Sensory gating deficit following cocaine exposure in the rat.

The purpose of this research was to examine changes in the ratio and amplitude of the N40 component of the auditory event-related potential (ERP) in the paired conditioning (C) test (T) stimulation paradigm following subchronic cocaine/vehicle administration. Free moving rats received cocaine (47.5 mg/kg) or saline for 7 consecutive days in a longitudinal crossover design. ERPs were recorded 4 and 7 days after each treatment and again 4 and 7 days following withdrawal of the drug/vehicle. Cocaine led to a progressive increase in the T/C ratio indicating impaired inhibition of the test response. This trend continued throughout the 7-day drug regimen. Following withdrawal of the drug the T/C ratio gradually normalized over the next 7 days but remained elevated at 4 days postdrug. A significant increase in the test response accompanied by a less pronounced decrease in the conditioning response accounted for the observed results. Behavioral state as measured on a rating scale during ERP sampling did not differ across experimental conditions.

Functional auditory development in preterm and full term infants.

Bilateral ABRs were recorded from 452 infants 32-45 weeks conceptional age. Differences in laterality, gender and appropriateness for gestational age were investigated in order to increase our understanding of developmental processes in early life. Rate effects were also studied in a subsample of infants (145 ears). All subjects were free of conditions known to affect ABR parameters. Left/right differences were evident for all ABR measures except the amplitude of wave I. Shorter interwave intervals and larger amplitudes were consistently observed on the right. Females exhibited shorter absolute latencies for waves III and V and larger wave I amplitudes than males. Small for gestational age (SGA) infants displayed shorter wave V latencies and interwave intervals relative to AGA infants. These differences, however, disappeared by term age whereas the contrasts in laterality persisted. Increasing the rate of stimulation reduced wave I amplitude irrespective of conceptional age and increased wave V amplitude prior to term. An increase in wave V latency was more pronounced at the higher rate on the left than the right. There was no interaction between rate and appropriateness for gestational age, although SGA infants had shorter wave V and interwave latencies. Our data indicate a slight but significant right ear advantage in the processing of auditory signals. Gender differences were apparent as well. While research on adults and older children have reported similar findings, no other studies to date have observed these results in neonates. The present work also lends support to the view that accelerated neurological development occurs in growth-retarded infants.

Transient evoked otoacoustic emissions: feasibility in the nursery.

OBJECTIVE: To assess the feasibility of obtaining transient-evoked otoacoustic emissions (TEOAEs) directly in the nursery, to examine the nature of failures in this population, and to determine the time requirements for this test relative to the auditory brain stem response (ABR). DESIGN: TEOAEs and ABRs were recorded from 149 ears, at bedside, in the recovery or intensive care nursery. Subjects were selected according to the risk criteria developed by the Joint Committee on Infant Hearing (1991). Parametric and nonparametric statistical procedures were conducted to describe demographics and test results, to evaluate TEOAE measures by subgroups, and to compare infants by pass/fail outcome. Multivariate techniques were applied to the data to test implicit hypotheses regarding the source of TEOAE failures. In addition, the time required to carry out each test was evaluated in an analysis of variance design. RESULTS: 63.5% of the ears studied passed both procedures, 5% failed both, and 31.5% passed the ABR but failed the TEOAE. Although infants who failed the TEOAE had lower birthweights, shorter gestational periods, and were younger at the time of testing, no statistical differences were found for nursery (intensive care nursery/recovery), bed type (isolette/open crib), ear (left/right), or gender. Infants < 38 wk postconceptional age had smaller TEOAE responses and lower noise levels than did those > 37 wk. There were no differences in environmental noise levels (at the microphone) for passed or failed ears or whether infants were in isolettes or open cribs. Statistically prolonged ABR wave I latencies (Z-scores) at 60 and 30 dB among infants who passed the ABR but failed the TEOAE indicated some obstruction to the acoustic stimulus, whereas TEOAE noise measures neither distinguished these groups nor identified this condition. Three summary times involved in the performance of these tests were obtained: (a) actual test time, measured from start to completion of data collection with a stopwatch; (b) total test time, defined by the actual test time plus the respective preparation, setup, and cleanup (ABR) time; and (c) time reported by the computer system during intrinsic sampling. There were no significant differences in actual or total test times, but these values were distinguished from the machine time, which represented an underestimate of the time required to effectively conduct each test. CONCLUSIONS: These findings show that TEOAEs can be acquired in the nursery, but the high false-positive rate suggests that alternative or additional screening methods, for example, the ABR, must also be available. It must be recognized that TEOAE failures increase test time, thereby negating any savings relative to ABR screening alone.

