Caroline Hartley

fMRI reveals neural activity overlap between adult and infant pain

Limited understanding of infant pain has led to its lack of recognition in clinical practice. While the network of brain regions that encode the affective and sensory aspects of adult pain are well described, the brain structures involved in infant nociceptive processing are less well known, meaning little can be inferred about the nature of the infant pain experience. Using fMRI we identified the network of brain regions that are active following acute noxious stimulation in newborn infants, and compared the activity to that observed in adults. Significant infant brain activity was observed in 18 of the 20 active adult brain regions but not in the infant amygdala or orbitofrontal cortex. Brain regions that encode sensory and affective components of pain are active in infants, suggesting that the infant pain experience closely resembles that seen in adults. This highlights the importance of developing effective pain management strategies in this vulnerable population. DOI: http://dx.doi.org/10.7554/eLife.06356.001

Neurophysiological measures of nociceptive brain activity in the newborn infant – the next steps

Infants within neonatal intensive care units can receive multiple medically essential painful procedures per day. How they respond to these events, how best to alleviate the negative effects, and the long‐term consequences for the infant are all significant questions that have yet to be fully answered. In recent years, several studies have examined cortical responses to noxious stimuli in the neonate through the use of near‐infrared spectroscopy (NIRS) and electroencephalography (EEG). These investigations dispel any notion that the newborn infant does not process noxious stimuli at a cortical level and open the way for future research. In this Viewpoint Article, we review these studies and discuss key clinical challenges which may be elucidated with the use of these techniques.

Long-Range Temporal Correlations in the EEG Bursts of Human Preterm Babies

The electrical activity in the very early human preterm brain, as recorded by scalp EEG, is mostly discontinuous and has bursts of high-frequency oscillatory activity nested within slow-wave depolarisations of high amplitude. The temporal organisation of the occurrence of these EEG bursts has not been previously investigated. We analysed the distribution of the EEG bursts in 11 very preterm (23–30 weeks gestational age) human babies through two estimates of the Hurst exponent. We found long-range temporal correlations (LRTCs) in the occurrence of these EEG bursts demonstrating that even in the very immature human brain, when the cerebral cortical structure is far from fully developed, there is non-trivial temporal structuring of electrical activity.

The relationship between nociceptive brain activity, spinal reflex withdrawal and behaviour in newborn infants

Measuring infant pain is complicated by their inability to describe the experience. While nociceptive brain activity, reflex withdrawal and facial grimacing have been characterised, the relationship between these activity patterns has not been examined. As cortical and spinally mediated activity is developmentally regulated, it cannot be assumed that they are predictive of one another in the immature nervous system. Here, using a new experimental paradigm, we characterise the nociceptive-specific brain activity, spinal reflex withdrawal and behavioural activity following graded intensity noxious stimulation and clinical heel lancing in 30 term infants. We show that nociceptive-specific brain activity and nociceptive reflex withdrawal are graded with stimulus intensity (p < 0.001), significantly correlated (r = 0.53, p = 0.001) and elicited at an intensity that does not evoke changes in clinical pain scores (p = 0.55). The strong correlation between reflex withdrawal and nociceptive brain activity suggests that movement of the limb away from a noxious stimulus is a sensitive indication of nociceptive brain activity in term infants. This could underpin the development of new clinical pain assessment measures.

Identification of criticality in neuronal avalanches: I. A theoretical investigation of the non-driven case

In this paper, we study a simple model of a purely excitatory neural network that, by construction, operates at a critical point. This model allows us to consider various markers of criticality and illustrate how they should perform in a finite-size system. By calculating the exact distribution of avalanche sizes, we are able to show that, over a limited range of avalanche sizes which we precisely identify, the distribution has scale free properties but is not a power law. This suggests that it would be inappropriate to dismiss a system as not being critical purely based on an inability to rigorously fit a power law distribution as has been recently advocated. In assessing whether a system, especially a finite-size one, is critical it is thus important to consider other possible markers. We illustrate one of these by showing the divergence of susceptibility as the critical point of the system is approached. Finally, we provide evidence that power laws may underlie other observables of the system that may be more amenable to robust experimental assessment.

