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AbstractBackgroundIn the absence of verbal communication it is challenging to infer an individual’s sensory and emotional experience. In adults, fMRI has been used to develop multivariate brain activity signatures, which reliably capture elements of human pain experience. We translate whole-brain fMRI signatures that encode pain perception in adults to the newborn infant brain, to advance understanding of functional brain development and pain perception in early life.MethodsA cohort of adults (n=10; mean age=28.3 years) and 2 cohorts of healthy infants (Cohort A: n=15; Cohort B: n=22; mean postnatal age=3 days) were stimulated with low intensity nociceptive stimuli (64-512mN) during acquisition of functional MRI data. fMRI pain signatures were applied directly to the adult data and transformed such that they could be applied to the infant brain. In each cohort, we assessed the concordance of the signatures with the brain responses using cosine-similarity scores, and we assessed stimulus intensity encoding of the signature responses using Spearman rank correlation. Brain activity in ‘pro-pain’ and ‘anti-pain’ brain regions were also examined.FindingsThe Neurologic Pain Signature (NPS), which reflects aspects of nociceptive pain experience, was activated in both the adults and infants, and reliably encoded stimulus intensity. However, the Stimulus Intensity Independent Pain Signature (SIIPS1), which reflects higher-level cognitive modulation of nociceptive input, was only expressed in adults. ‘Pro-pain’ brain regions showed similar activation patterns in adults and infants, whereas, ‘anti-pain’ brain regions exhibited divergent responses.InterpretationBasic intensity encoding of nociceptive information is similar in adults and infants. However, translation of adult brain signatures into infants reveals significant differences in infant cerebral processing of nociceptive information, which may reflect their lack of expectation, motivation and contextualisation. This study expands the use of brain activity pain signatures to non-verbal patients and provides a potential approach to assess analgesic interventions in infancy.FundingThis work was funded by Wellcome (Senior Research Fellowship awarded to Prof. Rebeccah Slater) and SSNAP “Support for Sick and Newborn Infants and their Parents” Medical Research Fund (University of Oxford Excellence Fellowship awarded to Dr Eugene Duff).Research in contextEvidence before this studyWe searched PubMed for research articles published prior to March 2020 using terms including ‘fMRI’, ‘infant or neonate’, and ‘pain or nociception’ in the title or abstract. Due to the relatively new emergence of this field, and the experimental and analytical challenges involved in studying cerebral processing of pain in the MRI environment in healthy newborn infants, only five fMRI studies have examined infant brain responses to nociceptive input.In a foundational pilot study, Williams et al., applied an experimental noxious stimulus to a single infant, evoking widespread brain activity that included several brain regions involved in pain processing in adults. Goksan et al., subsequently performed an observational cohort study and used regional analyses to compare active brain regions in infants (n=10) and adults (n=10), concluding that the evoked patterns of brain activity were broadly similar in infants and adults. Further follow-up analysis in the infant cohort revealed that the functional connectivity of brain regions involved in descending pain modulation influences the magnitude of pain-related brain activity. Two further studies focused on methodological advances, providing evidence-based recommendations for fMRI acquisition parameters and image processing in order to maximise the quality of infant data, and these methods have been implemented in this study.Added value of this studyThis study translates validated adult pain fMRI brain signatures to a nonverbal patient population in which the assessment and management of pain presents a significant clinical challenge. Application of fMRI brain signatures to newborn infants expands on previous fMRI studies that provided only qualitative evidence that noxious stimulation commonly activates brain regions in the adult and infant brain. Here we demonstrate that the basic encoding of the sensory discriminative aspects of pain, as represented by the Neurologic Pain Signature (NPS), occurs in both adults and infants, whereas higher-level cognitive modulation of pain, represented by the Stimulus Intensity Independent Pain Signature (SIIPS1) is only present in adults and not observed in infants. The differences in how the immature infant brain processes pain, relative to the mature adult brain, are likely to reflect differences in their expectation, motivation and contextualisation of external events rather than differences in their core nociceptive cerebral processing of pain. This work allows us to use quantitative fMRI observations to make stronger inferences related to pain experience in nonverbal infants.Implications of all the available evidenceBehavioural pain scores used in neonatal clinical care offer limited sensitivity and specificity to pain. Neonatal clinical trials that use these scores as outcome measures frequently report a lack of efficacy of common analgesic interventions, resulting in few evidence-based drugs for treating pain. The value of using brain-based neuroimaging markers of pain as a means of providing objective evidence of analgesic efficacy in early proof of concept studies is well recognised in adults, even in the absence of behavioural pain modulation. Similarly, in infants EEG-based measures of noxious-evoked brain activity have been used as outcome measures in clinical trials of analgesics to overcome some of the inherent limitations of using behavioural observations to quantify analgesic efficacy. Considering the successful translation of the Neurologic Pain Signature (NPS) and its sensitivity to analgesic modulation in adults, this novel methodology represents an objective brain-based fMRI approach that could be used to advance the discovery and assessment of analgesic interventions in infancy.

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