A Sensitive Time in Development
A litany of milestones—the first heartbeat of a fetus, the first movements, and finally, birth—mark the early development of a human being. And, somewhere along the way, comes the ability to feel pain. A new study looks in the brain to see when that might happen. Researchers led by Lorenzo Fabrizi, Rebeccah Slater, and Maria Fitzgerald at University College London in the U.K. studied the electroencephalogram (EEG) activity of premature and full-term newborns, and found that at approximately 35 to 37 weeks of gestation, the brain’s response to a painful stimulus shifts from nonspecific neuronal bursts to adult-like activity. Their paper was published online September 8 in Current Biology.
The findings suggest that this timeframe, right at the end of gestation, may represent a critical period in the development of somatosensory processing in the human brain when infants begin to distinguish between painful and painless experiences. Further, because burst activity is an important driver of nervous system development, the observation that noxious stimuli strongly evoke burst activity in premature infants supports the idea that early painful events have the potential to disrupt development at a vulnerable time.
In previous studies, the team found that in full-term infants, painful or gentle contact evoked distinct, adult-like patterns of brain EEG activity (Slater et al., 2010). By placing electrodes on the babies’ scalps, they could measure electrical activity immediately after a gentle touch (a light tap on the heel) or noxious stimulus (a heel lance required for a blood sample). Evoked potentials in electrodes near the midline of the brain increased in response to both types of stimuli, but part of the signal extracted from one electrode was specifically elevated by the lance. The researchers say that the lance-evoked signals observed in infants line up with pain-related brain activity in adults (Bromm and Scharein, 1982).
In the new study, Fabrizi, Slater, and coworkers looked at brain activity in premature versus full-term newborns. They found that in premature newborns, light tap or heel lance evoked stimulus-specific activity less frequently in premature infants than in babies who had been born at full gestation: Touch-specific potentials occurred in only 7 percent of premature infants, compared to 30 percent of those at full term, and nociceptive-specific potentials occurred in 33 percent of preemies versus 63 percent of full-term infants.
While nociceptive-specific potentials were less apparent at early gestational ages, noxious stimuli did boost nonspecific neuronal bursting at widespread locations around the brain. In premature infants, bursts occurred spontaneously in 13 percent of background measurements, heel tap increased the frequency to 27 percent, and noxious heel lance increased it further, to 57 percent. (In full-term infants, noxious stimuli only marginally increased the burst rate compared to background.)
Comparing EEG activity from newborns of a range of gestational ages (24 to 45 weeks at the time of testing) revealed that over time, nonspecific burst behavior was gradually replaced by the more adult-like, stimulus-specific activity. For both touch and nociceptive responses, the switch happened at approximately 35 to 37 weeks, a moment the authors call “a critical crossover period in brain development.” Interestingly, this transition in the processing of mechanical stimuli coincides with a similar switch recently identified in visual processing (Colonnese et al., 2010).
One interpretation of the work is that the crossover period is when babies acquire the ability to tell painful stimuli from benign touch, but that is difficult to prove. “We cannot be sure that the brain does not distinguish noxious from gentle stimulation early in development, but we can say they are not distinguished in the same way we distinguish them later in life,” Fabrizi told PRF.
The work also suggests that nociceptive activity in premature newborns could have lasting effects, Fabrizi and his coauthors said. During normal brain development, spontaneous burst activity drives the formation of neuronal circuits. The new findings show that the same type of activity is also strongly evoked by a painful procedure. Thus, tissue-damaging stimuli—which premature infants experience frequently during medical treatment—has the potential to interfere with normal cortical development, and could account for the abnormal pain perception reported among children born premature (e.g., see Hohmeister et al., 2010).
The observation that premature babies’ brains respond to noxious stimuli with neuronal burst activity shows just how special their brains are. “The central nervous system [of premature newborns] is not just a scaled version of the one in term infants; it’s different. We know very little about the term ones, but we know almost nothing about the premature ones,” Fabrizi said. “We need to know more.” The goal, he said, is to combine brain activity, behavior, and reflex responses into an integrated framework that could be used to assess infants’ pain in the clinic.
Image credit: L. Fabrizi, University College London
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