Alan Worley

Cortical Pain Responses in Human Infants

Despite the recent increase in our understanding of the development of pain processing, it is still not known whether premature infants are capable of processing pain at a cortical level. In this study, changes in cerebral oxygenation over the somatosensory cortex were measured in response to noxious stimulation using real-time near-infrared spectroscopy in 18 infants aged between 25 and 45 weeks postmenstrual age. The noxious stimuli were heel lances performed for routine blood sampling; no blood tests were performed solely for the purpose of the study. Noxious stimulation produced a clear cortical response, measured as an increase in total hemoglobin concentration [HbT] in the contralateral somatosensory cortex, from 25 weeks (mean Δ[HbT] = 7.74 μmol/L; SE, 1.10). Cortical responses were significantly greater in awake compared with sleeping infants, with a mean difference of 6.63 μmol/L [95% confidence interval (CI) limits: 2.35, 10.91 μmol/L; mean age, 35.2 weeks]. In awake infants, the response in the contralateral somatosensory cortex increased with age (regression coefficient, 0.698 μmol/L/week; 95% CI limits: 0.132, 1.265 μmol/L/week) and the latency decreased with age (regression coefficient, −0.9861 μmol/L/week; 95% CI limits: −1.5361, −0.4361 μmol/L/week; age range, 25–38 weeks). The response was modality specific because no response was detected after non-noxious stimulation of the heel, even when accompanied by reflex withdrawal of the foot. We conclude that noxious information is transmitted to the preterm infant cortex from 25 weeks, highlighting the potential for both higher-level pain processing and pain-induced plasticity in the human brain from a very early age.

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

Summary 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.

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.

Evoked potentials generated by noxious stimulation in the human infant brain

While human infants can display distinctive behavioural and physiological spinal cord and brainstem responses to noxious stimulation, it is not known whether cortical neurons are specifically activated by noxious stimuli in newborns. Here, using a novel approach to time‐lock an EEG recording to a clinically required heel lance, we show the presence of a distinct nociceptive‐specific potential in newborn infants (35–39 weeks postmenstrual age). The potential can be observed in single trials in the central electrodes (Cz and CPz) and using principal component analysis is characterised by a positivity that occurs at approximately 560 ms post‐stimulus (N420–P560; P, positive; N, negative). The magnitude of the nociceptive‐specific potential is not dependent on sleep state, whereas an earlier potential (N150–P260–N430), which is sleep‐state dependent, is evoked by both noxious and non‐noxious stimulation. These results provide the first direct evidence of specific noxious‐evoked neural activity in the infant brain and suggest that newborn infants are capable of the sensory‐discriminative aspects of pain experience.

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

Summary 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.

Multi-modal pain measurements in infants.

Highlights ► We describe a method to measure neural responses to noxious stimulation in infants. ► Multi-modal recordings (EEG, EMG, ECG, NIRS) are synchronised within this method. ► The method meets ethical and safety standards. ► The method incorporates a novel event-locking interface to a disposable medical device. ► We have successfully used the method on more than 100 test occasions.

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.

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.