Developmental trajectory of movement-evoked cortical oscillations during REM sleep in pre-term and full-term human infants

<div><b>Abstract</b></div><div>Newborn infants spend 50% of their time in active sleep (precursor to REM sleep). This vigilance state is characterised by frequent isolated limb movements, which in neonatal animal models provide early proprioceptive input to the immature somatosensory system and are somatotopically encoded in the cortex by fast alpha-beta oscillations (8-20 Hz) until the equivalent of human full-term. Similar neural patterns have been identified following isolated limb movements in very pre-term human infants, but it is unknown whether they too persist until full-term age. In a cohort of 19 pre-term and term neonates (31-42 corrected gestational weeks) we showed that these same somatotopically distributed oscillations continue to occur after isolated hand movements well into the perinatal period (paired tests comparing epochs pre- and post-movement p ≤ .030), but disappear at 40 weeks corrected gestational age (equivalent to the end of gestation) (r - .253, p = .002). We also showed that these highly localised alpha-beta oscillations are associated with a more diffuse increase in delta oscillations which extends to the superior frontal area and does not decline with age. These results suggest that the frequent movements during active sleep prior to full-term could have an important role in somatomotor developmental programming, representing a fundamental mechanism of somatosensory maturation during the equivalent of the third trimester of human gestation.</div><div><br></div><div>This is a pre-print of an article published in Scientific Reports. The final authenticated version is available online at: <a href="https://doi.org/10.1038/s41598-018-35850-1" rel="noopener noreferrer" target="_blank">https://doi.org/10.1038/s41598-018-35850-1</a><br></div

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

<div><b>Abstract</b></div><div>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 to sleep states in healthy pre-term infants, and the factors which influence this, is poorly understood. To investigate whether cortical activity has a different developmental profile in each vigilance state, we characterised the trajectory of delta, theta and alpha-beta oscillations in wakefulness, active sleep and non-REM sleep in 115 infants 34–43 weeks corrected age, with 0.5-17 days of postnatal age.</div><div><br></div><div>Delta oscillations in wakefulness and active sleep decrease with corrected age, particularly in the temporal region, but not in non-REM sleep. Theta oscillations increase with corrected age in sleep, especially non-REM sleep, but not in wakefulness. On the other hand, alpha-beta oscillations decrease predominantly with postnatal age, independently of vigilance state, particularly in the occipital region.</div><div><br></div><div>The developmental trajectory of delta and theta rhythms is state-dependent, and results in changed cortical activity patterns across states with corrected age. The prominent changes in delta activity in wakefulness and active sleep, and in theta activity in non-REM sleep, may suggest that these frequency bands have particular functional roles in each state. Interestingly, postnatal age is associated with a decrease in alpha-beta oscillations overlying primary visual cortex in every vigilance state, suggesting that postnatal experience (including the first visual input through open eyes during periods of wakefulness) may especially modulate resting-state visual cortical activity.</div

The emergence of hierarchical somatosensory processing in late prematurity

<div><b>Abstract</b></div><div><br></div><div>The somatosensory system has a hierarchical organization. Information processing increases in complexity from the contralateral primary sensory cortex to bilateral association cortices and this is represented by a sequence of somatosensory event related potentials of increasing latencies, recorded in scalp EEGs. The mammalian somatosensory system is known to mature over the early postnatal period in a rostro-caudal progression, but little is known about the development of hierarchical information processing in the human infant brain. To investigate the normal human development of the somatosensory hierarchy, we recorded event related potentials evoked by mechanical stimulation of hands and feet in 34 infants between 34 and 42 weeks corrected age, with median postnatal age of 3 days. We show that the shortest latency potential was evoked from both hands and feet at all ages with a stable contralateral somatotopic distribution. However, the longer latency responses matured with age, gradually emerging for the foot and, although always present, showing a shift from contralateral to bilateral hemispheric activation for the hand. These results demonstrate the rostro-caudal development of human somatosensory hierarchy and suggest that development of the higher tiers of this hierarchy are complete only just before normal birth, when bilateral integration becomes possible.</div

EEG, behavioural, and physiological responses to a painful procedure in human neonates with full medical history

<p>We present a dataset combining the cortical, behavioural, and physiological responses of a neonatal population to a single painful stimulus. Responses were recorded from 112 neonates (29–47 weeks corrected age) using a 20 channel electroencephalogram (EEG), which was time-locked to a clinically required heel lance, and a standard behavioral and physiological composite pain score (Premature Infant Pain Profile, PIPP). The dataset also includes the responses to a non-painful control and an auditory stimulus. The infant’s medical history was collected up to the day of the study and collated into an extensive database of variables such as: the condition at birth, diagnoses, medications, previous painful procedures, and injuries, and selected maternal information. This dataset can be used to further investigate the development of cortical, physiological, and behavioural responses to painful stimuli and the impact of various medical conditions and experiences upon these responses, with the potential for understanding complex pain phenotypes. </p

