Brainstem auditory evoked response development in preterm and term baboons (Papio hamadryas).

Brainstem auditory evoked responses were recorded longitudinally from 11 neonatal baboons (Papio hamadryas), 6 of which were preterm. Recordings were made in unsedated animals from day 161 to day 362 after conception (term = 182 days). The pattern of development of both waveform morphology and of wave latency was consistent with that seen in the human neonate, with a rapid maturation of the response during the perinatal period, and then a slower development to adult values. Brainstem conduction time was measured from the wave I to wave IV interval, and this demonstrated a similar pattern, with a rapid decrease in latency up to term, and then decreasing more slowly to reach adult values by 4 months of age in the baboon.

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.

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.

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.

Patterns of functional innervation in the auditory nuclei of the chick brainstem following early unilateral removal of the otocyst.

Neurons in the third-order auditory nuclei in the brainstem of chicks (nuclei laminares, NL) receive functional innervation from the ipsilateral and contralateral second-order nuclei (nuclei magnocellulares, NM) which is restricted to the dorsal and ventral dendrites respectively. This pattern of innervation in NL is established by embryonic stage 40 (day 15 of incubation). We have examined the distribution of this innervation in both NL at this age or older in embryos from which one otocyst had been removed or damaged on day 3 of incubation. The distribution of functional synapses was determined by analysis of the changes in polarity of field potentials evoked by electrical stimulation of either the ipsilateral or contralateral NM. The distribution of field potential polarity in NL of 40% of recordings in operated embryos and in all sham-operated embryos was the same as that observed in unoperated embryos. However, in the remaining operated embryos, the time course of the field potentials and the changes in the polarity of the responses as the recording electrode penetrated NL were abnormal. The abnormal complexity of responses and the abnormal distribution of field potential amplitude in NL in the operated embryos suggests that loss or damage to the first-order auditory innervation can result in (a) the formation of novel, functional synapses between second-order auditory neurons, and/or (b) disruption of processes that produce segregated innervation of the dendrites of the third-order auditory neurons.

Middle latency auditory evoked responses in normal term infants: a longitudinal study.

Middle latency auditory evoked responses (MLAERs) were measured in 21 normal term infants, three to five days after birth and then at 6 weeks, 7 months and 1 year of age. A polyphasic waveform was elicited during natural sleep in all infants at each recording session by monaural click stimulation at a rate of 9 per second. A 70 dBHL stimulus was found to be optimal as the MLAER became less well defined when the stimulus intensity approached the threshold hearing level. The first 60 to 70 msec of the waveform was found to be most stable, with decreasing detectability of peaks at longer latencies. There was no change in wave latency or reproducibility of MLAERs recorded during different sleep states. Waves Po and Na showed a significant decrease in latency with increasing stimulus intensity at term and/or 6 weeks of age. This was not evident for the remainder of the waveform. Waves Po, Na, Pa, Nb, Pb and Nc exhibited significant decreases in latency with age, attaining values indistinguishable from adults by 7 months of age.

Development of functional innervation in the second and third order auditory nuclei of the chick.

The neurones that constitute the auditory nuclei of the brainstem in the chick (nuclei magnocellularis, NM, and laminaris, NL) are generated between days 2 and 4 of incubation. These neurones migrate towards the dorsal surface of the brainstem over the next few days and reach their final destination at about day 9 of incubation. We have examined the development of functional connections between the auditory nerve and neurones in NM and between neurones in NM and NL in embryos from stage 34 (day 8 of incubation) using electrophysiological techniques and electron and light microscopy. The earliest extracellular recordings of electrically evoked field and spike potentials were made in NM with stimulation of the ipsilateral auditory nerve and in NL with stimulation of the ipsilateral NM at stage 35 (day 9). No activity could be recorded in NL with stimulation of the auditory nerve at this stage. By stage 37 (day 11), direct stimulation of the contralateral NM evoked responses in NL and by stage 38 (day 12) stimulation of the auditory nerves evoked stable field potentials in NL. These potentials changed polarity as the electrode penetrated NL in a direction that was perpendicular to the laminar arrangement of neurone somas and parallel to the dendritic axes of these neurones. In 18 of 26 analyses of current-source density in NL of 12 preparations between stages 38 and 40 there was a sink of current associated with synaptic activity at levels both above and below the source of current (cell somas) following stimulation of the ipsilateral auditory nerve. In the remaining analyses, and in all 15 analyses from preparations older than stage 40, stimulation of the ipsilateral input evoked only a single sink of current above the level of the cell somas. In all preparations from embryos at stage 38 and older, stimulation of the contralateral auditory nerve was associated with a single sink of current below the level of the cell somas. The axon projections to the ipsilateral NL from neurones in NM were examined using HRP labelling between stages 38 and 40. The presence of terminal fields of single axons in both the dorsal and ventral dendritic regions of the ipsilateral NL at these ages was confirmed. Furthermore, dense vesicles within synaptic terminals in both the dorsal and ventral dendritic fields could be identified in preparations at stage 36 following injection of HRP into NL and stimulation of the ipsilateral NM.(ABSTRACT TRUNCATED AT 400 WORDS)

