Cortical pain responses in human infants

Abstract

Despite the recent increase in our understanding of the development of pain processing, it is still not known whether premature infants are capable of processing pain at a cortical level. In this study, changes in cerebral oxygenation over the somatosensory cortex were measured in response to noxious stimulation using real-time near-infrared spectroscopy in 18 infants aged between 25 and 45 weeks postmenstrual age. The noxious stimuli were heel lances performed for routine blood sampling; no blood tests were performed solely for the purpose of the study. Noxious stimulation produced a clear cortical response, measured as an increase in total hemoglobin concentration [HbT] in the contralateral somatosensory cortex, from 25 weeks (mean Delta[HbT] = 7.74 micromol/L; SE, 1.10). Cortical responses were significantly greater in awake compared with sleeping infants, with a mean difference of 6.63 micromol/L [95% confidence interval (CI) limits: 2.35, 10.91 micromol/L; mean age, 35.2 weeks]. In awake infants, the response in the contralateral somatosensory cortex increased with age (regression coefficient, 0.698 micromol/L/week; 95% CI limits: 0.132, 1.265 micromol/L/week) and the latency decreased with age (regression coefficient, -0.9861 micromol/L/week; 95% CI limits: -1.5361, -0.4361 micromol/L/week; age range, 25-38 weeks). The response was modality specific because no response was detected after non-noxious stimulation of the heel, even when accompanied by reflex withdrawal of the foot. We conclude that noxious information is transmitted to the preterm infant cortex from 25 weeks, highlighting the potential for both higher-level pain processing and pain-induced plasticity in the human brain from a very early age.

Figure 1.

A, Optode placement. A photograph of a premature infant (33 + 4 weeks PMA) with optodes positioned over the somatosensory cortex is shown. B, Hemodynamic response. A sample trace in a single infant (29 + 5 weeks PMA) is shown, demonstrating the evoked change in [HbT] in the contralateral and ipsilateral somatosensory cortex after a painful stimuli given at t = 20 s. Sampling frequency, 2 Hz.

Figure 2.

A, Group results for awake infants. A bar chart shows individual ipsilateral and contralateral maximum Δ[HbT] after heel lance in each awake infant. The age of each infant (completed postmenstrual weeks) is shown. B, Effect of age on hemodynamic response. A developmental profile of the maximum Δ[HbT] in the contralateral somatosensory cortex after heel lance in infants at different PMAs is shown [regression coefficient for awake infants (squares): 0.698 μmol/L/week, 95% CI limits: 0.132, 1.265 μmol/L/week; asleep infants (triangles): −0.291 μmol/L/week, 95% CI limits: −1.004, 0.423 μmol/L/week]. Connected points represent repeated measures in individual infants. Unfilled points represent infants receiving morphine; these infants are excluded from the regression analysis.

Figure 3.

Hemodynamic response in the youngest infant. A sample trace in the youngest infant in our sample (25 + 5 weeks PMA) is shown, demonstrating the evoked change in [HbT] in the contralateral and ipsilateral somatosensory cortex after a painful stimuli given at t = 20 s. Sampling frequency, 6 Hz.