Due to maturation-related plasticity of the developing nociceptive system, neonatal nociceptive input, as induced by medical procedures in the neonatal intensive care unit (NICU), may cause long-term alterations in pain processing. Using functional magnetic resonance imaging, this study investigated the cerebral pain response in school-aged children and adolescents (11-16 yr) with experience in a NICU after preterm (or=37 weeks gestational age, N=9) as compared to fullterm control children without early hospitalization (N=9). NICU children had been recruited retrospectively among former patients of the Children's University Hospital Mannheim. All children had participated in our previous studies [46,49] entailing psychophysical measurements. In response to tonic (30s) heat stimuli of individually adjusted moderate pain intensity, which were of comparable temperature across groups, the preterm but not the fullterm NICU children exhibited significant activations in a number of brain regions (thalamus, anterior cingulate cortex, cerebellum, basal ganglia, and periaquaeductal gray) that were not significantly activated in controls. The preterms showed significantly higher activations than controls in primary somatosensory cortex, anterior cingulate cortex, and insula. This exaggerated brain response was pain-specific and was not observed during non-painful warmth stimulation. Preterms' continuous pain ratings revealed a tendency for increased sensitization within and a lack of habituation across trials. In highly vulnerable children such as preterms, neonatal nociceptive input may, aside from other neurodevelopmental consequences, persistently increase the gain within pain pathways.

Studies in animals and humans suggest that neonatal and early infant pain or stress experiences can induce long-term alterations in somatosensory and pain processing. We studied pain and sensory sensitivity in school-aged children (9-16 years) who had suffered moderate (N=24) or severe (N=24) burn injuries in infancy (6-24 months of age) and 24 controls. Quantitative sensory testing entailing detection and pain thresholds for thermal and mechanical stimuli and perceptual sensitization to tonic heat and repetitive mechanical stimuli was performed. Two testing sites (thenar, trigeminal region), both not affected by the burn injury, were used to determine whether there are global changes in pain sensitivity. The result pattern suggests a differential impact of burn severity. Compared to controls, moderately burned children showed significantly higher mechanical detection thresholds (thenar) and significantly lower mechanical pain thresholds and significantly greater perceptual sensitization to repetitive mechanical stimuli (both testing sites). No significant alterations were observed for thermal stimuli. In contrast, severely burned children showed, compared to controls, primarily alterations in thermal pain sensitivity (elevated pain thresholds at both testing sites, significantly greater perceptual sensitization at the thenar). In these children, mechanical pain sensitivity and detection thresholds were not consistently altered. This differential pattern of altered sensory and pain sensitivity may reflect differences in experienced stress, pain and analgesic treatment between moderately and severely burned children. Most importantly, our findings suggest that early traumatic and painful injuries, such as burns, can induce global, long-term alterations in sensory and pain processing.

There is evidence in humans and animals that neonatal and early infant pain and stress may sensitize excitatory pain pathways. Possibly such experiences may result in long-term diminished activation of phasic endogenous pain inhibitory mechanisms. We studied stress-induced activation of endogenous pain inhibitory mechanisms in school-aged children (10-16 years) who had suffered moderate (N= =12) or severe (N=10) burn injuries in infancy (6-24 months of age) and 20 controls. Before and after the stress phase, pain threshold and pain tolerance (heat, pressure, ischemic pain) were assessed. Stress was successfully induced in all children as reflected by increases in heart rate, blood pressure and perceived stress. In the controls, there was evidence for stress-induced hypoalgesia as reflected by significant increases in heat pain threshold, heat pain tolerance and pressure pain tolerance. Pressure pain thresholds were not significantly altered. A similar pattern was observed in the moderately burned children. By contrast, children with severe burn injuries failed to show significant stress-related changes in heat and pressure pain sensitivity. In all groups, ischemic pain sensitivity was elevated post stress. The children reported being more distressed by the perceived loss of strength than by pain and had difficulties differentiating between the two. It is possible that ischemic pain may be less suitable for measuring pain sensitivity in children. The present study provides first evidence that pain and stress exposure due to severe burns in infancy may be associated with an attenuated stress-induced activation of phasic endogenous pain inhibitory mechanisms later in childhood and adolescence.