Functional abnormality of the auditory brainstem in high-risk late preterm infants

Clinical Neurophysiology 123 (2012) 993–1001

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Functional abnormality of the auditory brainstem in high-risk late preterm infants Ze D. Jiang a,b,⇑,1, Li L. Ping a,1, Andrew R. Wilkinson b a b

Department of Pediatrics, Children’s Hospital, Fudan University, Shanghai, China Neonatal Unit, Department of Paediatrics, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK

See Editorial, pages 852–853

a r t i c l e

i n f o

Article history: Available online 5 October 2011 Keywords: Auditory evoked potentials Brainstem auditory function Later preterm infants Perinatal brain damage

h i g h l i g h t s  Little is known bout whether high-risk late preterm infants has brainstem impairment.  Maximum length sequence brainstem auditory evoked response was found to be abnormal in these infants.  This suggests that more central regions of the auditory brainstem are impaired in high-risk late preterm infants.

a b s t r a c t ObjectiveTo examine whether late preterm infants with perinatal problems are at risk of brainstem auditory impairment. Methods: 68 high-risk late preterm infants (gestation 33–36 weeks) with perinatal problems or conditions were studied at term using maximum length sequence brainstem auditory evoked response. The controls were 41 normal term infants and 37 low-risk late preterm infants. Results: Compared with normal term infants, the high-risk late preterm infants demonstrated a significant abnormal increase in MLS BAER variables that mainly reflect more central function of the brainstem auditory pathway, including wave V latency, III–V and I–V interpeak intervals, and III–V/I–III interval ratio. The abnormalities were more significant at higher than at lower click rates. The slopes of MLS BAER-rate function for these variables were increased. Compared with low-risk late preterm infants, the high-risk infants showed similar, though slightly less significant, abnormalities, mainly a significant increase in III–V and I–V intervals. Conclusions: Maximum length sequence brainstem auditory evoked response components that mainly reflect central function of the auditory brainstem were abnormal at term in high-risk late preterm infants. Significance: More central regions of the auditory brainstem are impaired in high-risk late preterm infants, which is mainly caused by associated perinatal problems or conditions. Ó 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction A decrease in gestational age is associated with an increased incidence of neurodevelopmental abnormalities or deficits such as cerebral palsy, even for those infants born at late pregnancy or late preterm (Petrini et al., 2009). Of all preterm births, late preterm births comprises about 70% (Barros et al., 2005; Buitendijk ⇑ Corresponding author at: Neonatal Unit, Department of Paediatrics, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK. Tel.: +44 1865 221364; fax: +44 1865 221366. E-mail address: [email protected] (Z.D. Jiang). 1 These authors contributed equally to the research.

et al., 2003; Davidoff et al., 2006; Moser et al., 2007). Therefore, late preterm infants are an important population in preterm infants. Unlike in very preterm infant, so far there is a lack of extensive clinical, physiologic, neuroanatomic, and neurochemical studies in late preterm infants. Numerous previous studies have shown that infants who are born at very or extremely preterm are predisposed to brain damage and neurological, including auditory, impairment (Marlow et al., 2005; Romeo et al., 2010; Xoinis et al., 2007). On the other hand, limited information is available for brain function and neurodevelopment in early life in infants who are born at late preterm (Adams-Chapman, 2006; Billiards et al., 2006; CohenWolkowiez et al., 2009; Darnall et al., 2006; Hunt, 2006; Kinney 2006; Sarici et al., 2004). In recent years, there is an increased

1388-2457/$36.00 Ó 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2011.08.032

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interest in studying neurodevelopment in late preterm infants (Petrini et al., 2009; Romeo et al., 2010; Talge et al., 2010). For instance, Talge et al. (2010) reported that children born at late preterm birth is associated with behavioral problems and lower IQ, independent of maternal IQ, residential setting, and sociodemographics. Quantitative MRI studies in infants born at preterm, including late preterm, have demonstrated dramatic increases in brain growth (and its tissue subclasses) and microstructural organization of the brain after premature birth (Huppi et al., 1998a,b; Limperopoulos et al., 2005). This rapid growth phase may render the immature brain particularly susceptible for injury, leading to impaired growth of cerebral cortical gray matter and myelination of white matter, disturbed development of white matter microstructure (Huppi et al., 2001). A 3-dimensional volumetric MRI study in preterm infants revealed that during late gestation the rapid cerebellar growth is impeded by preterm birth (Limperopoulos et al., 2005). However, detailed MRI and neurophysiological studies of the brainstem in late preterm infants remain very limited. Research into brainstem development and injury in late preterm infants will not only enhance our understanding of brainstem maturation during later preterm period, but also help develop focused plans to optimize management and prevent adverse neurological outcomes in these infants. There was a recent report on maximum length sequence brainstem auditory evoked response (MLS BAER) in preterm infants who were born at late preterm (33–36 weeks gestation) without any major perinatal problems or conditions (i.e. low-risk late preterm infants) (Li et al., 2011). The authors found that MLS BAER in these infants was basically normal, except for an increase in III–V interval at high-rate stimulation. Such a finding implies that low-risk late preterm infants only have a mild delay in neural conduction in the auditory brainstem. However, whether high-risk late preterm infants (i.e. later preterm infants who have major perinatal problems or conditions) have any abnormalities in the auditory brainstem is still open to speculation. Recently, we studied the MLS BAER at term in high-risk late preterm infants to detect any abnormalities in the auditory brainstem. We also compared MLS BAER results in these infants with those in age-matched low-risk infants to help clarify whether any MLS BAER abnormalities in high-risk late preterm infants are caused by late preterm birth or by associated perinatal conditions occurring in these infants.

