The Adverse Effect Of BPD And NEC On Central Regions Of The Immature Auditory Brainstem In Very Preterm Infants

With the great development of neonatal intensive care, the survival rate of preterm infants has significantly increased. The preterm infants often experience many kinds of serious perinatal complications, including bronchopulmonary dysplasia (BPD) and necrotizing enterocolitis (NEC).BPD is the most severe chronic lung diseases in very preterm infants. Infants with BPD manifested by prolonged requirements for mechanical ventilation and supplemental oxygen are at increased risk of long-term neurologic and motor abnormalities. Our knowledge of the pathophysiological mechanism of neurologic impairment and motor abnormalities after BPD remains very limited. Recent study showed that poor myelination and synaptic function of the brainstem in infants with BPD resulted in impaired functional integrity of auditory brainstem. However, the understanding of the functional development of auditory brainstem in preterm infants with BPD from birth to term date remains unclear.NEC is recognized as the most common acute gastrointestinal disease in very preterm infants. Previous studies showed that NEC was associated with the long-term neurodevelopmental delay and functional disorder. Many perinatal risk factors that are related to NEC, including infection, asphyxia and prematurity, could also lead to neurodevelopmental disorder and brain injury. However, the effect of NEC on auditory brainstem function and long-term neurodevelopment of preterm infants is still unclear.Recently, the brainstem auditory evoked response (BAER) has been used to assess functional integrity and development of the auditory system and the brain in conditions that affect the brainstem auditory pathway. As a non-invasive and objective test, BAER is particularly suitable in very young or sick infants. Increase in the repetition rate of click stimuli could improve the detection of neuropathology. Maximum length sequence brainstem auditory evoked response (MLS-BAER) can present acoustic stimuli up to 910/s or even higher, which can improve the sensitivity of BAER in detecting some neuropathology. Previous studies used the MLS BAER to study brainstem auditory function and assess the value of MLS BAER in the detection of neurological abnormalities in infants.Children are found to be capable of distinguishing speech sounds from as early as one month of age. Privileged status of consonantal over vocalic information has been found in infants learning words in their native language. However, there are no reported studies regarding phonological specificity in Mandarin in British baby.We studied the time course in functional development of the auditory brainstem in infants with BPD from birth to term date, using MLS-BAER technology. Paticular attention has been paid to the relative development of central and peripheral regions in auditory brainstem of infants with BPD from birth to term date. And we explored the association of changes in MLS-BAER with BPD and the adverse effect of NEC on neural conduction of the rostral brainstem in preterm babies. In order to improve the assessment of long-term neurodevelopmental outcome of these babies, we developed the novel eye-gaze monitoring and HPP to assess the cognitive development of 6 months old British infants.Part I:The association of changes in MLS-BAER with BPD during the preterm periodObjective:This study aimed to find out the association of changes in MLS-BAER with BPD during the preterm period.Methods:We double blindly recruited 336 preterm infants (gestational age<32 weeks) to carry out a perspective study. MLS-BAER was recorded at PCA of 32,34 and 36weeks respectively. After the diagnosis of BPD (PCA of 36 weeks), all subjects were divided into BPD group (122 infants) and non-BPD group (214 infants). ROC analysis was conducted to find out the association of changes in MLS-BAER with BPD.Results:The areas under ROC of wave V latency, and Ⅲ-Ⅴ and Ⅰ-Ⅴ interpeak intervals were significantly larger than 0.5 from PCA of 32-36 weeks. The areas under ROC of wave Ⅲ latency, Ⅲ-Ⅴ/Ⅰ-Ⅲ interval ratio and I-Ⅲ interval were significantly larger than 0.5 from PCA of 34-36 weeks. The areas under