Alan G. Pettigrew

Clinical Apnea and Brain-Stem Neural Function in Preterm Infants

We assessed the relation between clinical apnea and brain-stem neuronal function in 58 preterm babies. The brain-stem conduction time of the auditory evoked response (Wave V-I interval) was longer in babies with apnea than in those without it at a similar postconceptional age (at 32 to 33 weeks: mean, 6.16 vs. 5.35 msec, P less than 0.001; at 34 to 35 weeks: mean, 5.98 vs. 5.33 msec, P less than 0.002). The number of apneas per day decreased over a period that was similar to the period during which brainstem conduction time decreased. In general, apneas ceased when the conduction time decreased to the levels observed in babies of a similar age who did not have apnea. Short brain-stem conduction times were observed in some infants who had prenatal stress, such as intrauterine growth retardation or maternal hypertension. These results suggest that the occurrence of apnea in preterm infants is correlated with neural function in the brain stem.

Adaptive Changes in the Developing Brain during Intrauterine Stress

Maturation of neurological performance in moderately to severely growth-retarded newborn infants (SGA) can be accelerated by 3 to 4 weeks or more when compared to the development of appropriately grown infants (AGA) of the same gestation. This is particularly the case in multiple pregnancies or pregnancies characterized by maternal hypertension. This clinical finding has been confirmed by neurophysiological studies on the maturation of brainstem auditory evoked responses (BAERs). The possible mechanisms which underly this phenomenon are not yet elucidated. Glucocorticoids, other steroid hormones and catecholamines are elevated in pregnancies with placental dysfunction, and it is known that these substances have multiple actions on neuronal maturation, particularly on mechanisms of release of neurotransmitters. These observations suggest that the acceleration of brain maturation, and lung maturation, in SGA infants reflects an adaptation of the fetus to early extrauterine life. However, if the placental dysfunction progresses, these mechanisms of adaptation will be overwhelmed by severe malnutrition and anoxia which result in cerebral lesions and risk of death. The clinical goal at the present time for obstetric management of these risk pregnancies is to distinguish between these two periods.

The influence of intra-uterine growth retardation on brainstem development of preterm infants

This study examined brainstem function in 76 appropriate‐for‐gestational‐age (AGA) and 25 small‐for‐gestational‐age (SGA) infants born at less than 35 weeks gestation, using brainstem auditory evoked responses. During the preterm period the mean brainstem conduction time (BCT) of the 25 SGA infants was significantly shorter than that of AGA babies of the same gestation. The BCTs of the AGA infants decreased rapidly during postnatal development to term‐equivalent age; those of the SGA infants did not change significantly. It is likely that prenatal factors are responsible for the alteration of early development in the neural function of non‐asphyxiated SGA infants. This change in neural development may be important in determining later neurological performance.

Directional properties of the auditory periphery in the guinea pig

The directional sensitivity of the outer ear of the guinea pig was determined by recording changes in the amplitude of the cochlear microphonic to frequencies between 1 and 20 kHz as the location of the sound source was changed throughout 360 degrees of horizontal auditory space. The directional responses to frequencies below 3 kHz were almost omnidirectional. The directional responses for frequencies between 3 and 12 kHz were progressively more directional toward the anterior midline. The responses for frequencies above 12 kHz were highly directional along the ipsilateral interaural axis. In contrast, the directional responses to all frequencies in animals whose pinnae had been removed were orientated along the ipsilateral interaural axis. The observations suggest that the orientation and strength of the directional response of the auditory periphery in the guinea pig are dependent on frequency and that this dependence is attributable, at least in part, to the acoustic properties of the pinna. The observations also indicate that there is a substantial change in the interaural intensity difference at various frequencies and in the spectral transfer function of the ear according to the location of the sound source in the ipsilateral hemifield. The observation that these changes are asymmetrical about the interaural axis for a substantial part of the auditory range of the animal is consistent with the hypothesis that the frequency dependent directionality of the auditory periphery provides a spectral cue for the localization of broad band sounds in the free field.