2. Materials and methods 2.1. Study populations There are one study group and two healthy or normal control groups. High-risk late preterm infants (study group) — 68 late preterm infants who had various perinatal problems or conditions. They were born between 33 and 36 weeks (34.3 ± 1.6 weeks) of gestation, determined by the best estimate of last menstrual period, obstetrical record, and clinical examination. Birthweights ranged between 1305 and 3,060 g (1858 ± 572 g). The perinatal problems or conditions mainly included hypoglycaemia (n = 11), metabolic acidosis (n = 15), patent ductus arteriosus (n = 2), apnea (n = 5), preterm rupture of membranes (n = 7), respiratory distress syndrome (n = 6), sepsis (n = 15), periventricular leukomalacia (n = 3), hyperbilirubinemia at a serum level requiring exchange transfusion (n = 9), bacterial meningitis (n = 1), pneumonia (n = 8). Of these infants, some had more than one problem or complication. Recent studies in preterm, including late preterm, infants demonstrated that perinatal asphyxia or hypoxia–ischemia affects the MLS BAER, indicating that perinatal asphyxia damages functional

integrity of the auditory brainstem (Jiang, 2008; Jiang et al., 2009b,c). To exclude the known effect and better understand the effect of perinatal problems other than asphyxia on the auditory brainstem, any infants who had perinatal asphyxia were excluded. Infants who had significant peripheral hearing loss (BAER threshold P40 dB normal hearing level, nHL) were also excluded to minimize any significant effect of peripheral hearing loss on the measurements of BAER components, so that functional integrity of the auditory brainstem could be analyzed more accurately and reliably. Low-risk late preterm control infants — 35 infants who had none of the above perinatal problems or conditions. Gestation ranged between 33 and 36 weeks (34.2 ± 1.2 weeks), which did not differ significantly from the high-risk late preterm infants. Birthweight ranged between 1505–3250 g (2032 ± 518 g). Normal term control infants — 41 healthy term infants. Gestation ranged between 37 and 41 weeks (39.1 ± 1.2 weeks), and birthweight between 2569 and 4539 g (3464 ± 473 g). At time of MLS BAER testing, monaural hearing thresholds in the controls were all 20 dB nHL and less, determined by conventional BAER with clicks of a repetition rate 21/s. None had any major perinatal problems or conditions, particularly those specified in the high-risk infants. 2.2. MLS BAER recording and analysis Recording of MLS BAER was made at term (37–42 weeks postconceptional age – PCA) for all subjects. The PCA was 39.2 ± 1.6 weeks for the high-risk late preterm infants, 39.6 ± 1.3 for the low-risk late preterm controls, and 39.3 ± 1.3 weeks for the normal term controls. No statistical significant differences were found between these groups. The procedures of MLS BAER recording and analysis were approved by the Central Oxford Research Ethics Committee. Informed consent of parents was obtained for each subject before the study entry. Nicolet Spirit 2000 Portable Evoked Potential System (Nicolet Biomedical Inc. Madison, WI, USA) was used to record and analyse MLS BAER. As in our previous MLS BAER studies, for all subjects only the left ear was tested to keep consistency in recording conditions and reduce recording time (Jiang et al., 2009a,b,c, 2010). Recording of MLS BAER was made while the infant fell asleep naturally, often after a feed, without using any sedatives. Following site skin preparation, three gold-plated disk electrodes were placed, respectively, at middle forehead (positive), ipsilateral earlobe (negative) and contralateral earlobe (ground). The impedance between any two electrodes was kept <5 kX. Rarefaction clicks with a duration 100 ls were used as acoustic stimuli, which were delivered monaurally through a TDH 39 headphone to the left ear. All subjects were tested at the intensity 60 dB nHL. For those with a BAER threshold >20 dB nHL (four infants at 25 and two at 30 dB nHL), higher intensities (70 and 80 dB nHL, respectively) were also used to collect MLS BAER data at a hearing level slightly higher than 40 dB above the threshold of each subject, the same as our previous studies (Jiang, 2008; Jiang et al., 2003, 2007, 2008, 2009a, 2010; Wilkinson et al., 2007). As such, any effect of threshold elevation and peripheral hearing loss on MLS BAER components was minimized, and the MLS BAER data in the high-risk late preterm infants were compared with the controls at a similar hearing level. Sweep duration was set at 24 ms. Recording of MLS BAER commenced immediately after the infant fell asleep. The infant remained asleep throughout the recording session. Evoked brain responses to 1500 trains of clicks were preamplified, bandpassed at 100–3000 Hz, and then averaged for each run of recording. For each stimulus condition, two runs of MLS BAER recording were made to evaluate reproducibility of the recorded waveforms. The clicks were presented at the sequence of 91 (8 clicks/sweep), 227 (16 clicks/sweep), 455 (32 clicks/