Risk for ABR abnormalities in the nursery.

The records of 1087 full- and pre-term infants with normal hearing were reviewed for auditory brain-stem response (ABR) abnormalities. Subjects were classified according to various complications common to the newborn. A logistic regression analysis was performed in order to determine the risk of incurring ABR deviations associated with specific diagnoses in the nursery. Infants exposed to cocaine in utero and those with neurological signs or demonstrable brain anomalies were 4-5 times more likely to exhibit deviant ABRs. The synergistic effects of selected predictor variables further increased the risk for abnormal responses depending on gestational age and type of disorder. These results suggest subtle neurologic influences persisting at the time of discharge.

Cocaine exposure prebreeding to weaning: maternal and offspring effects.

In a model emphasizing prebreeding cocaine administration, rats exposed to cocaine (50 mg/kg) daily were compared to saline-injected and noninjected controls with respect to weight changes, food and water intake, maternal behavior, offspring weight, and activity. During the first 21 days cocaine-treated dams lost weight, while the control dams gained. Throughout gestation and the first 14 days of lactation all groups gained weight, but the cocaine-exposed dams never completely recovered from the initial anorectic effect. Except during the first week of exposure, cocaine dams ate and drank more than the normal controls and drank more than the saline group. During gestation there was no difference in food intake, although the cocaine dams continued to drink more than controls. During lactation there were no differences in food and water consumption across groups. However, the cocaine dams exhibited more nursing behavior. From birth to day 21, the offspring of cocaine-treated dams were smaller than those of either control group. By 51 days of age, group differences had disappeared. Cocaine-exposed pups and saline offspring tested at days 28 and 85 were more active than those of noninjected controls. The results indicate that administration of cocaine for a period prior to breeding and during gestation and lactation, a protocol which closely resembles human drug abuse patterns, is more devastating than the administration during gestation.

Perinatal cocaine exposure and functional brainstem development in the rat.

Rat pups exposed to cocaine via maternal intromission throughout gestation and lactation displayed significantly prolonged auditory brainstem response component latencies and interwave intervals. Longitudinal analysis revealed that this effect was most pronounced on the 22nd postnatal day. Increasing the rate of stimulation further impaired neurosensory transmission in the caudal auditory pathway. These results indicate that both axonal and synaptic events may be affected to some degree and the timing (age) of optimum cocaine influence suggests that delayed myelination may be involved. The corresponding retardation in general development of the cocaine exposed pups further implicates maternal, fetal and postnatal utilization of nutritional resources as the basis for this outcome.

Topographic mapping and habituation of event related EEG alpha band desynchronization.

Habituation of alpha wave suppression to an external auditory signal was studied using computer assisted EEG quantification procedures. Topographic maps of alpha amplitude were constructed from multiple electrode placements for seven healthy adults. The EEG preceding and following 10 standard or habituating stimuli, and 1 novel or sensitizing stimulus, was spectrally analyzed and stored as color amplitude maps. Individual and group composite maps were read-out and comparisons in alpha amplitude were made across stimulus conditions. The initial standard stimulus produced a sharp reduction in alpha amplitude whereas the 10th trial had no appreciable effect on spontaneous EEG activity. The novel stimulus immediately restored alpha desynchronization. The colormaps permitted easy visualization and quantification of the process of habituation and sensitization of the alpha rhythm.

Neonatal status and hearing loss in high-risk infants.