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

&NA; Clinically required noxious cannulation performed in children receiving sevoflurane monoanaesthesia causes a change in electrophysiological brain activity. &NA; 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.

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

A measure of nociceptive brain activity that can be used to assess analgesic efficacy in infants is derived and validated. Reading babies’ minds to relieve pain In the medical setting, infants and young children are often subjected to painful procedures requiring pain relief. However, the infants cannot use words or numerical scales to describe and rate their pain, and it is difficult to accurately assess and treat these patients. Hartley et al. report studies of full-term and late preterm infants who were exposed to medically necessary painful stimuli, experimental stimuli that were mildly noxious, and non-noxious control stimulation to derive a quantifiable encephalographic measure of pain-related brain activity. The measure was responsive to local analgesia, confirming its relevance for monitoring of pain relief. 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.

Changing Balance of Spinal Cord Excitability and Nociceptive Brain Activity in Early Human Development

Summary In adults, nociceptive reflexes and behavioral responses are modulated by a network of brain regions via descending projections to the spinal dorsal horn [1]. Coordinated responses to noxious inputs manifest from a balance of descending facilitation and inhibition. In contrast, young infants display exaggerated and uncoordinated limb reflexes [2]. Our understanding of nociceptive processing in the infant brain has been advanced by the use of electrophysiological and hemodynamic imaging [3, 4, 5, 6]. From approximately 35 weeks’ gestation, nociceptive-specific patterns of brain activity emerge [7], whereas prior to this, non-specific bursts of activity occur in response to noxious, tactile, visual, and auditory stimulation [7, 8, 9, 10]. During the preterm period, refinement of spinal cord excitability is also observed: reflex duration shortens, response threshold increases, and improved discrimination between tactile and noxious events occurs [2, 11, 12]. However, the development of descending modulation in human infants remains relatively unexplored. In 40 infants aged 28–42 weeks’ gestation, we examined the relationship between nociceptive brain activity and spinal reflex withdrawal activity in response to a clinically essential noxious procedure. Nociceptive-specific brain activity increases in magnitude with gestational age, whereas reflex withdrawal activity decreases in magnitude, duration, and latency across the same developmental period. By recording brain and spinal cord activity in the same infants, we demonstrate that the maturation of nociceptive brain activity is concomitant with the refinement of noxious-evoked limb reflexes. We postulate that, consistent with studies in animals, infant reflexes are influenced by the development of top-down inhibitory modulation from maturing subcortical and cortical brain networks.

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

Highlights • Noxious stimulation during anaesthesia evokes a significant increase in delta activity that does not differ between term-born and premature-born children.• Background EEG activity recorded during anaesthesia is different in premature-born and term-born children.• EEG-derived measures that can be used to titrate anaesthetic depth may be influenced by premature birth.

Identification of criticality in neuronal avalanches: II. A theoretical and empirical investigation of the Driven case

The observation of apparent power laws in neuronal systems has led to the suggestion that the brain is at, or close to, a critical state and may be a self-organised critical system. Within the framework of self-organised criticality a separation of timescales is thought to be crucial for the observation of power-law dynamics and computational models are often constructed with this property. However, this is not necessarily a characteristic of physiological neural networks—external input does not only occur when the network is at rest/a steady state. In this paper we study a simple neuronal network model driven by a continuous external input (i.e. the model does not have an explicit separation of timescales from seeding the system only when in the quiescent state) and analytically tuned to operate in the region of a critical state (it reaches the critical regime exactly in the absence of input—the case studied in the companion paper to this article). The system displays avalanche dynamics in the form of cascades of neuronal firing separated by periods of silence. We observe partial scale-free behaviour in the distribution of avalanche size for low levels of external input. We analytically derive the distributions of waiting times and investigate their temporal behaviour in relation to different levels of external input, showing that the system’s dynamics can exhibit partial long-range temporal correlations. We further show that as the system approaches the critical state by two alternative ‘routes’, different markers of criticality (partial scale-free behaviour and long-range temporal correlations) are displayed. This suggests that signatures of criticality exhibited by a particular system in close proximity to a critical state are dependent on the region in parameter space at which the system (currently) resides.