Z.D. Jiang et al. / Clinical Neurophysiology 123 (2012) 993–1001

sweep), and 910/s (64 clicks/sweep) in the first run. A reverse sequence was used in the second run. During the signal averaging, amplitude artifact rejection was active to eliminate any on-line signals with amplitude exceeding +/–25 lV. The tester kept monitoring the ongoing filtered EEG and the running averaged MLS BAER, and manually discontinued sampling whenever there were excessive muscle artefacts on the monitoring oscilloscope. As such, contamination of artefacts to the recorded MLS BAER waveforms was minimized. The hearing levels (i.e. the dB above the thresholds of individual subjects), at which measurements of MLS BAER recordings were

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made and analyzed, were 50.5 ± 6.6 dB nHL for the high-risk late preterm infants, 51.1 ± 4.2 dB nHL for the low-risk late preterm controls and 49.9 ± 5.6 dB nHL for the normal term controls, which did not differ significantly between different groups of infants. BAER variables were measured blind to the medical history and clinical data of each subject. Wave peak of each MLS BAER components was picked by manually moving the cursor on the analysis screen. For waveforms that had good morphology, with well-formed, sharply peaked wave components and no artefact affecting the peak, the point on a wave component that produces the greatest amplitude was selected as the peak. There was often only one clear major peak for one wave components. In some MLS BAER waveforms, the top portion of a BAER wave component is rounded or consists of a couple of small peaks, without a sharp peak of maximum amplitude that can be picked as the wave peak. In such situation, we extended lines from the two slopes of the wave component to a point where the two lines intersect. This point was then taken as the peak of the wave component. After the peak of each MLS BAER wave component was selected, the latencies of waves I, III, and V were then measured, and I–V, I–III and III–V interpeak intervals and the interval ratio of III–V and I–III (i.e. III–V/I–III interval ratio) were calculated. As shown by the schematic drawing in Fig. 1 of our previously paper (Jiang et al., 2009a), wave I amplitude was measured from its peak to the lowest trough between waves I and III, wave III amplitude from the lowest trough between waves I and III to the peak of wave III, and wave V amplitude from the positive peak to the negative trough immediately after the peak (Jiang et al., 2008; Lasky, 1997). The amplitude ratios of V/I and V/III were then calculated. 2.3. Statistical analysis A SPSS package (SPSS, Chicago, IL) was used for statistical analysis of the MLS BAER data. For each infant, the measurements from two replicated MLS BAER recordings to each stimulus condition were averaged for further data analysis. Mean and standard deviation of each BAER variable at each stimulus condition were obtained for each of the three groups of infants. Comparison of the mean and standard deviation of each MLS BAER variable at each stimulus condition was made between different groups of infants. There were no significant differences in postconceptional age, and click intensity above BAER threshold between different groups of infants. In order to minimize any possible insignificant differences, analysis of covariance (ANCOVA) was performed for comparison of MLS BAER data between different groups of infants. The dependent variables are mean and standard deviation of each BAER variable at each stimulus condition, with postconceptional age, gender and the click intensity above BAER threshold as covariates. The Bonferroni correction was applied to the alpha level (0.05) to judge statistical significance for multiple comparisons. The relationship of each MLS BAER variable with click rate was examined using correlation analysis. Regression analysis was carried out for those variables that were significantly correlated with click rate. Thereafter, the latency-, interval-, or amplitude-rate functions were obtained, and, in turn, the slope for each latency-, interval-, and amplitude-rate function was calculated. For those functions that were significantly greater than zero at the 0.05 level or better, comparison of the slopes between different groups of infants were made using Student t test to detect any differences in click rate-dependent changes.

Fig. 1. Sample MLS BAER recordings in infants from each of the normal term group (A), low-risk late preterm group (B) and high-risk late preterm group (C). There are no apparent differences in MLS BAER waveforms between normal term infants (A, female, 39 week gestation) and low-risk late preterm infant (B, female, 33 week gestation). However, the high-risk late preterm infant (C, male, 34 week gestation, with sepsis) shows an increase in wave V latency and I–V interval, particularly at higher click rates.

3. Results As shown by the sample MLS BAER recordings in infants from each of the three groups studied in Fig. 1, the high-risk late preterm

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Table 1 Means and standard deviations (SD) of MLS BAER wave latencies and interpeak intervals (>40 dB above BAER threshold of each subject) and comparisons of high-risk late preterm (LP) with low-risk LP and normal term infants. BAER variables

Subjects

91/s Mean ± SD

227/s Mean ± SD

455/s Mean ± SD

910/s Mean ± SD

I (ms)

Normal Low-risk LP High-risk LP

2.40 ± 0.17 2.40 ± 0.23 2.32 ± 0.26

2.58 ± 0.16 2.56 ± 0.24 2.51 ± 0.26

2.71 ± 0.16 2.71 ± 0.23 2.62 ± 0.26

2.75 ± 0.16 2.76 ± 0.22 2.66 ± 0.26

III (ms)

Normal Low-risk LP High-risk LP

5.23 ± 0.24 5.27 ± 0.24 5.20 ± 0.35

5.60 ± 0.24 5.57 ± 0.26 5.57 ± 0.34

5.86 ± 0.23 5.90 ± 0.29 5.85 ± 0.34

5.92 ± 0.21 5.94 ± 0.27 5.92 ± 0.21

V (ms)

Normal Low-risk LP High-risk LP

7.53 ± 0.27 7.62 ± 0.32 7.58 ± 0.37

8.16 ± 0.27 8.21 ± 0.36 8.31 ± 0.42*

8.72 ± 0.24 8.88 ± 0.38 8.99 ± 0.44**,+

8.78 ± 0.24 8.90 ± 0.36 9.05 ± 0.41***,+

I–III (ms)

