Investigating pain in the developing human brain
Keywords: morphine
fMRI
EEG
noxious
neonates
pain

Infants born prematurely or critically ill require a plethora of painful procedures during a period of extensive structural and functional neurodevelopment. Pain is however inconsistently and inadequately managed in neonatal care due to the inherent challenges of pain assessment and a lack of evidence-based analgesics. Noxious stimuli provoke behavioural and cardiorespiratory responses, which are valuable indicators of pain in the absence of verbal report. These measures can however be subjective and limited in specificity and sensitivity. EEG and fMRI can provide objective measures of noxious-evoked brain activity with which to investigate the development of nociceptive processing, its modulation in early life, and efficacy of analgesics.
In this thesis, I used electrophysiological measures to characterise the development of noxious-evoked brain and spinal reflex activity in the preterm period. Nociceptive-specific brain activity increased in magnitude with gestational age, whereas reflex withdrawal activity decreased in amplitude, duration, and latency. The relative proportion of these responses was strongly correlated with gestational age, suggesting a developmental relationship between spinal and supraspinal maturation. FMRI was subsequently used to investigate the relationship between noxious-evoked brain activity and connectivity of the periaqueductal grey (PAG), a core region of endogenous pain modulation and common target of analgesics. Functional connectivity of the PAG to the middle frontal gyrus and anterior cingulate cortex was negatively correlated with noxious-evoked BOLD activity. Developing connectivity of the PAG may begin to influence noxious-evoked brain activity in term neonates and influence the developmental relationship between electrophysiological measures.
Many external and internal factors influence pain. Sex differences in pain sensitivity and nociceptive processing are extensively reported in adults and animals. I therefore used electrophysiology and fMRI to investigate sex differences in nociceptive processing in healthy term infants. Noxious stimulation evoked greater magnitude of electrophysiological activity and greater BOLD activity across multiple brain regions in female compared to male infants.
Morphine is a commonly used analgesic in neonates despite inconclusive evidence of its efficacy. In my final study, noxious-evoked brain activity was employed as a co-primary outcome with clinical pain scoring to investigate the efficacy of oral morphine for procedural pain relief in infants born prematurely. The placebo-controlled trial was terminated early due to safety concerns. Despite significant cardiorespiratory effects, morphine did not attenuate multimodal measures of pain, raising questions concerning the balance of safety and efficacy of this drug.
In summary, this thesis demonstrates that age, connectivity of endogenous pain modulatory brain regions, and sex affect noxious-evoked brain activity, and this valuable biomarker of pain can be used alongside multimodal outcome measures and rigorous physiological monitoring to assess the efficacy of analgesic agents in neonates.