Development of ionic conductances in neurons of the inferior olive in the rat: an in vitro study.

Neurons of the inferior olive of the rat were studied at different stages of their postnatal (PN) development by using the current clamp technique in slices maintained in vitro. Antidromic and synaptic activation of inferior olivary neurons could be achieved in preparations as young as PN day 2. Neurons at this age already exhibited a variety of ionic conductances which included fast sodium-dependent spikes, high-threshold and low-threshold calcium spikes, potassium-dependent currents, Ca-dependent after-hyperpolarizing potentials (AHPS), and both instantaneous and time-dependent inward rectification at hyperpolarized levels of membrane potential. The two types of Ca-dependent responses recorded in olivary neurons during the first postnatal week were graded with the magnitude of the depolarization imposed on the cells. Furthermore, the high-threshold Ca spikes were only clearly observed during this early period when K conductances were depressed by the injection of caesium into the cells or by bath application of 4-aminopyridine. In contrast, the high-threshold Ca spikes could be obtained without suppression of K currents and were all-or-none in character in some neurons after PN day 8 and in all neurons after PN day 11. The observations suggest that the balance between K and Ca currents changes throughout maturation and is largely in favour of the K current until about the end of the first PN week. At all ages studied, the low-threshold Ca spikes were much less sensitive to the Ca channel blocker cadmium than were the high-threshold Ca spikes. Finally, spontaneous, regular oscillations of the membrane potential were observed for the first time at PN day 16 and were only commonly observed after PN day 19, suggesting a late development of electrotonic coupling between olivary neurons.

Perinatal risk factors in preterm infants with moderate-to-profound hearing deficits.

The perinatal histories of 16 preterm infants with confirmed moderate-to-profound hearing loss were examined to determine the perinatal factors that might have been associated with their abnormal auditory development. Of the 11 factors that were examined, eight factors occurred significantly more frequently in hearing-impaired infants when they were compared with 226 preterm infants who were cared for in the same intensive care unit in 1984. However, when the histories of the 16 infants with hearing loss were compared with those of 16 infants with normal hearing, who were matched according to gestational age, birthweight percentile and sex, there were no differences. The prevalence of aminoglycoside therapy was high in both groups of infants, but the mean duration of therapy in the infants with a hearing deficit was significantly longer (15 days compared with eight days; P less than 0.025). These observations suggest that younger, smaller, preterm infants with a complicated perinatal course and prolonged aminoglycoside therapy are at higher risk of auditory handicap. We recommend that the early identification of preterm infants with a hearing deficit should be achieved by recording brainstem auditory-evoked responses just before discharge from the intensive care unit.

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.

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.

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.

Screening for auditory dysfunction in high risk neonates.

Brainstem auditory evoked responses were recorded in 117 pre-term and 71 full-term infants from the general population of infants born at a referral obstetric unit. The threshold intensity required to evoke a reliable BAER was determined at different post-menstrual ages (PMAs) and in many cases at follow-up clinics. The BAER thresholds for 12 infants born and tested at less than 31 wk PMA were all greater than or equal to 50 dBHL. Sixty-two low-gestational-age infants who were tested between 31 and 36 wk PMA had BAER thresholds between less than or equal to 30 dBHL and greater than or equal to 80 dBHL. The majority of pre-term and term infants tested at term equivalent age had BAER thresholds less than or equal to 30 dBHL. Longitudinal studies also indicated that BAER thresholds can decline rapidly during the pre-term period. Follow-up studies showed that those pre-term and term infants with BAER thresholds less than or equal to 30 dBHL had normal auditory thresholds as determined using conventional behavioural testing at 4 or more months of age. Of those infants with BAER thresholds greater than or equal to 40 dBHL at the time of discharge or at term equivalent age, 67% (n = 16) were confirmed later as having a moderate to profound hearing deficit. The remaining 8 infants in this group had had BAER thresholds at term of 40 or 50 dBHL and had normal BAER and behavioural thresholds at follow-up. The cross-sectional and longitudinal data indicate that the majority of low-gestational-age infants who are at risk of hearing deficit achieve BAER thresholds less than or equal to 30 dBHL by term equivalent age. We recommend that auditory screening of infants in this group is best performed at the time of discharge from hospital or at term equivalent age, whichever is the later. Those infants with thresholds greater than or equal to 40 dBHL at that time should be encouraged to attend follow-up testing and, if high thresholds persist, they should then be referred on for behavioural testing and assessment for habilitative support.