Normal Low-risk LP High-risk LP

2.83 ± 0.16 2.87 ± 0.17 2.86 ± 0.21

3.03 ± 0.18 3.01 ± 0.21 3.06 ± 0.23

3.16 ± 0.18 3.20 ± 0.21 3.23 ± 0.24

3.18 ± 0.17 3.19 ± 0.21 3.24 ± 0.19

III–V (ms)

Normal Low-risk LP High-risk LP

2.31 ± 0.16 2.36 ± 0.15 2.39 ± 0.16*

2.57 ± 0.16 2.64 ± 0.17 2.74 ± 0.22***,+

2.85 ± 0.17 2.97 ± 0.18* 3.13 ± 0.26***,++

2.86 ± 0.16 2.97 ± 0.18* 3.13 ± 0.28***,++

I–V (ms)

Normal Low-risk LP High-risk LP

5.14 ± 0.21 5.23 ± 0.26 5.25 ± 0.29*

5.60 ± 0.21 5.65 ± 0.32 5.80 ± 0.35**,+

6.01 ± 0.20 6.16 ± 0.28* 6.37 ± 0.38***,++

6.03 ± 0.20 6.18 ± 0.27* 6.37 ± 0.33***,+

III–V/I–III

Normal Low-risk LP High-risk LP

0.82 ± 0.07 0.82 ± 0.07 0.84 ± 0.08

0.85 ± 0.08 0.88 ± 0.06 0.90 ± 0.09*

0.90 ± 0.08 0.91 ± 0.08 0.97 ± 0.10***,+

0.90 ± 0.07 0.92 ± 0.08 0.96 ± 0.10***,+

* ** *** + ++

P < 0.05, in ANCOVA for comparison between LP and normal term infants. P < 0.01, in ANCOVA for comparison between LP and normal term infants. P < 0.001, in ANCOVA for comparison between LP and normal term infants. P < 0.05, for comparison between high-risk and low-risk LP infants. P < 0.01 for comparison between high-risk and low-risk LP infants.

Table 2 Means and standard deviations (SD) of BAER wave amplitudes and amplitude ratios at term (>40 dB above BAER threshold of each subject) and comparisons of high-risk late preterm (LP) with low-risk LP and normal term infants.

* +

BAER variables

Subjects

91/s Mean ± SD

227/s Mean ± SD

455/s Mean ± SD

910/s Mean ± SD

I (lV)

Normal Low-risk LP High-risk LP

0.127 ± 0.041 0.120 ± 0.038 0.122 ± 0.053

0.084 ± 0.029 0.098 ± 0.030 0.083 ± 0.033

0.051 ± 0.018 0.061 ± 0.017 0.050 ± 0.024+

0.036 ± 0.015 0.040 ± 0.023 0.034 ± 0.021

III (lV)

Normal Low-risk LP High-risk LP

0.188 ± 0.055 0.181 ± 0.056 0.191 ± 0.064

0.140 ± 0.041 0.129 ± 0.044 0.131 ± 0.044

0.088 ± 0.028 0.086 ± 0.030 0.086 ± 0.031

0.059 ± 0.026 0.057 ± 0.025 0.055 ± 0.022

V (lV)

Normal Low-risk LP High-risk LP

0.160 ± 0.059 0.172 ± 0.058 0.174 ± 0.054

0.109 ± 0.047 0.141 ± 0.046* 0.110 ± 0.041+

0.082 ± 0.033 0.087 ± 0.043 0.076 ± 0.031

0.053 ± 0.025 0.051 ± 0.027 0.044 ± 0.020

V/I

Normal Low-risk LP High-risk LP

1.425 ± 0.563 1.710 ± 1.022 1.652 ± 0.767

1.458 ± 0.810 1.535 ± 0.552 1.488 ± 0.552

1.731 ± 0.836 1.597 ± 0.854 1.772 ± 0.881

1.691 ± 1.212 1.413 ± 0.554 1.653 ± 0.981

V/III

Normal Low-risk LP High-risk LP

0.929 ± 0.406 1.042 ± 0.299 0.975 ± 0.360

0.803 ± 0.286 1.137 ± 0.340* 0.951 ± 0.458

0.911 ± 0.316 1.068 ± 0.375 0.947 ± 0.392

0.906 ± 0.299 0.972 ± 0.425 0.891 ± 0.367

P < 0.05 in ANCOVA for comparison between LP and normal term infants. P < 0.05 for comparison between high-risk and low-risk LP infants.

infants demonstrated that as the click rate was increased all wave latencies and interpeak intervals were increased and all wave amplitudes were reduced. This was generally similar to that in the low-risk late preterm infants and the normal term infants, although there were some differences. Table 1 presents means and standard deviations of MLS BAER wave latencies and interpeak intervals for the study and two control groups are presented, while Table 2 presents those of wave amplitudes. The results of statistical comparisons of the data between the high-risk late preterm infants and the two control groups are also presented in the two tables. Table 3 presents the results of linear regression analysis between wave variables and click rate (91–455/s) in the three groups. The following results were obtained for the comparison between the

high-risk late preterm infants and normal term controls, except for those that were explained otherwise. 3.1. Wave latencies and interpeak intervals Compared with the normal term controls, the high-risk late preterm infants did not shown any significant differences in both waves I and III latencies in MLS BAER at all 91–910/s clicks. However, wave V latency was significantly increased at 227, particularly, 455 and 910/s (P < 0.05–0.001, Table 1). The I–V interpeak interval in the high-risk late preterm infants was increased at all 91–910/s clicks, and the difference from the controls was increased with the increase in click rate (P < 0.05–0.001, Table 1). Similarly,

