processes a stimulus and not simply the degree of cortical activation. This suggests that neonates who exhibit clinically significant pain behaviours process the stimulus differently and that neonatal pain-related behaviours reflect just a portion of the overall cortical pain response.

Widespread nociceptive maps in the human neonatal somatosensory cortex.

Topographic cortical maps are essential for spatial localisation of sensory stimulation and generation of appropriate task-related motor responses. Somatosensation and nociception are finely mapped and aligned in the adult somatosensory (S1) cortex, but in infancy, when pain behaviour is disorganised and poorly directed, nociceptive maps may be less refined. We compared the topographic pattern of S1 activation following noxious (clinically required heel lance) and innocuous (touch) mechanical stimulation of the same skin region in newborn infants (n = 32) using multioptode functional near-infrared spectroscopy (fNIRS). Within S1 cortex, touch and lance of the heel elicit localised, partially overlapping increases in oxygenated haemoglobin concentration (Δ[HbO]), but while touch activation was restricted to the heel area, lance activation extended into cortical hand regions. The data reveals a widespread cortical nociceptive map in infant S1, consistent with their poorly directed pain behaviour.

Oral sucrose as an analgesic drug for procedural pain in newborn infants: a randomised controlled trial.

BACKGROUND: Many infants admitted to hospital undergo repeated invasive procedures. Oral sucrose is frequently given to relieve procedural pain in neonates on the basis of its effect on behavioural and physiological pain scores. We assessed whether sucrose administration reduces pain-specific brain and spinal cord activity after an acute noxious procedure in newborn infants. METHODS: In this double-blind, randomised controlled trial, 59 newborn infants at University College Hospital (London, UK) were randomly assigned to receive 0·5 mL 24% sucrose solution or 0·5 mL sterile water 2 min before undergoing a clinically required heel lance. Randomisation was by a computer-generated randomisation code, and researchers, clinicians, participants, and parents were masked to the identity of the solutions. The primary outcome was pain-specific brain activity evoked by one time-locked heel lance, recorded with electroencephalography and identified by principal component analysis. Secondary measures were baseline behavioural and physiological measures, observational pain scores (PIPP), and spinal nociceptive reflex withdrawal activity. Data were analysed per protocol. This study is registered, number ISRCTN78390996. FINDINGS: 29 infants were assigned to receive sucrose and 30 to sterilised water; 20 and 24 infants, respectively, were included in the analysis of the primary outcome measure. Nociceptive brain activity after the noxious heel lance did not differ significantly between infants who received sucrose and those who received sterile water (sucrose: mean 0·10, 95% CI 0·04-0·16; sterile water: mean 0·08, 0·04-0·12; p=0·46). No significant difference was recorded between the sucrose and sterile water groups in the magnitude or latency of the spinal nociceptive reflex withdrawal recorded from the biceps femoris of the stimulated leg. The PIPP score was significantly lower in infants given sucrose than in those given sterile water (mean 5·8, 95% CI 3·7-7·8 vs 8·5, 7·3-9·8; p=0·02) and significantly more infants had no change in facial expression after sucrose administration (seven of 20 [35%] vs none of 24; p<0·0001). INTERPRETATION: Our data suggest that oral sucrose does not significantly affect activity in neonatal brain or spinal cord nociceptive circuits, and therefore might not be an effective analgesic drug. The ability of sucrose to reduce clinical observational scores after noxious events in newborn infants should not be interpreted as pain relief. FUNDING: Medical Research Council.

Sleep-wake regulation in preterm and term infants.

STUDY OBJECTIVES: In adults, wakefulness can be markedly prolonged at the expense of sleep, e.g. to stay vigilant in the presence of a stressor. These extra-long wake bouts result in a heavy-tailed distribution (highly right-skewed) of wake but not sleep durations. In infants, the relative importance of wakefulness and sleep are reversed, as sleep is necessary for brain maturation. Here, we tested whether these developmental pressures are associated with the unique regulation of sleep-wake states. METHODS: In 175 infants of 28-40 weeks postmenstrual age (PMA), we monitored sleep-wake states using electroencephalography and behavior. We constructed survival models of sleep-wake bout durations and the effect of PMA and other factors, including stress (salivary cortisol), and examined whether sleep is resilient to nociceptive perturbations (a clinically necessary heel lance). RESULTS: Wake durations followed a heavy-tailed distribution as in adults and lengthened with PMA and stress. However, differently from adults, active sleep durations also had a heavy-tailed distribution, and with PMA, these shortened and became vulnerable to nociception-associated awakenings. CONCLUSIONS: Sleep bouts are differently regulated in infants, with especially long active sleep durations that could consolidate this state's maturational functions. Curtailment of sleep by stress and nociception may be disadvantageous, especially for preterm infants given the limited value of wakefulness at this age. This could be addressed by environmental interventions in the future.

