Sensory event-related potential morphology predicts age in premature infants.

OBJECTIVE: We investigated whether sensory-evoked cortical potentials could be used to estimate the age of an infant. Such a model could be used to identify infants who deviate from normal neurodevelopment. METHODS: Infants aged between 28- and 40-weeks post-menstrual age (PMA) (166 recording sessions in 96 infants) received trains of visual and tactile stimuli. Neurodynamic response functions for each stimulus were derived using principal component analysis and a machine learning model trained and validated to predict infant age. RESULTS: PMA could be predicted accurately from the magnitude of the evoked responses (training set mean absolute error and 95% confidence intervals: 1.41 [1.14; 1.74] weeks,p = 0.0001; test set mean absolute error: 1.55 [1.21; 1.95] weeks,p = 0.0002). Moreover, we show that their predicted age (their brain age) is correlated with a measure known to relate to maturity of the nervous system and is linked to long-term neurodevelopment. CONCLUSIONS: Sensory-evoked potentials are predictive of age in premature infants and brain age deviations are related to biologically and clinically meaningful individual differences in nervous system maturation. SIGNIFICANCE: This model could be used to detect abnormal development of infants' response to sensory stimuli in their environment and may be predictive of neurodevelopmental outcome.

The PiNe box: Development and validation of an electronic device to time-lock multimodal responses to sensory stimuli in hospitalised infants.

Recording multimodal responses to sensory stimuli in infants provides an integrative approach to investigate the developing nervous system. Accurate time-locking across modalities is essential to ensure that responses are interpreted correctly, and could also improve clinical care, for example, by facilitating automatic and objective multimodal pain assessment. Here we develop and assess a system to time-lock stimuli (including clinically-required heel lances and experimental visual, auditory and tactile stimuli) to electrophysiological research recordings and data recorded directly from a hospitalised infant's vital signs monitor. The electronic device presented here (that we have called 'the PiNe box') integrates a previously developed system to time-lock stimuli to electrophysiological recordings and can simultaneously time-lock the stimuli to recordings from hospital vital signs monitors with an average precision of 105 ms (standard deviation: 19 ms), which is sufficient for the analysis of changes in vital signs. Our method permits reliable and precise synchronisation of data recordings from equipment with legacy ports such as TTL (transistor-transistor logic) and RS-232, and patient-connected networkable devices, is easy to implement, flexible and inexpensive. Unlike current all-in-one systems, it enables existing hospital equipment to be easily used and could be used for patients of any age. We demonstrate the utility of the system in infants using visual and noxious (clinically-required heel lance) stimuli as representative examples.

Robotic communication with ants.

We used a robotic gantry to test the hypothesis that tandem running in the ant Temnothorax albipennis can be successful in the absence of trail laying by the leader. Pheromone glands were placed on a pin attached to a gantry. This set-up substituted for the leader of a tandem run. Neither the pin nor the glands touched the substrate and thus the ant following the robot was tracking a plume of airborne pheromones. The robot led individual workers from their current nest to a potential new one. The robotic gantry was programmed to allow for human intervention along its path to permit the following ant to stop and survey its surroundings and then catch up with its mechanical leader. The gantry then automatically tracked the precise route taken by each ant from the new nest back to the old one. Ants led by the robot were significantly more successful at finding their way home than those we carried to the new nest that had no opportunity to learn landmarks. The robot was programmed to take either a straight or a sinusoidal path to the new nest. However, we found no significant difference in the abilities of ants that had been led on such direct or sinuous paths to find their way home. Here, the robot laid no trail but our findings suggest that, under such circumstances, the following ant may lay a trail to substitute for the missing one.

Broadband-NIRS System Identifies Epileptic Focus in a Child with Focal Cortical Dysplasia-A Case Study.