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Z.D. Jiang et al. / Clinical Neurophysiology 123 (2012) 993–1001 Table 3 Linear regression between MLS BAER variables and rate (91–455/s) in high-risk late preterm (LP) and normal term infants. MLS BAER Variable

Subjects

Intercept

Slope (/decade)

T

P

Mean

SE

I (ms)

Normal Low-risk LP High-risk LP

2.344 2.349 2.266

0.030 0.042 0.040

0.008 0.008 0.009

0.001 0.002 0.001

8.102 4.64 6.261

<0.001 <0.001 <0.001

III (ms)

Normal Low-risk LP High-risk LP

5.124 5.142 5.069

0.044 0.060 0.059

0.017 0.017 0.019

0.002 0.002 0.002

11.105 8.074 8.991

<0.001 <0.001 <0.001

V (ms)

Normal Low-risk LP High-risk LP

7.307 7.361 7.295

0.049 0.080 0.072

0.032 0.034 0.039

0.002 0.003 0.003

14.747 12.576 15.165

<0.001 <0.001 <0.001

I–II (ms)

Normal Low-risk LP High-risk LP

2.781 2.799 2.802

0.033 0.039 0.039

0.009 0.008 0.010

0.001 0.001 0.001

7.653 6.245 7.168

<0.001 <0.001 <0.001

III–V (ms)

Normal Low-risk LP High-risk LP

2.189 2.223 2.227

0.031 0.040 0.036

0.015 0.015 0.020

0.001 0.001 0.001

14.540 12.989 15.442

<0.001 <0.001 <0.001

I–V (ms)

Normal Low-risk LP High-risk LP

4.966 5.014 5.028

0.040 0.065 0.059

0.024 0.026 0.030

0.001 0.002 0.002

17.632 11.802 14.181

<0.001 <0.001 <0.001

III–V/I–III

Normal Low-risk LP High-risk LP

0.796 0.803 0.806

0.015 0.014 0.015

0.003 0.003 0.004

0.001 0.001 0.001

5.079 7.166 7.079

<0.001 <0.001 <0.001

I amp (lV)

Normal Low-risk LP High-risk LP

0.139 0.134 0.130

0.006 0.007 0.006

0.002 0.002 0.002

0.000 0.000 0.000

10.293 6.841 9.625

<0.001 <0.001 <0.001

III amp (lV)

Normal Low-risk LP High-risk LP

0.183 0.199 0.193

0.008 0.011 0.008

0.003 0.003 0.003

0.000 0.000 0.000

10.039 7.204 8.672

<0.001 <0.001 <0.001

V amp (lV)

Normal Low-risk LP High-risk LP

0.169 0.198 0.181

0.009 0.011 0.009

0.002 0.002 0.002

0.000 0.000 0.000

6.790 6.330 8.099

<0.001 <0.001 <0.001

the III–V interval was increased at all rates used, which was more significant at higher than at lower rates (P < 0.05–0.001, Table 1). The differences from the controls in the two intervals were both increased with the increase in click rate. By comparison, the I–III

interval in the high-risk late preterm infants did not show any significant difference from the controls at any click rate. The III–V/I–III interval ratio in the high-risk infants was significantly increased at high rates (P < 0.05 at 227/s, P < 0.001 at both 455 and 910/s). Fig. 2 is a sample distribution of the data points of I–V interval, obtained with 455/s clicks, in individual infants for each of the high-risk and low-risk late preterm infants, and normal term infants. Clearly, the interval in the high-risk late preterm infants is distributed much higher than those in the normal term controls, and also higher than those in the low-risk late preterm infants. Such differences are more significant at younger age than at older age, reflected by the differences in data points at different PCA (Fig. 1). Similar differences are seen in the distribution of data points of wave V latency, III–V interval and III–V/I–III interval ratio at click rates 455 and 910/s. 3.2. Wave amplitudes Although all amplitudes of waves I, III and V in the high-risk late preterm infants were slightly smaller than in the term controls, none differed significantly from the term controls at any click rates. The V/I and V/III amplitude ratios in the high-risk late preterm infants tended to be greater than those in the term controls at most click rates, but did not differ significantly from those in the term controls at any rates. 3.3. Changes in MLS BAER variables with click rate

Fig. 2. Scatterplot of data points of I–V interval in individual infants in each of highrisk and low-risk late preterm infants, and normal term infants (NT) in MLS BAER recorded with 455/s clicks. The data points in high-risk group are distributed much higher than those in normal term group, and also higher than those in low-risk group. This is particularly obvious in younger infants.

