Nociceptive Cortical Activity Is Dissociated from Nociceptive Behavior in Newborn Human Infants under Stress

Abstract

SummaryNewborn infants display strong nociceptive behavior in response to tissue damaging stimuli, and this is accompanied by nociceptive activity generated in subcortical and cortical areas of the brain [1, 2]. In the absence of verbal report, these nociceptive responses are used as measures of pain sensation in newborn humans, as they are in animals [3, 4]. However, many infants are raised in a physiologically stressful environment, and little is known about the effect of background levels of stress upon their pain responses. In adults, acute physiological stress causes hyperalgesia [5, 6, 7], and increased background stress increases pain [8, 9, 10], but these data cannot necessarily be extrapolated to infants. Here we have simultaneously measured nociceptive behavior, brain activity, and levels of physiological stress in a sample of 56 newborn human infants aged 36–42 weeks. Salivary cortisol (hypothalamic pituitary axis), heart rate variability (sympathetic adrenal medullary system), EEG event-related potentials (nociceptive cortical activity), and facial expression (behavior) were acquired in individual infants following a clinically required heel lance. We show that infants with higher levels of stress exhibit larger amplitude cortical nociceptive responses, but this is not reflected in their behavior. Furthermore, while nociceptive behavior and cortical activity are normally correlated, this relationship is disrupted in infants with high levels of physiological stress. Brain activity evoked by noxious stimulation is therefore enhanced by stress, but this cannot be deduced from observation of pain behavior. This may be important in the prevention of adverse effects of early repetitive pain on brain development.

Composite Pain Biomarker Signatures for Objective Assessment and Effective Treatment

“…Responses to noxious stimulation can be quantified through a variety of behavioral (e.g., reflex withdrawal) and physiological (e.g., rise in heart rate, fall in oxygen saturation) changes (Moultrie et al, 2017). While such surrogate measures can guide treatment options, several studies indicate that these underestimate likely pain experience in infants and possibly contribute to an under-recognition and under-treatment of infant pain (Jones et al, 2017;Slater et al, 2008). Similarly, using an isolated forearm test during anesthesia has led to the recognition that a minority of anesthetized patients are ''aware'' and responsive (Pandit et al, 2014)-alerting us to the need for better measures to assess whether these patients are also in pain (Ní Mhuircheartaigh et al, 2013).…”

“…Other neuroimaging areas being developed with potential as biomarkers, include functional neuroimaging of the spinal cord (Eippert et al, 2017;Sprenger et al, 2012;Stroman et al, 2014) and infant pain biomarkers of pain and analgesic efficacy (Moultrie et al, 2017;Slater et al, 2010). These latter studies demonstrate that pain-related behavioral measures may underestimate pain experience in infants (Jones et al, 2017).…”

Prematurity alters skin conductance and behavioural scoring after acute stress in term‐equivalent age infants

“…Recently, Jones et al reported impaired behavioural responses to painful challenges in infants experiencing high background levels of stress. Surprisingly, the cortical response was preserved (25). These results highlighted that behavioural assessment could lead to underestimation of newborn pain in the NICU.…”

Functional and diffusion MRI reveal the functional and structural basis of infants’ noxious-evoked brain activity

“…Previous studies in infants have demonstrated the sensitivity of infant noxious-evoked cerebral activity to sleep state 15 and physiological stress 16 . To disambiguate temporally stable trait effects, arguably of higher relevance for clinical pre-emptive decision making, from temporally transient state effects, we assessed the correlation between infants' nociceptive haemodynamic response amplitude and underlying white matter microstructure using diffusion MRI (dMRI) data.…”