The impact of parental contact upon cortical noxious-related activity in human neonates.

BACKGROUND: Neonates display strong behavioural, physiological and cortical responses to tissue-damaging procedures. Parental contact can successfully regulate general behavioural and physiological reactivity of the infant, but it is not known whether it can influence noxious-related activity in the brain. Brain activity is highly dependent upon maternal presence in animal models, and therefore this could be an important contextual factor in human infant pain-related brain activity. METHODS: Global topographic analysis was used to identify the presence and inter-group differences in noxious-related activity in three separate parental contexts. EEG was recorded during a clinically required heel lance in three age and sex-matched groups of neonates (a) while held by a parent in skin-to-skin (n = 9), (b) while held by a parent with clothing (n = 9) or (c) not held at all, but in individualized care (n = 9). RESULTS: The lance elicited a sequence of 4-5 event-related potentials (ERPs), including the noxious ERP (nERP), which was smallest for infants held skin-to-skin and largest for infants held with clothing (p=0.016). The nERP was then followed by additional and divergent long-latency ERPs (> 750 ms post-lance), not previously described, in each of the groups, suggesting the engagement of different higher level cortical processes depending on parental contact. CONCLUSIONS: These results show the importance of considering contextual factors in determining infant brain activity and reveal the powerful influence of parental contact upon noxious-related activity across the developing human brain. SIGNIFICANCE: This observational study found that the way in which the neonatal brain processes a noxious stimulus is altered by the type of contact the infant has with their mother. Specifically, being held in skin-to-skin reduces the magnitude of noxious-related cortical activity. This work has also shown that different neural mechanisms are engaged depending on the mother/infant context, suggesting maternal contact can change how a baby's brain processes a noxious stimulus.

Premature infants display increased noxious-evoked neuronal activity in the brain compared to healthy age-matched term-born infants.

This study demonstrates that infants who are born prematurely and who have experienced at least 40days of intensive or special care have increased brain neuronal responses to noxious stimuli compared to healthy newborns at the same postmenstrual age. We have measured evoked potentials generated by noxious clinically-essential heel lances in infants born at term (8 infants; born 37-40weeks) and in infants born prematurely (7 infants; born 24-32weeks) who had reached the same postmenstrual age (mean age at time of heel lance 39.2+/-1.2weeks). These noxious-evoked potentials are clearly distinguishable from shorter latency potentials evoked by non-noxious tactile sensory stimulation. While the shorter latency touch potentials are not dependent on the age of the infant at birth, the noxious-evoked potentials are significantly larger in prematurely-born infants. This enhancement is not associated with specific brain lesions but reflects a functional change in pain processing in the brain that is likely to underlie previously reported changes in pain sensitivity in older ex-preterm children. Our ability to quantify and measure experience-dependent changes in infant cortical pain processing will allow us to develop a more rational approach to pain management in neonatal intensive care.

Distinct Age-Dependent C Fiber-Driven Oscillatory Activity in the Rat Somatosensory Cortex.

When skin afferents are activated, the sensory signals are transmitted to the spinal cord and eventually reach the primary somatosensory cortex (S1), initiating the encoding of the sensory percept in the brain. While subsets of primary afferents mediate specific somatosensory information from an early age, the subcortical pathways that transmit this information undergo striking changes over the first weeks of life, reflected in the gradual emergence of specific sensory behaviors. We therefore hypothesized that this period is associated with differential changes in the encoding of incoming afferent volleys in S1. To test this, we compared S1 responses to A fiber skin afferent stimulation and A + C skin afferent fiber stimulation in lightly anaesthetized male rats at postnatal day (P)7, P14, P21, and P30. Differences in S1 activity following A and A + C fiber stimulation changed dramatically over this period. At P30, A + C fiber stimulation evoked significantly larger γ, ß, and α energy increases compared with A fiber stimulation alone. At younger ages, the changes in S1 oscillatory activity evoked by the two afferent volleys were not significantly different. Silencing TRPV1+ C fibers with QX-314 significantly reduced the γ and ß S1 oscillatory energy increases evoked by A + C fibers, at P30 and P21, but not at younger ages. Thus, C fibers differentially modulate S1 oscillatory activity only from the third postnatal week, well after the functional maturation of the somatosensory cortex. This age-related change in afferent evoked S1 oscillatory activity may underpin the maturation of sensory discrimination in the developing brain.