The latencies of waves I, III and V in the high-risk late preterm infants were correlated positively and significantly with click rate (r = 0.476, 0.584, and 0.713, all P < 0.001). The I–III, III–V and I–V

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intervals were also correlated positively and significantly with click rate (r = 0.492, 0.692, and 0.685, all P < 0.001). The same was true of the III–V/I–III interval ratio (r = 0.448, P < 0.001). Conversely, the amplitudes of waves I, III and V in the high-risk late preterm infants were correlated negatively and significantly with the rate (r = 0.645, 0.678, and 0.659, all P < 0.001). Neither the V/I amplitude ratio, nor the V/III amplitude ratio had any significant correlation with click rate. These click rate-related changes in MLS BAER variables in the high-risk late preterm infants were generally similar to those in the term controls, but there were some differences in the degrees of the changes, as shown by the following results of regression analysis. In any MLS BAER recordings, as click rate is increased from 91/ s to 455/s, there is a progressive increase in wave latencies and interpeak intervals, i.e. MLS BAER wave latencies and intervals change linearly with varying click rate. However, as the rate is increased from 455/s to 910/s, wave latencies and interpeak intervals do not show any further notable increase. The measurements of all wave latencies and interpeak intervals obtained at 910/s are almost the same as, or slightly longer or shorter than, those obtained at 455/s, although wave amplitudes are smaller than those at 455/s. The measurements of wave latencies and intervals at 910/s are often similar or slightly shorter than those at 455/s in younger infants, though often slightly longer than at 455/s in older infants. Such trivial differences between click rates 455/s and 910/s in any group subjects do not reach statistical significance. This is true of all our previous MLS BAER studies in infants. Obviously, the measurements of MLS BAER wave latencies and intervals reach a plateau from the rate 455/ s. Further increase in click rate to 910/s cannot linearly or significantly increase wave latencies and intervals, i.e. MLS BAER wave latencies and intervals no longer change linearly with the increase in click rate. In the present study, the abnormalities in wave V latency and the III–V and I–V intervals in the high-risk late preterm infants were increased with the increase in click rate. However, the abnormalities at the very high click rates 455/s and 910/s were similar. That is, when click rate is increased to 455/s, further increasing the rate cannot significantly further improve the detection of brainstem auditory abnormality. We compared the mean and standard deviation for each of the MLS BAER wave latencies and intervals between the click rates 455/s and 910/s using analysis of variance, but did not detect any significant differences. At the two click rates, none of the MLS BAER wave latencies and intervals was correlated significantly with click rate, suggesting that these MLS BAER variables are no longer to change linearly with click rate above 455/s. These findings in the high-risk later preterm infants were also true in the low-risk later preterm infants and normal term controls. As such, in order to examine the linear relationship between wave latencies and intervals and the repetition rate of clicks the linear regression analysis in the present study were performed for MLS BAER recordings between 91 and 455/s, instead of between 91 and 910/s. The regression analysis was performed for MLS BAER variables that were correlated significantly with click rate (Table 3). The slopes of wave I and III latency-, and I–III interval-rate functions in the high-risk late preterm infants were similar to those in the term controls. However, the slopes of wave V latency-, and I–V and III–V interval-rate functions were significantly greater than those in the term controls (P < 0.05–0.01). The slope of the III–V/I–III interval ratio-function was also greater than in the term controls (P < 0.05). As to wave amplitude-rate functions, the slopes for waves I, III and V were all similar to the term controls, without any significant difference.

3.4. Comparison with low-risk late preterm infants Wave I and III latencies and I–III interval in the high-risk infants were all similar to those in the low-risk infants. On the other hand, wave V latency in the high-risk infants was increased at the higher rates 227–910/s, and differed significantly from the low-risk infants at 455/s and 910/s (P < 0.05 and 0.05, Table 1). The III–V and I–V intervals in the high-risk infants were increased, and differed significantly from those in the low-risk infants at 227–910/ s, particularly 455/s (P < 0.05–0.01, Table 1). The III–V/I–III interval ratio in the high-risk infants was increased significantly at 455/s and 910/s (P < 0.05 and 0.05, Table 1). The amplitudes of waves I and V in the high-risk infants both tended to be smaller than those in the low-risk infants at higher rates, and differed significantly at 455/s for wave I amplitude and at 227/s for wave V amplitude (P < 0.05 and 0.05, Table 2). None of wave III amplitude, V/I and V/III amplitude ratios had any significant difference between the two groups of preterm infants. Compared with the low-risk infants, the high-risk infants showed significant greater slopes for wave V latency-, and I–V and III–V interval-rate functions than in the low-risk infants (all P < 0.05, Table 3). This was generally similar to the result of comparison with the normal term controls. The slopes of other MLS BAER variable-rate functions in the high-risk infants were all similar to or slightly greater than those in the low-risk infants, without any significant differences.

