Clinical value of cortical bursting in preterm infants with intraventricular haemorrhage.

BACKGROUND: In healthy preterm infants, cortical burst rate and temporal dynamics predict important measures such as brain growth. We hypothesised that in preterm infants with germinal matrix-intraventricular haemorrhage (GM-IVH), cortical bursting could provide prognostic information. AIMS: We determined how cortical bursting was influenced by the injury, and whether this was related to developmental outcome. STUDY DESIGN: Single-centre retrospective cohort study at University College London Hospitals, UK. SUBJECTS: 33 infants with GM-IVH ≥ grade II (median gestational age: 25 weeks). OUTCOME MEASURES: We identified 47 EEGs acquired between 24 and 40 weeks corrected gestational age as part of routine clinical care. In a subset of 33 EEGs from 25 infants with asymmetric injury, we used the least-affected hemisphere as an internal comparison. We tested whether cortical burst rate predicted survival without severe impairment (median 2 years follow-up). RESULTS: In asymmetric injury, cortical burst rate was lower over the worst- than least-affected hemisphere, and bursts over the worst-affected hemisphere were less likely to immediately follow bursts over the least-affected hemisphere than vice versa. Overall, burst rate was lower in cases of GM-IVH with parenchymal involvement, relative to milder structural injury grades. Higher burst rate modestly predicted survival without severe language (AUC 0.673) or motor impairment (AUC 0.667), which was partly mediated by structural injury grade. CONCLUSIONS: Cortical bursting can index the functional injury after GM-IVH: perturbed burst initiation (rate) and propagation (inter-hemispheric dynamics) likely reflect associated grey matter and white matter damage. Higher cortical burst rate is reassuring for a positive outcome.

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.

Prognostic value of neonatal EEG following therapeutic hypothermia in survivors of hypoxic-ischemic encephalopathy.

OBJECTIVE: Early prediction of neurological deficits following neonatal hypoxic-ischemic encephalopathy (HIE) may help to target support. Neonatal animal models suggest that recovery following hypoxia-ischemia depends upon cortical bursting. To test whether this holds in human neonates, we correlated the magnitude of cortical bursting during recovery (≥postnatal day 3) with neurodevelopmental outcomes. METHODS: We identified 41 surviving infants who received therapeutic hypothermia for HIE (classification at hospital discharge: 19 mild, 18 moderate, 4 severe) and had 9-channel electroencephalography (EEG) recordings as part of their routine care. We correlated burst power with Bayley-III cognitive, motor and language scores at median 24 months. To examine whether EEG offered additional prognostic information, we controlled for structural MRI findings. RESULTS: Higher power of central and occipital cortical bursts predicted worse cognitive and language outcomes, and higher power of central cortical bursts predicted worse motor outcome, all independently of structural MRI findings. CONCLUSIONS: Clinical EEG after postnatal day 3 may provide additional prognostic information by indexing persistent active mechanisms that either support recovery or exacerbate brain damage, especially in infants with less severe encephalopathy. SIGNIFICANCE: These findings could allow for the effect of clinical interventions in the neonatal period to be studied instantaneously 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.

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.

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.

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.

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.

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.

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.

Developmental trajectory of movement-related cortical oscillations during active sleep in a cross-sectional cohort of pre-term and full-term human infants.

In neonatal animal models, isolated limb movements during active sleep provide input to immature somatomotor cortex necessary for its development and are somatotopically encoded by alpha-beta oscillations as late as the equivalent of human full-term. Limb movements elicit similar neural patterns in very pre-term human infants (average 30 corrected gestational weeks), suggesting an analogous role in humans, but it is unknown until when they subserve this function. In a cohort of 19 neonates (31-42 corrected gestational weeks) we showed that isolated hand movements during active sleep continue to induce these same somatotopically distributed oscillations well into the perinatal period, but that these oscillations decline towards full-term and fully disappear at 41 corrected gestational weeks (equivalent to the end of gestation). We also showed that these highly localised alpha-beta oscillations are associated with an increase in delta oscillations which extends to the frontal area and does not decline with age. These results suggest that isolated limb movements during active sleep could have an important role in experience-dependent somatomotor development up until normal birth in humans.

A novel sensor design for accurate measurement of facial somatosensation in pre-term infants.

Facial somatosensory feedback is critical for breastfeeding in the first days of life. However, its development has never been investigated in humans. Here we develop a new interface to measure facial somatosensation in newborn infants. The novel system allows to measure neuronal responses to touching the face of the subject by synchronously recording scalp electroencephalography (EEG) and the force applied by the experimenter. This is based on a dedicated force transducer that can be worn on the finger underneath a clinical nitrile glove and linked to a commercial EEG acquisition system. The calibrated device measures the pressure applied by the investigator when tapping the skin concurrently with the resulting brain response. With this system, we were able to demonstrate that taps of 192 mN (mean) reliably elicited facial somatosensory responses in 7 pre-term infants. These responses had a time course similar to those following limbs stimulation, but more lateral topographical distribution consistent with body representations in primary somatosensory areas. The method introduced can therefore be used to reliably measure facial somatosensory responses in vulnerable infants.

