Pain in infants is under-treated and poorly understood, representing a significant clinical problem. In part, this is due to our inability to objectively measure pain in non-verbal populations. Here, we present an EEG-based measure of infant nociceptive brain activity that is evoked following acute noxious stimulation and is sensitive to analgesic modulation. This measure will be valuable for both mechanistic investigations and for testing analgesic efficacy in the infant population.
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.
SummaryA subclass of C fibre sensory neurons found in hairy skin are activated by gentle touch [1] and respond optimally to stroking at ∼1–10 cm/s, serving a protective function by promoting affiliative behaviours. In adult humans, stimulation of these C-tactile (CT) afferents is pleasant, and can reduce pain perception [2]. Touch-based techniques, such as infant massage and kangaroo care, are designed to comfort infants during procedures, and a modest reduction in pain-related behavioural and physiological responses has been observed in some studies [3]. Here, we investigated whether touch can reduce noxious-evoked brain activity. We demonstrate that stroking (at 3 cm/s) prior to an experimental noxious stimulus or clinical heel lance can attenuate noxious-evoked brain activity in infants. CT fibres may represent a biological target for non-pharmacological interventions that modulate pain in early life.
Highlights
Multi-modal sensory stimulation is used to assess premature infant brain function.
A template analysis approach is outlined for multi-modal stimulus-evoked EEG activity.
Stimulus-evoked template magnitudes change with age.
Prematurity results in accelerated maturation of visual and tactile sensory systems.
Despite the high burden of pain experienced by hospitalised neonates there are few analgesics with proven efficacy. Testing analgesics in neonates is experimentally and ethically challenging and minimising the number of neonates required to demonstrate efficacy is essential. EEG-derived measures of noxious-evoked brain activity can be used to assess analgesic efficacy, however, as variability exists in neonate's responses to painful procedures, large sample sizes are often required. Here we present a novel experimental paradigm to account for individual differences in noxious-evoked baseline sensitivity which can be used to improve the design of analgesic trials in neonates. The paradigm is developed and tested across four observational studies using clinical, experimental and simulated data (92 neonates). We provide evidence of the efficacy of gentle brushing and paracetamol, substantiating the need for randomised controlled trials of these interventions. This work provides an important step towards safe, cost-effective clinical trials of analgesics in neonates.
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