Epileptic seizures are transiently occurring symptoms due to abnormal excessive or synchronous neuronal activity in the brain. Previous functional near-infrared spectroscopy (fNIRS) studies during seizures have focused in only monitoring the brain oxygenation and haemodynamic changes. However, few tools are available to measure actual cellular metabolism during seizures, especially at the bedside. Here we use an in-house developed multichannel broadband NIRS (or bNIRS) system, that, alongside the changes in oxy-, deoxy- haemoglobin concentration (HbO2, HHb), also quantifies the changes in oxidised cytochrome-c-oxidase Δ(oxCCO), a marker of cellular oxygen metabolism, simultaneously over 16 different brain locations. We used bNIRS to measure metabolic activity alongside brain tissue haemodynamics/oxygenation during 17 epileptic seizures at the bedside of a 3-year-old girl with seizures due to an extensive malformation of cortical development in the left posterior quadrant. Simultaneously Video-EEG data was recorded from 12 channels. Whilst we did observe the expected increase in brain tissue oxygenation (HbD) during seizures, it was almost diminished in the area of the focal cortical dysplasia. Furthermore, in the area of seizure origination (epileptic focus) ΔoxCCO decreased significantly at the time of seizure generalization when compared to the mean change in all other channels. We hypothesize that this indicates an incapacity to sustain and increase brain tissue metabolism during seizures in the region of the epileptic focus.

Hide-and-seek strategies and post-contact immobility.

To understand why an animal might gain by playing dead, or more precisely, exhibit post-contact immobility (PCI), we consider the context in which this behaviour occurs. Is it, for example, a method by which a potential victim encourages a predator to direct its attention elsewhere? We investigate this possibility by using the marginal value theorem to analyse predator behaviour in the context of this defence strategy by potential prey. We consider two models. In the first, (random revisiting) the predator may return to sites it has already depleted within the patch. In the second, (systematic search) the predator goes only to new sites within the patch. The results of the two models are qualitatively extremely similar. We show that when prey occur in patches, PCI favours prey survival. Indeed, certain antlion larvae have PCI durations characterized by very long half-lives. These appear to be of such long durations that further increases would convey no substantial benefits in redirecting potential predators to other antlions within the patch and subsequently to other patches.

Post-contact immobility and half-lives that save lives.

A wide variety of animals become completely immobile after initial contact with a potential predator. This behaviour is considered to be a last-ditch escape strategy. Here, we test the hypothesis that such immobility should have an extremely unpredictable duration. We find that it spans more than three orders of magnitude in antlion larvae. We also analyse the second period of immobility that follows the first bout of immobility, and consider the distributions of both first and second immobility periods within the context of the intermittence that characterizes the movement of most organisms. Both immobility durations were fitted best by exponential distributions. Therefore, both were characterized by high variability and hence, unpredictability. The immobility half-life, its mean duration and standard deviation were greater for the first than the second immobility. Furthermore, individual consistency was weak or absent in repeated measures of the first immobility and between the first and second immobilities. Our quantitative approach can be replicated across taxa and would help link an understanding of immobility after an initial predator contact in both vertebrates and invertebrates. To facilitate this, we contend that the terminology should be simplified, and we advocate the use of the term post-contact immobility (PCI).

Social flocculation in plant-animal worms.

Individual animals can often move more safely or more efficiently as members of a group. This can be as simple as safety in numbers or as sophisticated as aerodynamic or hydrodynamic cooperation. Here, we show that individual plant-animal worms (Symsagittifera roscoffensis) can move to safety more quickly through flocculation. Flocs form in response to turbulence that might otherwise carry these beach-dwelling worms out to sea. They allow the worms to descend much more quickly to the safety of the substrate than single worms could swim. Descent speed increases with floc size such that larger flocs can catch up with smaller ones and engulf them to become even larger and faster. To our knowledge, this is the first demonstration of social flocculation in a wild, multicellular organism. It is also remarkable that such effective flocculation occurs where the components are comparatively large multicellular organisms organized as entangled ensembles.

Digging the optimum pit: antlions, spirals and spontaneous stratification.