Development and properties of spontaneous oscillations of the membrane potential in inferior olivary neurons in the rat

Previous experiments have shown that the conductances that are thought to underlie the spontaneous oscillations of the membrane potential in inferior olivary (IO) neurons of the mature rat are present at 2 days postnatal (PN). In this study intracellular recordings of transmembrane potentials were made in 209 IO neurons in brainstem slices from rats aged 4-25 days PN. Membrane potential oscillations were not found before 9 days PN but were observed in 41% of neurons examined at 10-15 days PN and in 95% of neurons after 16 days PN. These oscillations exhibited a wide range of frequencies (0.5-9.5 Hz) and amplitudes (2-23 mV). The waveforms of the oscillations in different neurons varied from having 2-3 non-harmonic frequencies of unequal amplitude to being almost sinusoidal. There was a positive relationship between the age of the animal and the frequency (P less than 0.0001) and amplitude (P less than 0.002) of the oscillations. The timecourse of development of the membrane potential oscillations is consistent with ultrastructural data which indicate that neuro-neuronal gap junctions in the rat IO nucleus mature between 10 and 15 days PN. Exposure of the neurons to pharmacological agents that induce oscillations in adult IO neurons failed to induce oscillations in neurons less than 9 days PN. Our findings support the hypothesis that oscillations of the membrane potential in IO neurons depend not only on specific membrane conductances but also on electrotonic coupling between the neurons.

Distribution of frequency sensitivity in the superior colliculus of the guinea pig

A field potential could be recorded in the deep layers of the superior colliculus (SCd) in the guinea pig following presentation of pure tone bursts at frequencies between 1 and 22 kHz, bursts of white noise, and clicks presented in the free field. The potentials evoked by these stimuli at different intensities had two negative and one positive component associated with the onset of the stimulus. The amplitude of the negative components of the potential varied according to the location of the recording electrode along the dorso-ventral and rostro-caudal axes of the SC and with the frequency of pure tone stimuli. The largest amplitude potentials were recorded in the deep grey layer of the SCd midway along the rostro-caudal axis of the nucleus. The distribution of frequency sensitivity along the rostro-caudal axis of the SCd was determined by recording the amplitude of the negative components of the field potential evoked by 10 ms pure tone bursts at a constant intensity. The distribution of frequency sensitivity across the nucleus was not cochleotopic. The caudal pole of the nucleus had largest responses to frequencies above 15 kHz, with a peak sensitivity around 20 kHz. In contrast, the rostral pole of the nucleus was most sensitive to frequencies around 10 kHz and the sensitivity to frequencies around 20 kHz was relatively low. At a point midway along the rostro-caudal axis of the SCd, the nucleus was sensitive to a broad range of frequencies from 5 to 25 kHz. The patterns of frequency sensitivity recorded in the rostral, middle and caudal SCd are qualitatively similar to the frequency transfer characteristics of the auditory periphery for sounds located in the anterior, orthogonal and posterior regions respectively of contralateral space. The correspondence between these two sets of data suggests that the pattern of frequency sensitivity along the SCd may provide a mechanism by which the nervous system can encode the spectral cues which are generated at the auditory periphery.

Peripheral nerve conduction velocity and brainstem auditory evoked responses in small for gestational age preterm infants

Ulnar nerve conduction velocity (NCV) and brainstem auditory evoked responses (BAER) were measured in each of 11 preterm small for gestational age (SGA) infants born at less than 35 weeks gestation. The mean motor NCV in the SGA infants was similar to that reported for infants who were appropriately grown for their gestational age (AGA). However, the mean central conduction time of the BAER in SGA infants was significantly shorter than that of AGA infants of the same post-menstrual age. Thus, the precocious development of auditory brainstem neural function in preterm SGA infants is not accompanied by changes in functional maturation of the peripheral motor nerves.