Long-range temporal organisation of limb movement kinematics in human neonates.

OBJECTIVE: Movement provides crucial sensorimotor information to the developing brain, evoking somatotopic cortical EEG activity. Indeed, temporal-spatial organisation of these movements, including a diverse repertoire of accelerations and limb combinations (e.g. unilateral progressing to bilateral), predicts positive sensorimotor outcomes. However, in current clinical practice, movements in human neonates are qualitatively characterised only during brief periods (a few minutes) of wakefulness, meaning that the vast majority of sensorimotor experience remains unsampled. Here our objective was to quantitatively characterise the long-range temporal organisation of the full repertoire of newborn movements, over multi-hour recordings. METHODS: We monitored motor activity across 2-4 h in 11 healthy newborn infants (median 1 day old), who wore limb sensors containing synchronised tri-axial accelerometers and gyroscopes. Movements were identified using acceleration and angular velocity, and their organisation across the recording was characterised using cluster analysis and spectral estimation. RESULTS: Movement occurrence was periodic, with a 1-hour cycle. Peaks in movement occurrence were associated with higher acceleration, and a higher proportion of movements being bilateral. CONCLUSIONS: Neonatal movement occurrence is cyclical, with periods consistent with sleep-wake behavioural architecture. Movement kinematics are organised by these fluctuations in movement occurrence. Recordings that exceed 1-hour are necessary to capture the long-range temporal organisation of the full repertoire of newborn limb movements. SIGNIFICANCE: Future work should investigate the prognostic value of combining these movement recordings with synchronised EEG, in at-risk infants.

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.

Quantification of neonatal procedural pain severity: a platform for estimating total pain burden in individual infants.

There is increasing evidence that long-term outcomes for infants born prematurely are adversely affected by repeated exposure to noxious procedures. These interventions vary widely, for example, in the extent of damage caused and duration. Neonatal intensive care unit (NICU) procedures are therefore likely to each contribute differently to the overall pain burden of individual neonates, ultimately having a different impact on their development. For researchers to quantify the procedural pain burden experienced by infants on NICU, we aimed to estimate the pain severity of common NICU procedures using published pain scores. We extracted pain scores over the first minute (pain reactivity) from the literature, using 59 randomized controlled trials for 15 different procedures. Hierarchical cluster analysis of average pain scores resulted in 5 discrete severity groups; mild (n = 1), mild to moderate (n = 3), moderate (n = 7), severe (n = 3), and very severe (n = 1). The estimate of the severity of individual procedures provided new insight into infant pain reactivity which is not always directly related to the invasiveness and duration of a procedure; thus, both heel lance and skin tape removal are moderately painful procedures. This estimate of procedural pain severity, based on pain reactivity scores, provides a novel platform for retrospective quantification of an individual neonate's pain burden due to NICU procedures. The addition of measures that reflect the recovery from each procedure, such as brain activity and behavioural regulation, would further improve estimates of the pain burden of neonatal intensive care.

Fronto-central slow cortical activity is attenuated during phasic events in rapid eye movement sleep at full-term birth.

Delta and theta power across fronto-central regions is lower during phasic (saccadic eye movements) than tonic rapid eye movement (active) sleep in full-term infants (n = 15). This indicates that the behavioural-electrophysiological pillars of rapid eye movement sleep micro-architecture are in place at birth.

Event-related potentials following contraction of respiratory muscles in pre-term and full-term infants.

OBJECTIVE: Involuntary isolated body movements are prominent in pre-term and full-term infants. Proprioceptive and tactile afferent feedback following limb muscle contractions is associated with somatotopic EEG responses. Involuntary contractions of respiratory muscles, primarily the diaphragm - hiccups - are also frequent throughout the human perinatal period during active behavioural states. Here we tested whether diaphragm contraction provides afferent input to the developing brain, as following limb muscle contraction. METHODS: In 13 infants on the neonatal ward (30-42 weeks corrected gestational age), we analysed EEG activity (18-electrode recordings in six subjects; 17-electrode recordings in five subjects; 16-electrode recordings in two subjects), time-locked to diaphragm contractions (n = 1316) recorded with a movement transducer affixed to the trunk. RESULTS: All bouts of hiccups occurred during wakefulness or active sleep. Each diaphragm contraction evoked two initial event-related potentials with negativity predominantly across the central region, and a third event-related potential with positivity maximal across the central region. CONCLUSIONS: Involuntary contraction of the diaphragm can be encoded by the brain from as early as ten weeks prior to the average time of birth. SIGNIFICANCE: Hiccups - frequently observed in neonates - can provide afferent input to developing sensory cortices in pre-term and full-term infants.