Most animal traps are constructed from self-secreted silk, so antlions are rare among trap builders because they use only materials found in the environment. We show how antlions exploit the properties of the substrate to produce very effective structures in the minimum amount of time. Our modelling demonstrates how antlions: (i) exploit self-stratification in granular media differentially to expose deleterious large grains at the bottom of the construction trench where they can be ejected preferentially, and (ii) minimize completion time by spiral rather than central digging. Both phenomena are confirmed by our experiments. Spiral digging saves time because it enables the antlion to eject material initially from the periphery of the pit where it is less likely to topple back into the centre. As a result, antlions can produce their pits-lined almost exclusively with small slippery grains to maximize powerful avalanches and hence prey capture-much more quickly than if they simply dig at the pit's centre. Our demonstration, for the first time to our knowledge, of an animal using self-stratification in granular media exemplifies the sophistication of extended phenotypes even if they are only formed from material found in the animal's environment.

Plant-animal worms round themselves up in circular mills on the beach.

Collective motion is a fascinating and intensely studied manifestation of collective behaviour. Circular milling is an impressive example. It occurs in fishes, processionary caterpillars and army ants, among others. Its adaptive significance, however, is not yet well understood. Recently, we demonstrated experimentally circular milling in the marine plant-animal worm Symsagittifera roscoffensis. We hypothesized that its function is to gather the worms and facilitate the dense films they form on the beach to promote the photosynthesis of their symbiotic algae. Here, we report for the first time, to our knowledge, the occurrence of S. roscoffensis circular mills in nature and show that it is by no means rare. The size and behaviour of circular mills in their natural environment is compatible with our earlier experimental results. This makes S. roscoffensis a good study system for understanding the proximate and ultimate mechanisms of circular milling.

Consensus-based guidelines for Video EEG monitoring in the pre-surgical evaluation of children with epilepsy in the UK.

PURPOSE: Paediatric Epilepsy surgery in the UK has recently been centralised in order to improve expertise and quality of service available to children. Video EEG monitoring or telemetry is a highly specialised and a crucial component of the pre-surgical evaluation. Although many Epilepsy Monitoring Units work to certain standards, there is no national or international guideline for paediatric video telemetry. METHODS: Due to lack of evidence we used a modified Delphi process utilizing the clinical and academic expertise of the clinical neurophysiology sub-specialty group of Children's Epilepsy Surgical Service (CESS) centres in England and Wales. This process consisted of the following stages I: Identification of the consensus working group, II: Identification of key areas for guidelines, III: Consensus practice points and IV: Final review. Statements that gained consensus (median score of either 4 or 5 using a five-point Likerttype scale) were included in the guideline. RESULTS: Two rounds of feedback and amendments were undertaken. The consensus guidelines includes the following topics: referral pathways, neurophysiological equipment standards, standards of recording techniques, with specific emphasis on safety of video EEG monitoring both with and without drug withdrawal, a protocol for testing patient's behaviours, data storage and guidelines for writing factual reports and conclusions. All statements developed received a median score of 5 and were adopted by the group. CONCLUSION: Using a modified Delphi process we were able to develop universally-accepted video EEG guidelines for the UK CESS. Although these recommendations have been specifically developed for the pre-surgical evaluation of children with epilepsy, it is assumed that most components are transferable to any paediatric video EEG monitoring setting.

Nociceptive brain activity as a measure of analgesic efficacy in infants.

Pain in infants is undertreated and poorly understood, representing a major clinical problem. In part, this is due to our inability to objectively measure pain in nonverbal populations. We present and validate an electroencephalography-based measure of infant nociceptive brain activity that is evoked by acute noxious stimulation and is sensitive to analgesic modulation. This measure should be valuable both for mechanistic investigations and for testing analgesic efficacy in the infant population.

Social behaviour and collective motion in plant-animal worms.

Social behaviour may enable organisms to occupy ecological niches that would otherwise be unavailable to them. Here, we test this major evolutionary principle by demonstrating self-organizing social behaviour in the plant-animal, Symsagittifera roscoffensis. These marine aceol flat worms rely for all of their nutrition on the algae within their bodies: hence their common name. We show that individual worms interact with one another to coordinate their movements so that even at low densities they begin to swim in small polarized groups and at increasing densities such flotillas turn into circular mills. We use computer simulations to: (i) determine if real worms interact socially by comparing them with virtual worms that do not interact and (ii) show that the social phase transitions of the real worms can occur based only on local interactions between and among them. We hypothesize that such social behaviour helps the worms to form the dense biofilms or mats observed on certain sun-exposed sandy beaches in the upper intertidal of the East Atlantic and to become in effect a super-organismic seaweed in a habitat where macro-algal seaweeds cannot anchor themselves. Symsagittifera roscoffensis, a model organism in many other areas in biology (including stem cell regeneration), also seems to be an ideal model for understanding how individual behaviours can lead, through collective movement, to social assemblages.