Measurement of facial somatosensation in pre-term infants

<div><b>Abstract</b></div><div><b><br></b></div><div>Facial somatosensory feedback is critical to breastfeeding, but its development in human infants has never been studied, in part due to inadequate existing stimulators. We developed a stimulation method for the sensitive facial area based on a seamless device wearable on the finger, to measure neural responses in infants. The novel subject-computer interface allows to synchronously record: (i) the force applied by the experimenter, (ii) 18-channels scalp electroencephalography (EEG), and (iii) video-recording. Taps of 203 mN (median) reliably elicited facial somatosensory neural responses with a comparable morphology to both hand and foot stimulation in 3 pre-term infants. The scalp distribution of the facial somatosensory response had a different focus to the foot response, and was less diffuse than the hand response, indicating that this method can discriminate differential spatial cortical activation according to stimulated body area. In addition, the accurate measurement of the applied force exhibited a monotonic relationship between the amplitude of the somatosensory response and force intensity. In comparison to existing forms of tactile stimulation, the method introduced is gentler, physiological, and can be finely controlled by the experimenter. This integrated system can provide reliable and reproducible measurements of facial somatosensory responses in vulnerable infants.</div

Single and repeated punctate stimulation evokes flexion activity that is gestational age dependent.

<p>A, Cutaneous sensory threshold to punctate stimulation significantly increases with gestational age; B, threshold force required to evoke leg withdrawal and example flexion reflex EMG traces from term and preterm infants are shown. C, Threshold flexion reflex EMG responses in preterm infants are significantly greater than in term (two-way ANOVA, ***p<0.0001 age group, **p = <0.0001 time; Fisher's unpaired t-test, 250 ms, *p = 0.02; 500 ms, ***p<0.0001, 750 ms, ***p<0.0001). Note- two EMG recordings excluded from the analysis due to technical artefact. D, Brief, low frequency repeated punctate stimulation sensitised infant flexion reflex EMG activity as shown by a significantly larger flexion response to a threshold hair after 10 seconds of repeated stimulation, compared to the responses to the same threshold hair when tested 10 s before the train (two-way ANOVA, *p = 0.04 treatment,***p = 0.002, time; Fisher's paired t-test, 250 ms, *p = 0,002, n = 11, pooled term and preterm.</p

Noxious stimulation evokes ipsilateral and contralateral flexion activity in preterm and term infants.

<p>A: Evoked activity on the two sides are not significantly different in A, term infants (n = 13) and B: preterm infants (n = 11). Inset: Experiment set-up, surface EMG leads were placed over the ipsilateral (filled lines) and contralateral (dashed lines) biceps femoris to record flexion reflex EMG activity evoked by a heel lance. Example trace from term and preterm infant below, arrow indicates time of noxious stimulus.</p

Demographic characterisation of the neonatal population.

<p>SDs are in parentheses. GA, Gestational Age.</p>*<p>Information unavailable for 2 infants. ⁺Information unavailable for 4 infants.</p

Flexion withdrawal reflex biceps femoris EMG activity evoked by noxious and tactile stimulation.

<p>Only data from those infants that displayed a paired tactile and lance response is shown here. A. term (n = 7) and B. preterm infants (n = 5). Data is expressed as fold increase in EMG activity measured in 250 ms time epochs for 4 secs post stimulus. While in term infants (A) the flexor reflex response to noxious lance stimulation is significantly greater than to tactile stimulation, in preterm infants, the two responses are not significantly different. [Term infants two-way ANOVA, **p = 0.006 time, ****p<0.0001 stimulus. Student's t-test, at 250 ms, *p = 0.014, at 500 ms, ***p = 0.0005, and at 750 ms, **p = 0.006].</p

A novel neonatal procedural pain index derived from adult self-report

<div><b>Abstact</b></div><div><b>Objective</b>: This study addresses the gap in our understanding of neonatal procedural pain intensity. We aimed to identify the most commonly performed neonatal procedures, devise a pain ranking of these procedures based on adult pain scores, and develop a new Neonatal Pain Index (NPI).</div><div><b>Design</b>: A retrospective analysis of neonatal procedures and an online literature search of adult procedural pain intensity.</div><div><b>Setting</b>: Neonatal wards in University College London Hospital.</div><div><b>Patients</b>: 138 neonates [23-42 weeks gestational age] for retrospective procedure history. Literature survey of 5405 adults receiving standard care or in control arms of clinical trials for pain ranking.</div><div>Interventions: 11 most common neonatal procedures in a hospital setting.</div><div><b>Main outcome measures</b>: Frequency of neonatal painful procedures. Pain scores derived from adult self-report.</div><div><b>Results</b>: Of 3,728 neonatal procedures, the heel lance was the most common (66%). Of the adult procedures reviewed, nasogastric tube insertion was the most painful (pooled mean score 5.9±2.7 out of 10) while lance was one of the least painful (pooled mean score 2.1±1.5). The adult scores differed from the estimates currently held by most neonatologists. A neonatal pain index (NPI) was developed to grade individual neonatal pain history based on the number of procedures and average adult pain score for each of those procedures.</div><div><b>Conclusion</b>: This systematic approach to neonatal procedural pain, through comparison to a gold standard adult measure, can be used as an index which quantifies the total pain experience of a neonate throughout their hospital admission.</div