EEG, behavioural and physiological recordings following a painful procedure in human neonates.

We present a 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. The infants' relevant medical and pain history was collected up to the day of the study and recorded in an extensive database of variables including clinical condition at birth, diagnoses, medications, previous painful procedures, injuries, and selected maternal information. This dataset can be used to investigate the cortical, physiological, and behavioural pain-related processing in human infants and to evaluate the impact of medical conditions and experiences upon the infant response to noxious stimuli. Furthermore, it provides information on the formation of individual pain phenotypes.

Emergence of mature cortical activity in wakefulness and sleep in healthy preterm and full-term infants.

Study Objectives: Cortical activity patterns develop rapidly over the equivalent of the last trimester of gestation, in parallel with the establishment of sleep architecture. However, the emergence of mature cortical activity in wakefulness compared with sleep states in healthy preterm infants is poorly understood. Methods: To investigate whether the cortical activity has a different developmental profile in each sleep-wake state, we recorded 11-channels electroencephalography (EEG), electrooculography (EOG), and respiratory movement for 1 hr from 115 infants 34 to 43 weeks-corrected age, with 0.5-17 days of postnatal age. We characterized the trajectory of δ, θ, and α-ß oscillations in wakefulness, rapid eye movement (REM) sleep, and non-REM sleep by calculating the power spectrum of the EEG, averaged across artifact-free epochs. Results: δ-Oscillations in wakefulness and REM sleep decrease with corrected age, particularly in the temporal region, but not in non-REM sleep. θ-Oscillations increase with corrected age in sleep, especially non-REM sleep, but not in wakefulness. On the other hand, α-ß oscillations decrease predominantly with postnatal age, independently of sleep-wake state, particularly in the occipital region. Conclusions: The developmental trajectory of δ and θ rhythms is state-dependent and results in changed cortical activity patterns between states with corrected age, which suggests that these frequency bands may have particular functional roles in each state. Interestingly, postnatal age is associated with a decrease in α-ß oscillations overlying primary visual cortex in every sleep-wake state, suggesting that postnatal experience (including the first visual input through open eyes during periods of wakefulness) is associated with resting-state visual cortical activity changes.

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.

Optimising the use of EEG in non-epileptic attack disorder: Results of a UK national service evaluation.

PURPOSE: To produce an evidence base to formulate guidelines for optimal performance of EEG in patients referred with a possible diagnosis of non-epileptic attack disorder (NEAD). METHODS: 51 UK EEG departments participated in the prospective study. A pro-forma was completed for all consecutive patients aged 5 years and over referred for EEG over a six month period. Information obtained included referral diagnosis, occurrence/type of attack during EEG, the use of suggestion, length of recording and who was present during the EEG. RESULTS: 11,298 patients were entered into the study. 376 psychogenic non-epileptic seizures (PNES) occurred of which 337 were considered to be of the habitual type. In those patients suspected of having NEAD prior to referral, the use of verbal suggestion increased the yield of habitual attacks by a factor of three in both adults and children. Using suggestive techniques twice, improved the yield further. Non-habitual attacks occurred equally whether or not suggestion was used. At least 90% of habitual PNES occurred within the first 30 min of recording even in those patients having prolonged EEGs. In EEGs where additional professional personnel were present, PNES occurred more frequently. CONCLUSION: This large multicentre study provides evidence to inform recommendations for EEG to investigate NEAD. We recommend the use of verbal suggestion at least twice and where practical the presence of additional professional staff. A thirty minute recording is sufficient to record a habitual PNES in most instances.

Nociceptive Cortical Activity Is Dissociated from Nociceptive Behavior in Newborn Human Infants under Stress.

Newborn infants display strong nociceptive behavior in response to tissue damaging stimuli, and this is accompanied by nociceptive activity generated in subcortical and cortical areas of the brain [1, 2]. In the absence of verbal report, these nociceptive responses are used as measures of pain sensation in newborn humans, as they are in animals [3, 4]. However, many infants are raised in a physiologically stressful environment, and little is known about the effect of background levels of stress upon their pain responses. In adults, acute physiological stress causes hyperalgesia [5-7], and increased background stress increases pain [8-10], but these data cannot necessarily be extrapolated to infants. Here we have simultaneously measured nociceptive behavior, brain activity, and levels of physiological stress in a sample of 56 newborn human infants aged 36-42 weeks. Salivary cortisol (hypothalamic pituitary axis), heart rate variability (sympathetic adrenal medullary system), EEG event-related potentials (nociceptive cortical activity), and facial expression (behavior) were acquired in individual infants following a clinically required heel lance. We show that infants with higher levels of stress exhibit larger amplitude cortical nociceptive responses, but this is not reflected in their behavior. Furthermore, while nociceptive behavior and cortical activity are normally correlated, this relationship is disrupted in infants with high levels of physiological stress. Brain activity evoked by noxious stimulation is therefore enhanced by stress, but this cannot be deduced from observation of pain behavior. This may be important in the prevention of adverse effects of early repetitive pain on brain development.