Ants determine their next move at rest: motor planning and causality in complex systems.

To find useful work to do for their colony, individual eusocial animals have to move, somehow staying attentive to relevant social information. Recent research on individual Temnothorax albipennis ants moving inside their colony's nest found a power-law relationship between a movement's duration and its average speed; and a universal speed profile for movements showing that they mostly fluctuate around a constant average speed. From this predictability it was inferred that movement durations are somehow determined before the movement itself. Here, we find similar results in lone T. albipennis ants exploring a large arena outside the nest, both when the arena is clean and when it contains chemical information left by previous nest-mates. This implies that these movement characteristics originate from the same individual neural and/or physiological mechanism(s), operating without immediate regard to social influences. However, the presence of pheromones and/or other cues was found to affect the inter-event speed correlations. Hence we suggest that ants' motor planning results in intermittent response to the social environment: movement duration is adjusted in response to social information only between movements, not during them. This environmentally flexible, intermittently responsive movement behaviour points towards a spatially allocated division of labour in this species. It also prompts more general questions on collective animal movement and the role of intermittent causation from higher to lower organizational levels in the stability of complex systems.

Electroencephalography during general anaesthesia differs between term-born and premature-born children.

OBJECTIVES: Premature birth is associated with a wide range of complications in later life, including structural and functional neurological abnormalities and altered pain sensitivity. We investigated whether during anaesthesia premature-born children display different patterns of background EEG activity and exhibit increased responses to nociceptive stimuli. METHODS: We examined background EEG and time-locked responses to clinical cannulation in 45 children (mean age (±SD) at study: 4.9(±3.0)years) under sevoflurane monoanaesthesia maintained at a steady-state end-tidal concentration of 2.5%. 15 were born prematurely (mean gestational age at birth: 29.2 ± 3.9 weeks) and 30 were age-matched term-born children. RESULTS: Background levels of alpha and beta power were significantly lower in the premature-born children compared to term-born controls (p=0.048). Clinical cannulation evoked a significant increase in delta activity (p=0.032), which was not significantly different between the two groups (p=0.44). CONCLUSIONS: The results indicate that whilst under anaesthesia premature-born children display different patterns of background brain activity compared to term-born children. SIGNIFICANCE: As electrophysiological techniques are increasingly used by anaesthetists to gauge anaesthetic depth, differences in background levels of electrophysiological brain activity between premature and term-born children may be relevant when considering titration of anaesthetic dose.

Noxious stimulation in children receiving general anaesthesia evokes an increase in delta frequency brain activity.

More than 235,000 children/year in the UK receive general anaesthesia, but it is unknown whether nociceptive stimuli alter cortical brain activity in anaesthetised children. Time-locked electroencephalogram (EEG) responses to experimental tactile stimuli, experimental noxious stimuli, and clinically required cannulation were examined in 51 children (ages 1-12 years) under sevoflurane monoanaesthesia. Based on a pilot study (n=12), we hypothesised that noxious stimulation in children receiving sevoflurane monoanaesthesia would evoke an increase in delta activity. This was tested in an independent sample of children (n=39), where a subset (n=11) had topical local anaesthetic applied prior to stimulation. A novel method of time-locking the stimuli to the EEG recording was developed using an event detection interface and high-speed camera. Clinical cannulation evoked a significant increase (34.2 ± 8.3%) in delta activity (P=0.042), without concomitant changes in heart rate or reflex withdrawal, which was not observed when local anaesthetic was applied (P=0.30). Experimental tactile (P=0.012) and noxious (P=0.0099) stimulation also evoked significant increases in delta activity, but the magnitude of the response was graded with stimulus intensity, with the greatest increase evoked by cannulation. We demonstrate that experimental and clinically essential noxious procedures, undertaken in anaesthetised children, alter the pattern of EEG activity, that this response can be inhibited by local anaesthetic, and that this measure is more sensitive than other physiological indicators of nociception. This technique provides the possibility that sensitivity to noxious stimuli during anaesthesia could be investigated in other clinical populations.