Brainstem auditory evoked responses in infants at risk of sudden infant death

Brainstem auditory evoked responses (BAERs) were recorded from 63 near-miss Sudden Infant Death Syndrome (NMSIDS) infants, 26 siblings of SIDS (SSIBS) infants and 67 control infants between 0 and 30 weeks post-term. The majority of BAERs recorded from the NMSIDS and SSIBS infants had normal form and interpeak intervals (V-I and V-IIn) within normal limits for their age. However, 15% of these infants had interpeak intervals outside the normal range, suggesting abnormal neural function in these cases. The distributions of interpeak intervals for all NMSIDS and SSIBS infants were skewed towards longer times compared to control infants. The distributions of V-IIn intervals for both groups of at risk infants were significantly different to that of control infants. While the observations confirm that the recording of BAERs is not suitable for identifying infants at risk of SIDS, they suggest, however, that maturation of neural processing in the brainstem of these infants may be delayed.

Changes in the brainstem auditory evoked response of the rabbit during the first postnatal month

Brainstem auditory evoked responses (BAERs) were recorded in 73 albino rabbits during the first postnatal month. Responses could not be evoked before the ninth day post-term using free field click stimulation at 60 dBHL. The onset of BAERs to these stimuli on or after day 9 was coincident with the onset of behavioural responses to sounds and, in the majority of animals, with eye opening. The onset of BAERs was delayed in animals with low body weight. The intensity required to evoke detectable BAERs in normally grown animals decreased rapidly after day 9 post-term. The most significant changes in the form of the BAER in the first postnatal month were an increase in the amplitude of peak III and the separation of peaks IV and V. Peak I and the negative dip after peak V (Vn) were consistent features of the BAER during development. The latencies of these deflections and the interval between them decreased by approximately 1.5 and 4 ms respectively up to the end of the first month post-term. On days 9 and 10 post-term, stimulation at a higher rate (40 Hz) failed to evoke a BAER in some animals. In other animals the change in stimulation rate from 10 to 40 Hz produced a large increase in the latency of peak V. The unusually large changes in the latencies of peaks and the interpeak intervals during the development of the rabbit indicate that this animal may be particularly suitable for studies of perinatal complications on development of the brainstem when the BAER is to be used as non-invasive measure of neural function.

The effect of bicarbonate-free artificial cerebrospinal fluid on spontaneous oscillations of the membrane potential in inferior olivary neurons of the rat

The membrane potential of mature inferior olivary (IO) neurons oscillates spontaneously at frequencies up to about 10 Hz. This behavior has been attributed to the complement of membrane conductances in these cells and electronic coupling of the neurons via dendro-dendritic gap junctions. In this study intracellular recordings of transmembrane potentials were made in 52 neurons in brainstem slices from rats aged 8-23 days postnatal. During the recordings in 31 neurons the extracellular solution was exchanged from a bicarbonate- to a tris-buffered solution with constant pH. In all cells the spontaneous oscillations of the membrane potential ceased within a few minutes and in 14 of these cells the oscillations resumed with re-exposure to bicarbonate-buffered solution. The spontaneous oscillations in another 6 neurons also ceased when they were exposed to bicarbonate-buffered solution containing 10 mmol NH4Cl. These experimental manipulations produce a rise in intracellular pH despite constant extracellular pH. The low- and high-threshold potentials associated with voltage-sensitive calcium conductances in these neurons and the large hyperpolarization that follows these potentials were unaffected by substitution of the extracellular solution. However, the anomalous rectification of the membrane potential in these neurons (which could be abolished by exposure of the neurons to 2 mM CsCl) was significantly increased by 12.6% in the tris-buffered solution. The data are consistent with the hypothesis that the continuity of oscillations of the membrane potential in IO neurons depends on the transfer of current between the dendro-dendritic junctions and the soma of each neuron. This transfer is reduced when rectifying K+ conductances in the neurons are increased and the ensemble properties of the group of neurons, and the membrane potential oscillations, are lost.