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.

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.

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.

Auditory responses in the torus semicircularis of the cane toad, Bufo marinus. I. Field potential studies.

Field potentials have been recorded in the torus semicircularis of the toad, Bufo marinus, in response to brief tones presented in the free field. The amplitude of the potentials varied with the frequency of the stimulus and location of the electrode along the rostro-caudal axis of the torus. All frequencies in the auditory range evoked largest potentials when the stimulus was located in the contralateral auditory field. Potentials evoked by low to mid frequencies were largest when the stimulus was located near the line orthogonal to the long axis of the animal. For progressively higher frequencies, the optimal stimulus position was progressively more anterior in the contralateral field. In animals in which one eighth nerve had been sectioned, field potentials evoked by tones of low to mid frequency were less sensitive to changes in stimulus direction than in normal animals. However, the directional sensitivity of field potentials evoked by mid to high frequencies was similar in monaural and normal animals. These observations suggest that binaural neural integration is important in determining the directional sensitivity of field potentials in the torus evoked by low to mid frequencies but not for potentials evoked by mid to high frequencies.

Auditory responses in the torus semicircularis of the cane toad, Bufo marinus. II. Single unit studies.

The responses of single units to brief tone bursts presented in the free field have been recorded in the torus semicircularis of the toad, Bufo marinus. The characteristic frequencies of the units fell into three main groups. The peri stimulus time histograms (p.s.t.h.s) for units in the torus showed a variety of forms but most histograms had a peak near the beginning of the response. The latencies of these peaks varied between 10 and 90 ms after the onset of the stimulus. As the intensity of a stimulus at the characteristic frequency was increased, the number of spikes elicited increased and the latency of the first peak in the p.s.t.h. decreased. All units that exhibited a high sensitivity to changes in stimulus intensity had characteristic frequencies in the low region of the auditory range and relatively long latencies. The number of spikes elicited and the latencies of the responses also varied as the location of the stimulus was changed. For those units whose spike output was highly sensitive to stimulus direction, the latency of the response was longer and showed greater variation with stimulus direction than the less sensitive units. The characteristic frequencies of the more highly sensitive units were also restricted to the low region of the auditory range. The properties of units with a high sensitivity to stimulus intensity were similar to the properties of units that were highly sensitive to stimulus direction. The difference between these properties and those of units with lower sensitivity to stimulus intensity and direction suggests that the auditory system in the brainstem of anura may be composed of at least two functionally distinct pathways. One of these pathways probably involves a more complex neuronal integration of the afferent input following low frequency stimulation.

Effects of alcohol on functional development of the auditory pathway in the brainstem of infants and chick embryos.

The effects of alcohol on the development of neural function in the auditory pathway of the brainstem have been examined in human neonates and chick embryos. Auditory brainstem evoked responses were recorded in six infants of mothers for whom there was evidence of alcohol abuse during pregnancy. In four of the infants, evoked responses were abnormal, with poorly defined, inconsistent peaks. Neurophysiological and histological studies were done on chick embryos which received a single dose of alcohol early incubation. In most surviving embryos the neuroanatomical arrangement of the auditory nuclei in the brainstem was normal. However, Golgi impregnation revealed abnormalities in the length and structure of the dendrites in nucleus laminaris. Electrically evoked neuronal activity revealed abnormalities of synaptic function and the distribution of nerve terminals. The results indicate that in infants and chick embryos the functional development of the auditory pathway in the brainstem is disrupted by exposure to alcohol. Such early changes in this sensory pathway may contribute to the behavioural and intellectual handicaps associated with the fetal alcohol syndrome.