Adult brain activation in response to pain is changed by neonatal painful stimulation according to sex: A manganese-enhanced MRI study.

Although it is known that nociceptive stimulation in the first postnatal week in rats is useful to model preterm pain, resulting in activation of specific brain areas, as assessed in vivo using manganese-enhanced magnetic resonance imaging (MEMRI), little is known about its long-term effects and sex specificity. Here we aimed to investigate whether inflammatory pain induced in male and female adult rats modify the pattern of brain activation between animals subjected or not to neonatal pain. For this, Complete Freund's adjuvant (CFA) was injected into the left hind paw of rat pups on postnatal day 1 (P1) or P8 to induce inflammatory response. During adulthood, CFA-treated and control animals were injected with CFA 1 hr prior MRI. MEMRI has the ability to enhance the contrast of selective brain structures in response to a specific stimulus, as the pain. MEMRI responses were consistent with activation of nociceptive pathways and these responses were reduced in animals treated with CFA on P1, but increased in animals treated on P8, mainly in the female group. In agreement, P8 female group showed exacerbated responses in the thermal nociceptive test. Using MEMRI, we conclude that the natural ability of adult rats to recognize and react to pain exposition is modified by neonatal painful exposition, mainly among females.

Preterm infants with peri/intraventricular hemorrhage have poorer habituation responses to external stimuli / Neonatos prematuros com hemorragia peri-intraventricular apresentam respostas de habituação piores a estímulos externos

ABSTRACT Objective: To evaluate the association between intra-ventricular hemorrhage and habituation responses to external stimuli in preterm infants at 36-38 weeks post-conceptual age. Methods: Cross-sectional study of infants with gestational age <32 weeks. Intra-ventricular hemorrhage was identified by cranial ultrasonography and classified according to Papile et al. (1978). The luminous (flashlight), sound (rattle, bell), and tactile stimuli were presented, and the responses were scored according to Lester and Tronik (2004). Habituation response scores were compared between groups by Student's t-test. The association between IVH and habituation scores was evaluated by linear regression adjusted for GA, clinical severity score, post-conceptual age at habituation assessment, sepsis, and bronchopulmonary dysplasia. Results: Sixty-five infants were studied, 20 with intra-ventricular hemorrhage (16 grades I/II; four grades III/IV) and 45 without intra-ventricular hemorrhage. Infants with intra-ventricular hemorrhage had lower gestational age (28.2 ± 2.2 vs. 29.7 ± 1.7 weeks) and birth weight (990 ± 305 vs. 1275 ± 360 g). Infants with intra-ventricular hemorrhage at 36-38 weeks post-conceptual age had lower habituation scores to light (4.21 ± 2.23 vs. 6.09 ± 2.44), rattle (3.84 ± 2.12 vs. 6.18 ± 2.27), and bell (3.58 ± 1.74 vs. 5.20 ± 2.47) after controlling for confounders. No differences were found for tactile stimulus. Conclusion: Infants with gestational age <32 weeks and intra-ventricular hemorrhage had poorer habituation responses to external stimuli than those without intra-ventricular hemorrhage at 36-38 weeks post-conceptual age.

RESUMO Objetivo: Avaliar a associação entre hemorragia intraventricular e as respostas de habituação a estímulos externos em neonatos prematuros com idade pós-conceptual de 36-38 semanas. Métodos: Estudo transversal com neonatos com idade gestacional < 32 semanas. A hemorragia intraventricular foi identificada por ultrassonografia craniana e classificada de acordo com Papile et al. (1978). Os estímulos luminosos (lanterna), sonoros (chocalho, sino) e táteis foram apresentados e as respostas foram pontuadas de acordo com Lester & Tronik (2004). Os escores das respostas de habituação foram comparadas entre os grupos pelo teste t de Student. A associação entre a hemorragia intraventricular e os escores de habituação foi avaliada por regressão linear ajustada para a idade gestacional, escore de gravidade clínica, idade pós-conceptual na avaliação da habituação, sepse e displasia broncopulmonar. Resultados: 65 neonatos foram estudados, 20 com hemorragia intraventricular (16 graus I/II;4 graus III/IV) e 45 sem hemorragia intraventricular. Os neonatos com hemorragia intraventricular apresentaram menor idade gestacional (28,2 ± 2,2 vs. 29,7 ± 1,7 semanas) e peso ao nascer (990 ± 305 vs. 1275 ± 360 g). Os neonatos com hemorragia intraventricular na idade pós-conceptual de 36-38 semanas apresentaram escores de habituação menores a luz (4,21 ± 2,23 vs. 6,09 ± 2,44), chocalho (3,84 ± 2,12 vs. 6,18 ± 2,27) e campainha (3,58 ± 1,74 vs. 5,20 ± 2,47) após controle para variáveis de confusão. Nenhuma diferença foi encontrada para os estímulos táteis. Conclusão: Neonatos com idade gestacional < 32 semanas e hemorragia intraventricular apresentaram respostas de habituação piores a estímulos externos que os sem hemorragia intraventricular, na idade pós-conceptual de 36-38 semanas.