4. Discussion 4.1. Functional impairment of the auditory brainstem in high-risk late preterm infants During the late gestation, there are dramatic and nonlinear developmental changes in the brain, including the brainstem. This may predispose the immature brain to various perinatal risk factors, resulting in brain injury. The brainstem development in infants born at late gestation has been found to be less mature than in infants born at full term (Darnall et al., 2006). As documented by neuroimaging and autopsy studies, some neuropathology, e.g. periventricular leukomalacia, occurs not only in very preterm infant, but also in near-term (late preterm) infants (Kinney 2006). In both very preterm and late preterm infants gray matter injury is associated with periventricular leukomalacia (Billiards et al., 2006; Kinney, 2006). Recently, there is an increased interest in studying neurodevelopment and outcome in late preterm infants (Baron et al., 2009; Inder, 2010; Petrini et al., 2009; Picone and Paolillo, 2010; Romeo et al., 2010; Romeo et al., 2011; Saluja et al., 2010; Talge et al., 2010; Wuttikul et al., 2008). In the present study, when compared with the normal term controls, the high-risk late preterm infants demonstrated a significant increase in wave V latency at 227–910/s clicks, and III–V and I–V intervals at all 91–910/s. There was also a significant increase in the III–V/I–III interval ratio at 277–910/s clicks. All these increases were more significant at higher than at lower click rates. On the other hand, there was no appreciable abnormality in the I–III interval, although the interval was slightly increased. All wave amplitudes were slightly reduced at higher click rates. The slopes of wave V latency-, I–V and III–V interval- and III–V/I–III interval ratio-rate functions were significantly increased. These results indicate that brainstem auditory function is abnormal in high-risk later preterm infants, and the abnormalities is more evident following more stressful high-rate stimulation. For these infants, there may be a need of some neuroprotective measures targeting to the central regions of the brainstem.

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The major MLS BAER variable — the I–V interval consists of the earlier I–III interval and the later III–V intervals. In the high-risk late preterm infants, the III–V and I–V intervals were significantly increased at all click rates used, while the I–III interval did not show any appreciable abnormality. This indicates that the significant increase in the I–V interval (and wave V latency) is predominantly produced by the significant increase in the III–V interval, which is further supported by the increase in the III–V/I–III interval ratio in the high-risk late preterm infants. In the BAER, the I–V interval is an important index of reflecting functional status of the auditory brainstem. The I–III interval reflects functional status of the more peripheral of the auditory brainstem, whereas the III–V interval reflects functional status of the more central regions (Jiang, 2008). As a major, fundamental abnormality in the MLS BAER in the high-risk late preterm infants, the significant increase in the III–V interval indicates that the functional abnormality occurs predominately in the more central regions of the auditory brainstem. The significant increase in the slopes of wave V latency-, I–V and III–V interval- and III–V/I–III interval ratio-rate functions in the high-risk late preterm infants implies that the click rate-dependent changes in these MLS BAER variables are increased in these infants. In the BAER, the rate-dependent change reflects the efficacy of synaptic transmission along the auditory brainstem (Jiang, 2008; Lasky, 1997). The increase in the rate-dependent changes in the high late preterm infants suggests a decrease in the efficacy of synaptic transmission in the auditory brainstem, mainly the more central regions or a decreased ability of central neurons to recover in time to transmit the next stimulus-evoked response. The efficacy of synaptic transmission — an important index of synaptic function is related to the mechanisms for synthesis, release and uptake of neurotransmitters that are known to play a crucial role in the regulation of neural development as distinct from their differentiated function as neural signal modulators (Jiang, 2008; Lasky, 1997). It is presumable that some of the perinatal conditions in our high-risk late preterm infants may disturb the metabolism of neurons and depresses the electrophysiological function of synapses which, in the developing brain, transmit developmental as well as regulatory signals between neurons. The stimulus repetition rate-dependent phenomena is related to sensory adaptation/fatigue, but may be also related to habituation, defined as a behavioral response decrement that results from repeated stimulation (Davis, 1970; Grissom and Bhatnagar, 2009; Rankin et al., 2009; Thompson, 2009). Habituation is termed ‘‘the simplest form of learning’’. Thus, the increased rate-dependent changes in the high-risk late preterm infants may also reflect a delayed or impaired development of learning processes due to some of the unfavorable perinatal conditions. 4.2. The brainstem auditory impairment is mainly produced by perinatal conditions With MLS BAER, Li et al. (2011) studied functional status of the auditory brainstem at term in infants born at 33–36 week gestation and without any major perinatal conditions, i.e. low-risk late preterm infants. The authors did not find any abnormalities in wave latencies and amplitudes, and I–V and I–III intervals at all click rates 91–910/s. There was also no abnormality in any of the slopes of MLS BAER variables-rate functions. The only abnormal finding in their low-risk late preterm infants was a increase in III–V interval at higher rates. Similarly, in the present study the low-risk late preterm infants did not show any major MLS BAER abnormalities, when compared with the normal term infants. Only the III–V and I–V intervals were increased at 455 and 910/s, (all P < 0.05, Table 1), and wave V amplitude was increased at 227/s (P < 0.05, Table 2). None of the slopes of MLS BAER variables-rate functions in the later preterm infants differed significantly from

