Stewart Boyd

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.

A Possible Role for Gap Junctions in Generation of Very Fast EEG Oscillations Preceding the Onset of, and Perhaps Initiating, Seizures

Summary:  Purpose: We propose an experimentally and clinically testable hypothesis, concerning the origin of very fast (>∼70 Hz) EEG oscillations that sometimes precede the onset of focal seizures. These oscillations are important, as they may play a causal role in the initiation of seizures.

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.

Buccal Absorption of Midazolam: Pharmacokinetics and EEG Pharmacodynamics

Summary: Purpose: To determine whether buccal/sublingual administration of midazolam (MDL) would lead to detectable venous concentrations and EEG changes in 10 healthy volunteers.

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.

Epilepsy in Angelman syndrome.

Angelman syndrome is a neurogenetic disorder caused by lack of UBE3A gene expression from the maternally inherited chromosome 15 due to various 15q11-q13 abnormalities. In addition to severe developmental delay, virtual absence of speech, motor impairment, a behavioural phenotype that includes happy demeanor, and distinctive rhythmic electroencephalographic features, over 90% of patients have epilepsy. Many different seizure types may occur, atypical absences and myoclonic seizures being particularly prevalent. Non-convulsive status epilepticus is common, sometimes in the context of the epileptic syndrome referred to as myoclonic status in non-progressive encephalopathies. Epilepsy predominates in childhood, but may persist or reappear in adulthood. Management is difficult in a proportion of patients. It might be improved by better understanding of pathophysiology. Current hypotheses involve abnormal inhibitory transmission due to impaired regulation of GABAA receptors related to functional absence of UBE3A and abnormal hippocampal CaMKII activity.

CO2 laser activation of nociceptive and non-nociceptive thermal afferents from hairy and glabrous skin.

&NA; In 8 healthy subjects we have recorded cerebral evoked potentials and reaction time (RT) to CO2 laser stimulation of the hairy and glabrous skin at low and high stimulus intensities, corresponding to subjective reporting of detection and pain, respectively. At each intensity we were able to identify an evoked potential; the latencies of the major vertex positive (VP) components fell into 2 distinct populations 320 ± 30 (VP300) and 778 ± 80 (VP800) which did not differ between stimulation sites. The frequency of the VP300 responses was greatest in the high stimulus conditions and lower in the low stimulus conditions whilst the opposite was true for the VP800 responses. Bimodal distributions of RT were seen at both stimulus intensities. In a further group of 10 subjects we recorded the latency shift of the vertex negativity following proximal and distal stimulation of hairy skin of the left upper limb and derived conduction velocities for the VP300 (13.21 ± 2.8 m/sec) and VP800 (1.26 ± 0.29 m/sec) responses. These results suggest that, following CO2 laser stimulation of both hairy and glabrous skin, two different fibre populations are activated. The VP300 responses appear to be related to A&dgr; activation, while the characteristics of the VP800 responses are consistent with activation of thermoreceptors mediated by C fibres.

Acute neurology and neurophysiology of haemolytic–uraemic syndrome

Involvement of the central nervous system (CNS) is found in around 30% of children with haemolytic–uraemic syndrome (HUS). This complication is the single most common cause of mortality and also a major contributor to the morbidity associated with HUS. We reviewed 22 children with HUS and acute CNS involvement. Both global and focal derangements occurred, and in survivors, early regional EEG abnormalities—especially those in the occipital and temporal areas—were prognostically useful.