Preterm infants with peri/intraventricular hemorrhage have poorer habituation responses to external stimuli.

OBJECTIVE: To evaluate the association between intra-ventricular hemorrhage and habituation responses to external stimuli in preterm infants at 36-38 weeks post-conceptual age. METHODS: Cross-sectional study of infants with gestational age <32 weeks. Intra-ventricular hemorrhage was identified by cranial ultrasonography and classified according to Papile et al. (1978). The luminous (flashlight), sound (rattle, bell), and tactile stimuli were presented, and the responses were scored according to Lester and Tronik (2004). Habituation response scores were compared between groups by Student's t-test. The association between IVH and habituation scores was evaluated by linear regression adjusted for GA, clinical severity score, post-conceptual age at habituation assessment, sepsis, and bronchopulmonary dysplasia. RESULTS: Sixty-five infants were studied, 20 with intra-ventricular hemorrhage (16 grades I/II; four grades III/IV) and 45 without intra-ventricular hemorrhage. Infants with intra-ventricular hemorrhage had lower gestational age (28.2±2.2 vs. 29.7±1.7 weeks) and birth weight (990±305 vs. 1275±360g). Infants with intra-ventricular hemorrhage at 36-38 weeks post-conceptual age had lower habituation scores to light (4.21±2.23 vs. 6.09±2.44), rattle (3.84±2.12 vs. 6.18±2.27), and bell (3.58±1.74 vs. 5.20±2.47) after controlling for confounders. No differences were found for tactile stimulus. CONCLUSION: Infants with gestational age <32 weeks and intra-ventricular hemorrhage had poorer habituation responses to external stimuli than those without intra-ventricular hemorrhage at 36-38 weeks post-conceptual age.

Sex-related long-term behavioral and hippocampal cellular alterations after nociceptive stimulation throughout postnatal development in rats.

Early noxious stimuli may alter the neurogenesis rate in the dentate gyrus and the behavioral repertoire of adult rats. This study evaluated the long-term effects of noxious stimulation, imposed in different phases of development, on nociceptive and anxiety-like behaviors, hippocampal activation, cell proliferation, hippocampal BDNF and plasma corticosterone levels in 40 day-old male and female adolescents. Noxious stimulation was induced by intra-plantar injection of Complete Freund's adjuvant (CFA), on postnatal days (P) 1 (group P1), 8 (P8) or 21 (P21). Control animals were not stimulated in any way. On P21 a subset of animals from each group received BrdU and was perfused on P40 for identification of proliferating cells in the granule cell layer of the dentate gyrus. Another subset of rats was subjected to behavioral testing on P40 and one week later, to magnetic resonance imaging (MRI) acquisition. Noxious stimulation evoked hypoalgesia in adolescents, mainly in females (P < 0.02), reflected by greater latency to withdraw the paw and less paw lickings in the hot plate test than controls (P < 0.001). It also resulted in more time spent in the open arms, e.g., less anxiety-like behavior than controls (P < 0.01), especially in females (P < 0.01, compared with males). Proliferative cell rate in the dentate gyrus was the highest in P8 males and females (P < 0.001), with males exhibiting more proliferation than females on P1 and P8, which was directly related to the hippocampal levels of BDNF and inversely related to plasma corticosterone. Sex differences were also detected in manganese-enhanced MRI signal, which was more prominent in P1 females than males (P < 0.01). This study represents the first step of investigation on the cellular basis of the sex-dependent long-term consequences of nociceptive stimuli in newborns.