Postnatal Temporal, Spatial and Modality Tuning of Nociceptive Cutaneous Flexion Reflexes in Human Infants

Abstract

Cutaneous flexion reflexes are amongst the first behavioural responses to develop and are essential for the protection and survival of the newborn organism. Despite this, there has been no detailed, quantitative study of their maturation in human neonates. Here we use surface electromyographic (EMG) recording of biceps femoris activity in preterm (<37 weeks gestation, GA) and term (≥37 weeks GA) human infants, less than 14 days old, in response to tactile, punctate and clinically required skin-breaking lance stimulation of the heel. We show that all infants display a robust and long duration flexion reflex (>4 seconds) to a single noxious skin lance which decreases significantly with gestational age. This reflex is not restricted to the stimulated limb: heel lance evokes equal ipsilateral and contralateral reflexes in preterm and term infants. We further show that infant flexion withdrawal reflexes are not always nociceptive specific: in 29% of preterm infants, tactile stimulation evokes EMG activity that is indistinguishable from noxious stimulation. In 40% of term infants, tactile responses are also present but significantly smaller than nociceptive reflexes. Infant flexion reflexes are also evoked by application of calibrated punctate von Frey hairs (vFh), 0.8–17.2 g, to the heel. Von Frey hair thresholds increase significantly with gestational age and the magnitude of vFh evoked reflexes are significantly greater in preterm than term infants. Furthermore flexion reflexes in both groups are sensitized by repeated vFh stimulation. Thus human infant flexion reflexes differ in temporal, modality and spatial characteristics from those in adults. Reflex magnitude and tactile sensitivity decreases and nociceptive specificity and spatial organisation increases with gestational age. Strong, relatively non-specific, reflex sensitivity in early life may be important for driving postnatal activity dependent maturation of targeted spinal cord sensory circuits.

What do we really know about newborn infant pain?

“…In contrast, the infant flexion reflex is remarkably long duration. A single heel lance evokes biceps femoris activity for at least 2-4 s, decreasing significantly between the preterm and term period, but remaining longer in duration than adult reflexes (Cornelissen et al 2013).…”

“…Within-individual infant comparisons show that in 29% of preterm infants, tactile stimulation evokes flexor reflex EMG activity that is indistinguishable from noxious stimulation, while in 40% of term infants, tactile responses are also present but significantly smaller than nociceptive reflexes (Cornelissen et al 2013).…”

“…These basic protective reflexes remove an affected region from the source of potential injury and can be quantified in terms of thresholds, amplitude and duration using surface EMG recordings from flexor muscles. All infants display a robust and long-duration flexion reflex (>4 s) to a single noxious skin lance, the magnitude of which decreases significantly with gestational age (Cornelissen et al 2013). In adults, these nociceptive reflexes are evoked by stimulation of small-diameter afferent nociceptive fibres and are a reliable and objective reflection of an individual's pain experience (Skljarevski & Ramadan, 2002).…”

“…Finally, repeated innocuous stimulation in infants causes a significant increase in reflex magnitude and a drop in threshold, which are the hallmarks of sensitization (Andrews & Fitzgerald, 1994;Cornelissen et al 2013). In contrast, flexion reflex temporal summation or sensitization occurs in adults only after repeated C fibre or noxious stimulation and is associated with increased pain ratings (Price, 1972).…”

“…These findings not only explain why human infant flexion reflexes differ in temporal, modality and spatial characteristics from those in adults, but also reveal the nature of the first-stage processing of sensory information that will be transmitted to higher centres in the newborn brain. The newborn dorsal horn facilitates sensory inputs and thereby strengthens activity-dependent synaptic connections, but this is at the cost of reduced sensory discrimination and poor spatial localization (Cornelissen et al 2013). Increased excitability is traded for selectivity and focus.…”