ROC of wave Ⅴ latency, and Ⅲ-Ⅴ and Ⅰ-Ⅴ interpeak intervals were significantly larger than those of Ⅴ/Ⅰ amplititude ratio at PCA of 36 weeks. The areas under ROC of the Ⅲ-Ⅴ interpeak interval were significantly larger than those of Ⅲ-Ⅴ/Ⅰ-Ⅲ interval ratio at PCA of 36 weeks.Conclusion:Our findings mainly reflected the high association of increase in MLS-BAER parameters, including wave V latency, and Ⅲ-Ⅴ and Ⅰ-Ⅴ interpeak intervals, with BPD during PCA of 32-36 weeks. During PCA of 34-36 weeks, there was high association of increase in MLS-BAER parameters, including the wave Ⅲ latency, and Ⅲ-Ⅴ/Ⅰ-Ⅲ interval ratio and Ⅰ-Ⅲ interval, with BPD. Our findings can help the prediction of BPD and the study of early neuroprotective treatments for BPD.Part Ⅱ:Time course of functional development of the auditory brainstem from preterm through to term date in BPD infantsObjective:This study aimed to find out the differences of time course between BPD group and the control groups in functional development of the auditory brainstem from preterm to term date.Methods:We recruited 217 preterm infants (PCA<32 weeks) to carry out a retrospective study. All preterm infants were divided into BPD group (122 infants) and HP group (95infants). MLS-BAER was recorded at PCA of 32,34,36,38,40 and 42 weeks respectively in preterm infants. In addition, we recruited 65 normal term infants. MLS-BAER was recorded at PCA of 38,40 and 42 weeks respectively in term infants. We retrospectively analyzed the records of BAER threshold and compared the MLS-BAER parameters between BPD group and control groups to find out the differences of time course in functional development of the auditory brainstem, performed by general liner model analysis. The relationship between the changes of MLS-BAER and click rates was analyzed by correlation analysis.Results:The wave Ⅴ latency and all interpeak intervals in BPD group decreased gradually and they were significantly longer than those in HP group from PCA 32 to 36 weeks (P<0.05; P<0.001). PCA of 38 weeks, the wave Ⅴ latency and all intervals in BPD group decreased and they were significantly longer than those in HP and NT group (P<0.05). PCA of 40 weeks, the wave Ⅴ latency and Ⅲ-Ⅴ, Ⅰ-Ⅴ intervals in BPD group decreased and they were significantly longer than those in HP and NT group (P<0.05; P<0.001). PCA of 42 weeks, the wave Ⅴ latency and Ⅲ-Ⅴ interval in BPD group decreased and they were significantly longer than those in HP and NT group; Ⅰ-Ⅴ interval in BPD group decreased and it was significantly longer than that in NT group (P<0.05; P<0.001). These differences were more significant with the increase of click rates. The latencies of wave Ⅰ, wave Ⅲ, wave Ⅴ, Ⅲ-Ⅴ, Ⅰ-Ⅴ and Ⅰ-Ⅲ interpeak intervals at higher click rates were significantly longer than those at lower click rates and there were significant differences among the four click rates (P<0.001). All wave latencies and interpeak intervals in all subjects correlated significantly and positively with click rates (r=0.211-0.801; P<0.001).Conclusion:From PCA 32 to 36 weeks, the wave V latency and all intervals in BPD group developed gradually and they were significantly longer than those in HP group. PCA of 38 weeks, there were still significant differences of the wave V latency and all intervals between BPD group and control groups. PCA of 40 weeks, the wave V latency and Ⅲ-Ⅴ, Ⅰ-Ⅴ intervals in BPD group were still abnormal. PCA of 42 weeks, there were still significant differences of the wave Ⅴ latency and Ⅲ-Ⅴ interval between BPD group and control groups; Ⅰ-Ⅴ interval in BPD group was significantly longer than those in NT group. Our findings reflected that efficiency of synaptic transmission significantly decreased and was vulnerable to the increase of click rate in infants with BPD. The function of neural conduction in auditory brainstem gradually recovered but still were abnormal from preterm to term date.Part Ⅲ:The relative development of central and peripheral regions of the auditory brainstem:comparison between preterm BPD infants and low risk preterm infantsObjective:This study aimed to find out the relative development of central and peripheral regions of auditory brainstem by comparison between preterm BPD infants and low risk