Postnatal temporal, spatial and modality tuning of nociceptive cutaneous flexion reflexes in human infants.

Cutaneous flexion reflexes are amongst the first behavioural responses to develop and are essential for the protection and survival of the newborn organism. Despite this, there has been no detailed, quantitative study of their maturation in human neonates. Here we use surface electromyographic (EMG) recording of biceps femoris activity in preterm (<37 weeks gestation, GA) and term (≥ 37 weeks GA) human infants, less than 14 days old, in response to tactile, punctate and clinically required skin-breaking lance stimulation of the heel. We show that all infants display a robust and long duration flexion reflex (>4 seconds) to a single noxious skin lance which decreases significantly with gestational age. This reflex is not restricted to the stimulated limb: heel lance evokes equal ipsilateral and contralateral reflexes in preterm and term infants. We further show that infant flexion withdrawal reflexes are not always nociceptive specific: in 29% of preterm infants, tactile stimulation evokes EMG activity that is indistinguishable from noxious stimulation. In 40% of term infants, tactile responses are also present but significantly smaller than nociceptive reflexes. Infant flexion reflexes are also evoked by application of calibrated punctate von Frey hairs (vFh), 0.8-17.2 g, to the heel. Von Frey hair thresholds increase significantly with gestational age and the magnitude of vFh evoked reflexes are significantly greater in preterm than term infants. Furthermore flexion reflexes in both groups are sensitized by repeated vFh stimulation. Thus human infant flexion reflexes differ in temporal, modality and spatial characteristics from those in adults. Reflex magnitude and tactile sensitivity decreases and nociceptive specificity and spatial organisation increases with gestational age. Strong, relatively non-specific, reflex sensitivity in early life may be important for driving postnatal activity dependent maturation of targeted spinal cord sensory circuits.

Galvanic vestibular stimulation modulates the electrophysiological response during face processing.

Although galvanic vestibular stimulation (GVS) is known to affect the speed and accuracy of visual judgments, the underlying electrophysiological response has not been explored. In the present study, we therefore investigated the effect of GVS on the N170 event-related potential, a marker commonly associated with early visual structural encoding. To elicit the waveform, participants distinguished famous from nonfamous faces that were presented in either upright or inverted orientation. Relative to a sham, stimulation increased the amplitude of the N170 and also elevated power spectra within the delta and theta frequency bands, components that have likewise been associated with face processing. This study constitutes the first attempt to model the effects of GVS on the electrophysiological response and, more specifically, indicates that unisensory visual processes linked to object construction are influenced by vestibular information. Given that reductions in the magnitude of both the N170 event-related potential and delta/theta activity accompany certain disease states, GVS may provide hitherto unreported therapeutic benefit.

A shift in sensory processing that enables the developing human brain to discriminate touch from pain.

When and how infants begin to discriminate noxious from innocuous stimuli is a fundamental question in neuroscience [1]. However, little is known about the development of the necessary cortical somatosensory functional prerequisites in the intact human brain. Recent studies of developing brain networks have emphasized the importance of transient spontaneous and evoked neuronal bursting activity in the formation of functional circuits [2, 3]. These neuronal bursts are present during development and precede the onset of sensory functions [4, 5]. Their disappearance and the emergence of more adult-like activity are therefore thought to signal the maturation of functional brain circuitry [2, 4]. Here we show the changing patterns of neuronal activity that underlie the onset of nociception and touch discrimination in the preterm infant. We have conducted noninvasive electroencephalogram (EEG) recording of the brain neuronal activity in response to time-locked touches and clinically essential noxious lances of the heel in infants aged 28-45 weeks gestation. We show a transition in brain response following tactile and noxious stimulation from nonspecific, evenly dispersed neuronal bursts to modality-specific, localized, evoked potentials. The results suggest that specific neural circuits necessary for discrimination between touch and nociception emerge from 35-37 weeks gestation in the human brain.

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.