Pain in the newborn brain: a neural signature

No one wants to see a baby in pain. Yet, for many decades neonatal health-care providers have debated whether neonates feel pain and at what age this neural capacity emerges.1McPherson C Miller SP El-Dib M Massaro AN Inder TE The influence of pain, agitation, and their management on the immature brain.Pediatr Res. 2020; 88: 168-175Crossref Scopus (55) Google Scholar This is a crucial issue because neonates who require intensive care are exposed to hundreds of painful procedures as part of life-saving medical procedures. Fortunately, clinicians now recognise that neonates sense pain and that appropriate strategies for analgesia and sedation are needed for their compassionate care. In the past 10 years, in preterm neonates—a major population in neonatal intensive care units—pain has emerged as a key predictor of delayed brain maturation, which has been associated with subsequent neurodevelopmental impairments.2Duerden EG Grunau RE Guo T et al.Early Procedural pain is associated with regionally-specific alterations in thalamic development in preterm neonates.J Neurosci. 2018; 38: 878-886Crossref PubMed Scopus (114) Google Scholar Despite the recognition that pain management is a key aspect of care for neonates, quantifying pain in newborn babies remains challenging. Neonatal pain assessments comprise observable indicators such as physiological changes (eg, heart rate), or behavioural indicators (eg, crying), which are influenced by contextual factors (eg, gestational age).1McPherson C Miller SP El-Dib M Massaro AN Inder TE The influence of pain, agitation, and their management on the immature brain.Pediatr Res. 2020; 88: 168-175Crossref Scopus (55) Google Scholar Pain management with analgesics or sedatives in neonates is associated with regional brain dysmaturation in brain structures associated with memory and motor coordination.3Duerden EG Guo T Dodbiba L et al.Midazolam dose correlates with abnormal hippocampal growth and neurodevelopmental outcome in preterm infants.Ann Neurol. 2016; 79: 548-559Crossref PubMed Scopus (99) Google Scholar, 4Zwicker JG Miller SP Grunau RE et al.Smaller cerebellar growth and poorer neurodevelopmental outcomes in very preterm infants exposed to neonatal morphine.J Pediatr. 2016; 172: 81-87Summary Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 5Anand KJ Hall RW Desai N et al.Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial.Lancet. 2004; 363: 1673-1682Summary Full Text Full Text PDF PubMed Scopus (416) Google Scholar Therefore, the identification of objective pain measures is crucial to effectively manage pain but also to promote brain health and prevent childhood disabilities. Evidence from functional MRI (fMRI) has shown noxious-stimulus evoked activation in pain-processing brain regions in newborn babies.6Goksan S Hartley C Emery F et al.fMRI reveals neural activity overlap between adult and infant pain.eLife. 2015; 4e08663Google Scholar Furthermore, functional-connectivity strength in core pain-processing regions is predicted by invasive procedures during intensive care in neonates.7Schneider J Duerden EG Guo T et al.Procedural pain and oral glucose in preterm neonates: brain development and sex-specific effects.Pain. 2018; 159: 515-525Crossref Scopus (55) Google Scholar However, defining a unique pain signature in newborn babies is challenging due to the absence of subjective reports of pain. Unique neural signatures specific for noxious stimuli (neurologic pain signature [NPS])8Wager TD Atlas LY Lindquist MA Roy M Woo CW Kross E An fMRI-based neurologic signature of physical pain.N Engl J Med. 2013; 368: 1388-1397Crossref PubMed Scopus (956) Google Scholar and cognitive pain modulation (stimulus intensity independent pain signature-1 [SIIPS1])9Woo CW Schmidt L Krishnan A et al.Quantifying cerebral contributions to pain beyond nociception.Nat Commun. 2017; 814211Crossref PubMed Scopus (97) Google Scholar have been identified in adults. Whether similar signatures (NPS, SIIPS1) emerge within the first weeks of life has remained unclear due to challenges examining pain in infants. In The Lancet Digital Health, Eugene Duff and colleagues10Duff EP Moultrie F van der Vaart M et al.Inferring pain experience in infants using quantitative whole-brain functional MRI signatures: a cross-sectional, observational study.Lancet Digital Health. 2020; 2: e458-e467Summary Full Text Full Text PDF Scopus (6) Google Scholar address the issue of identifying objective brain-based biomarkers for pain in the newborn brain. Initially, the authors examined the NPS and SIIPS1 in ten adults who were administered varying intensities of noxious stimuli during fMRI. The adults rated the intensity of the stimuli. The activation patterns in adults were evaluated in relation to predefined signatures for the NPS, SIIPS1, and four control signatures (the vicarious pain signature, the picture-induced negative emotion signature, the social rejection signature, and a global signal signature). Subsequently, in two prospective cohorts of healthy newborn babies, a similar stimulation protocol to that used in the adults, but consisting of milder intensities of noxious stimuli, was administered to elicit pain-related activation during fMRI. The resulting neonatal statistical parametric maps for the stimulus intensities were transformed into adult-template space to enable a direct quantitative analysis with the adult signatures. Infants had high concordance with the NPS observed in adults, reflecting core pain-processing brain regions. These findings suggest that newborn babies process nociceptive input in a similar way to adults. By contrast, divergent associations were observed between the neonatal pain-evoked activation signatures and the SIIPS1 signature in the adult brain. Findings were interpreted by the authors to indicate a similarity in nociceptive processing between newborns and adults, whereas developing pain modulatory systems diverge between newborns and adults. This study provides evidence for brain-derived biomarkers of pain-evoked activation in the neonatal brain. A unique signature for the experience of neonatal pain might offer opportunities to assess pharmaceutical therapies and non-pharmacological interventions that might be more clinically efficacious than the currently available options for neonatal pain. Furthermore, the findings might be used to corroborate in-hospital monitoring methods such as electroencephalography and functional near infrared spectroscopy to monitor discomfort when infants are unable to reliably express this non-verbally. Novel functional imaging methods might be used to complement observable indicators of pain to improve pain management and ultimately brain health in neonates. The study by Duff and colleagues is important for understanding pain in the neonatal brain. Considering the importance of pain as a predictor of brain health in preterm neonates, a key next step will be to understand the developmental emergence of the fMRI signature identified in this study. Similarly, since most critically-ill neonates, such as those born preterm, with congenital heart disease, or with hypoxic–ischaemic encephalopathy, are repeatedly exposed to painful stimuli of varying intensities as part of intensive care practices (eg, surgeries, chest intubations, heel lances), identifying how the pain signature evolves over time will inform more optimal pain management strategies. Application of this new imaging signature might enable understanding of how available pain management strategies mitigate the cerebral response to pain. Improving the experience of pain will improve the trajectory of brain development of neonates who require life-saving care. Until these issues are addressed, neonatal health-care providers are reminded by Duff and colleagues to do all they can to minimise the exposure of babies to pain. SPM reports grants from Canadian Institutes of Health Research. EGD declares no competing interests. Inferring pain experience in infants using quantitative whole-brain functional MRI signatures: a cross-sectional, observational studyBasic intensity encoding of nociceptive information is similar in adults and infants. However, translation of adult brain signatures to infants indicated substantial differences in infant cerebral processing of nociceptive information, which might reflect their absence of expectation, motivation, and contextualisation associated with pain. This study expands the use of brain activity pain signatures to non-verbal patients and provides a potential research approach to assess the impact of analgesic interventions on brain function in infants. Full-Text PDF Open Access

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