preterm infants, performed by MLS-BAER, which could provide valuable information for developing neuroprotective measures targeting at the specific region of the brainstem for infants with BPD.Methods:We recruited 217 preterm infants (PCA<32 weeks) to carry out a retrospective study. All preterm infants were divided into BPD group (122 infants) and HP group (95infants). MLS-BAER was recorded at PCA of 32,34,36,38,40 and 42 weeks respectively in preterm infants. In addition, we recruited 65 normal term infants. MLS-BAER was recorded at PCA of 38,40 and 42 weeks respectively in term infants. We retrospectively analyzed the records of BAER threshold and compared Ⅲ-Ⅴ, Ⅰ-Ⅲ intervals and Ⅲ-Ⅴ/Ⅰ-Ⅲ interval ratio between BPD group and control groups, performed by general liner model analysis. The relationship between the changes of MLS-BAER and PCA was analyzed by correlation analysis.Results:The Ⅲ-Ⅴ、Ⅰ-Ⅲ interpeak intervals in BPD group were significantly longer than those in control groups during PCA of 32-38 weeks (P<0.05). From PCA 40 to 42 weeks, the Ⅲ-Ⅴ interval in BPD group was still significantly longer than that in control groups (P<0.05). However, there was no significant difference of Ⅰ-Ⅲ interval between BPD group and control groups during PCA of 40-42 weeks (P>0.05). Ⅲ-Ⅴ/Ⅰ-Ⅲ interval ratio in BPD group was significantly longer than that in control groups during PCA of 32-34 weeks and 40-42 weeks (P<0.05). There was no significant difference of Ⅲ-Ⅴ/Ⅰ-Ⅲ interval ratio between BPD group and control groups during PCA of 36-38 weeks (P>0.05).Conclusion:Our study mainly reflected that there were delayed neural conduction and decreased efficacy of central synaptic transmission in more central part of auditory brainstem in infants with BPD. Our study showed that the impairment of central brainstem auditory function lasted from birth to term date, while peripheral auditory function recovered gradually. The changes of Ⅲ-Ⅴ/Ⅰ-Ⅲ interval ratio in BPD group could further prove the differences of fuctional development between central region and peripheral region in auditory brainstem. Our findings could provide valuable information for detecting and locating the impairment of auditory brainstem and for future studying and developing neuroprotective measures targeting at the more central or rostral regions of the brainstem for babies who suffer BPD.Part Ⅳ:Neonatal necrotizing enterocolitis adversely affects neural conduction of the rostral brainstem in preterm babiesObjective:Necrotizing enterocolitis (NEC) is a devastating neonatal disease, often leading to long term neurodevelopmental impairment. The effect of NEC on the immature brain remains not fully understood. We test the hypothesis that NEC adversely affects functional integrity, particularly neural conduction, of the preterm brainstem.Methods:Thirty-two preterm NEC babies (30-36 weeks gestation) were recruited at term age. Maximum length sequence brainstem auditory evoked response was recorded and analysed with click rates 91-910/s at term age. The results were compared with normal term babies and age-matched healthy preterm babies.Results. Wave Ⅴ latency,Ⅰ-Ⅴ and Ⅲ-Ⅴ intervals, and Ⅲ-Ⅴ/Ⅰ-Ⅲ interval ratio differed significantly among the three groups of babies at all click rates 91-910/s. Compared with normal term babies, preterm NEC babies showed significant increase in all these MLS BAER variables at all rates, with no apparent abnormalities in wave Ⅰ and Ⅲ latencies and Ⅰ-Ⅲ interval. All these abnormalities were more significant at higher than at lower click rates. No notable abnormalities were seen in wave amplitudes. Compared with age-matched healthy preterm babies, NEC babies showed similar abnormalities, although the abnormalities were relatively less significant.Conclusions:MLS BAER components that mainly reflect neural conduction in the more central regions of the auditory brainstem were abnormal in preterm NEC babies, although those components that mainly reflect peripheral function were generally normal. Neonatal NEC adversely affects myelination of the more rostral or central regions of the immature brainstem, resulting in delayed or impaired neural conduction. but spares the more peripheral regions. The findings are valuable