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those in the normal term infants. These relatively mild abnormalities brainstem in the low-risk late preterm infants are indicative of a slight delay in neural conduction in the more central regions of the auditory. Thus, late preterm birth per se only has a mild or very limited effect on functional development of the developing auditory brainstem. In contrast, the high-risk late preterm infants demonstrated some major abnormalities in MLS BAER, suggesting that the functional integrity of the more central regions of the auditory brainstem is impaired in these infants. The comparison between the high- and low-risk late preterm infants showed that wave V latency, and the III–V and I–V intervals in the high-risk late preterm infants were all increased significantly at very high click rates 455/s and 910/s. This was true of the III–V/I–III interval ratio. The III–V and I–V intervals were also increased significantly at 227/s. The slopes of wave V latency-, I–V and III–V interval-rate functions in the high-risk infants were steeper than those in the low-risk infants. Therefore, compared with those in the low-risk late preterm infants, MLS BAER variables that mainly reflect central auditory function were abnormal in the high-risk late preterm infants. There were no significant differences between the high- and low-risk infants in gestational age, postconceptional age (i.e. the age at time of MLS BAER study) and click intensity above BAER threshold of the subjects at which MLS BAER measurements were obtained. Any of these potential differences were further minimized by performing ANCOVA. The testing conditions and protocols were also the same in the two groups. The only difference between the two groups of infants was their difference in perinatal conditions, namely, the high-risk infants had major perinatal conditions while the low-risk infants did not. Since late preterm birth per se does not exert any significant effect on the immature auditory brainstem, the major MLS BAER abnormalities and, in turn, the functional impairment of the auditory brainstem in the high-risk late preterm infants must be predominately caused by the perinatal problems that occurred in these infants. This is consistent with some clinical observation that perinatal problems associated with late preterm birth contribute to the overall risk of brain injury in late preterm infants (Adams-Chapman, 2006). Some previous investigators studied auditory impairment in infants or children, and tried to identify the causes for the impairment. They found that there were often several potential causative factors for the impairment and no one cause could be identified (Meyer et al., 1999; Newton, 2001). To identify what risk factor(s) in the high-risk late preterm infants play(s) a major role in the damage to the late preterm brainstem, a substantial number of subjects are required so that each risk factor has a sufficient number of subjects for robust statistical analysis. In this study the highrisk late preterm infants had various perinatal conditions, i.e. perinatal risk factors for brainstem auditory impairment. There was only limited or relatively small number of infants for each of the risk factors, and some of the infants had more than one risk factor. Thus, it is difficult to accurately and reliably determine what risk factor(s) play(s) a major role in the MLS BAER abnormalities found in these neonates. We assume that there might be collective adverse effects, produced by more than one perinatal condition or risk factor, that contribute to the MLS BAER abnormalities found in the high-risk late preterm infants. With continuously recruiting new patients, the acumination of larger amount of data in the future will eventually enable us to carry out a robust data analysis to reliably identify major perinatal risk factors for brainstem auditory impairment in high-risk late preterm infants. Previous studies have revealed that perinatal hypoxia–ischemia has a major effect on MLS BAER in term infants (Jiang, 2008; Jiang et al., 2000, Jiang et al., 2003, Jiang et al., 2008). More recent studies show that perinatal hypoxia–ischemia also significantly affect MLS

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BAER in preterm, including late preterm, infants (Jiang, 2008; Jiang et al., 2009b,c). The present study demonstrates that MLS BAER abnormalities found in the high-risk late preterm infants with perinatal problems other than hypoxia–ischemia are relatively less significant. It appears that brainstem auditory impairment due to perinatal problems other than hypoxia–ischemia is less severe than that due to severe hypoxia–ischemia. In the present study, most of the perinatal problems or conditions in the high-risk later preterm infants do not lead to a discrete hypoxia, although some others may be associated with a certain degree of hypoxia, e.g. apnea, respiratory distress syndrome, and pneumonia. However, the degree of hypoxia in these perinatal conditions is much less severe, compared with the lethal hypoxia in perinatal hypoxia–ischemia. Furthermore, unlike perinatal hypoxia–ischemia, none of the perinatal conditions is associated with severe ischemia that has a detrimental effect on the auditory brainstem (Jiang et al., 2008; Sohmer et al., 1986). The differences between the high-risk infants and the two control groups of infants in major MLS BAER variables, including wave V latency, I–V (as shown in Fig. 2) and III–V intervals and III–V.I–III interval ratio, are all more significant in the younger than in the older infants. This finding suggests that with increasing age, the differences between the high-risk infants and the low-risk infants and term controls tend to be smaller. We have carried out a follow-up study of postnatal neurodevelopment, including MLS BAER, in our infants for several months. The preliminary MLS BAER results showed that the abnormalities initially detected in the high-risk late preterm infants gradually recovered with the improvement of clinical conditions and the increase in age. At 1 and 3 months of corrected postnatal age, there were still some, though less significant, differences between the high-risk late preterm infants and low-risk late preterm and term infants. It seems that brainstem auditory abnormalities in high-risk late preterm infants have largely, but not completely, recover during the first 3 months of postnatal life. The longer-term and larger amount MLS BAER data remain to be acuminated. It would be very interesting to see postnatal behavioral development, including motor and other brainstem functions (e.g. swallowing), and later developmental outcome in these high-risk late preterm infants. The preliminary results obtained so far from our follow-up study are insufficient to draw any sound conclusion and make any reliable comments. We hope that with acuminating more data from the follow-up study the results will eventually to enable us to understand how the early functional abnormality, reflected by the present MLS BAER findings, is interpreted in late life and whether the MLS BAER findings, particularly in relation to certain specific risk factors or combination of risk factors, have any predicative value for later neurodevelopmental outcome.

4.3. Conclusions The present study of MLS BAER in the high-risk late preterm infants found an increase in wave V latency and I–V and III–V intervals and III–V/I–III interval ratio. The increase was more significant at higher than at lower click rates. The slopes of wave V latency-, I–V and III–V interval- and III–V/I–III interval ratio-rate functions were significantly increased. These results indicate that the functional integrity of the auditory brainstem, mainly in the central regions, is impaired in late preterm infants with perinatal problems. Our findings shed some lights on functional integrity of the auditory brainstem in high-risk late preterm infants and provide valuable information for perinatal management of these infants.

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