for future studying and developing neuroprotective measures targeting at the more central or rostral regions of the brainstem for babies after NEC.Part V:Phonological specificity in Mandarin in British babies of 6 months oldObjective To find out whether 6 months old British baby can tell the tiny difference from shengmu change or yunmu change in Chinese word and whether there is also privileged status of shengmu over yunmu in distinguishing phonological specificity in Mandarin.Methods:We recruited 6 months old British babies without any major peri-and post-natal problems or complications and all infants have learned English in the United Kingdom from parents for whom English is the first language. We used modified Headturn Preference Procedure (HPP) and eye-gaze monitoring to measure whether children can distinguish phonological specificity in Mandarin under very carefully controlled experimental conditions.Results:1) The group of yunmu change:There was no significant difference of whole orientation time between label 1 and label 2 (P>0.05). There was also no significant difference of whole orientation time between label 5 and label 6 (P>0.05).2) The group of shengmu change:The whole orientation time of label 3 was significantly longer than that of label 4 (P<0.05). And the whole orientation time of label 7 was significantly longer than that of label 8(P<0.05).Conclusion:Our study found that 6 months old British baby can tell the tiny difference from shengmu change in Chinese word and there was also privileged status of shengmu over yunmu in distinguishing phonological specificity in Mandarin. Our findings could provide valuable information and new insight for the future clinical follow-up study to evaluate cognitive development of infants with BPD or NEC.Genera] Conclusion:Our findings reflected the high association of increase in MLS-BAER parameters, including wave Ⅴ latency, and Ⅲ-Ⅴ and Ⅰ-Ⅴ intervals, with BPD during PCA of 32-36 weeks. During PCA of 34-36 weeks, there was high association of increase in MLS-BAER parameters, including the wave Ⅲ latency, Ⅲ-Ⅴ/Ⅰ-Ⅲ interval ratio and Ⅰ-Ⅲ interpeak interval, with BPD. The efficiency of synaptic transmission significantly decreased and was vulnerable to the increase of click rate in infants with BPD. The function of neural conduction in auditory brainstem gradually recovered but still were abnormal from preterm to term date. There were delayed neural conduction and decreased efficacy of central synaptic transmission in more central part of auditory brainstem in infants with BPD. Our study showed that the impairment of central brainstem auditory function lasted from preterm to term date, while peripheral auditory function recovered gradually. The changes of Ⅲ-Ⅴ/Ⅰ-Ⅲ interval ratio in BPD group could further prove the differences of fuctional development between central region and peripheral region in auditory brainstem. Our findings can help the prediction of BPD and the study of early neuroprotective treatments for BPD. Our study provides valuable information for detecting and locating the impairment of auditory brainstem and for future studying and developing neuroprotective measures targeting at the more central or rostral regions of the brainstem for babies who suffer BPD.MLS BAER components that mainly reflect neural conduction in the more central regions of the auditory brainstem were abnormal in preterm NEC babies, although those components that mainly reflect peripheral function were generally normal. Neonatal NEC adversely affects myelination of the more rostral or central regions of the immature brainstem, resulting in delayed or impaired neural conduction, but spares the more peripheral regions. The findings are valuable for future studying and developing neuroprotective measures targeting at the more central or rostral regions of the brainstem for babies after NEC.6 months old British baby can tell the tiny difference from shengmu change in Chinese word and there is also privileged status of shengmu over yunmu in distinguishing phonological specificity in Mandarin. Our findings could provide valuable information and new insight for the future clinical follow-up study to evaluate cognitive development of infants with BPD or NEC.