Neurophysiologic and behavioral assessments of auditory function were performed on 224 very low birth weight (less than or equal to 1500 gm) infants requiring intensive care in the nursery. The subjects were studied prospectively from 36 weeks to 4 years of age, as available for follow-up. To classify them according to their neonatal status, we applied a principal components analysis to a number of variables representative of the extent of illness and of patient care in early postnatal life. The subjects were then divided into neonatal status quartiles and evaluated for hearing outcome. All those with sensorineural hearing loss fell exclusively into the lowest neonatal status quartile. Sensorineural hearing loss was statistically associated (1) with greater amounts of furosemide administration for longer durations and in combination with aminoglycoside antibiotics and (2) with more episodes of low pH, hypoxemia, or both, higher total bilirubin levels, and substantially lower neonatal status scores. Birth weight, gestational age, highest creatinine level, Apgar score, and aminoglycosides alone were not systematically related to hearing capacity. Subjects in the lowest neonatal status quartile also had a considerably higher incidence of middle ear disorders, characterized by elevated thresholds and prolonged auditory brain stem-response latencies reflective of conductive hearing loss. We conclude that protracted illness and its associated treatment, independently of specific diagnostic categories, constitute important risk factors for permanent hearing loss and for transient hearing loss in early life.

Development of ABR parameters in a preterm and a term born population.

Auditory brain stem responses were recorded in full term infants (N = 465) and in unselected preterm infants (N = 178) who were tested in, respectively, 10 and 12 age groups from birth until 5 yr. The latencies of waves I and V as well as the wave I-wave V delay and the wave V to wave I amplitude ratio were compared at the various age groups. It was found that the mean absolute latency values in the preterm group were significantly longer than for the full term group up to about 2 yr of age. In contrast, the I-V delay and the amplitude ratio were not different. It is concluded that prematurity does not cause a different rate of maturation for the ABR compared to full term infants. In addition, it is suggested that the differences in absolute latencies can be explained on the basis of a higher incidence of otitis media in the preterm population.

Neonatal status: an objective scoring method for identifying infants at risk for poor outcome.

The likelihood of sustaining neurological, sensory or cognitive deficits is considerably greater for very low birthweight (VLBW) infants who require intensive care in early postnatal life than those without major neonatal illness. Identifying which, if any, medical events are responsible for an adverse outcome is most difficult in the face of multiple concurrent complications. In this research, a principal components analysis was performed in order to arrive at a set of orthogonal variables which succinctly described clinical involvement in the nursery. With this procedure, a single hypothetical factor depicting neonatal status (NS) was computed. Principal component scores were then generated for NS and assigned to 252 VLBW (less than 1500 g) infants. These subjects were followed prospectively from birth to 4 years of age. Standardized measures of neurological, sensory and intellectual function were regularly administered. Neonatal status was shown to be significantly correlated with the various test results and predictive of long-term development. When subjects were divided into quartiles with respect to NS, a specific subgroup was identified as "at high risk" for poor outcome. Those subjects falling into the lower quartile incurred more neurological abnormalities persisting beyond the first year. They also suffered a higher incidence of intracranial hemorrhage and sensori-neural hearing loss. In addition, the lower 25%, as a group, scored well below all others on traditional tests of mental ability. These differences were sustained throughout infancy and early childhood and could not be attributed to a number of demographic variables including sex, gestational age, birthweight, Apgar scores or parental educational level.

Maturational time course for the ABR in preterm and full term infants.

Since maturation of ABR amplitude and latency in principle are dependent on innate as well as environmental factors and the health of the infant, it is conceivable that prematurely born infants show a maturation profile that is different from that of full term infants. In order to unequivocally address this we analyzed ABRs recorded in 465 full term infants and in 179 healthy prematurely born, of which 65 were tested once and 113 were tested (2-9 occasions) at different ages from birth up to 5 years of age. Our emphasis was on a description in terms of time constants of the exponential functions used to describe the maturational changes. In general one exponential function (time constant about 5 weeks) was needed to describe the changes in full term wave I latency. The sum of two exponentials was required to describe adequately the latency changes for full term wave V (time constants about 5 weeks and 100 weeks). In prematurely born infants all time constants for the wave I and wave V changes were longer than in the full term. For the wave I-wave V interval no difference was found between the two populations. The differences in the time course for wave I and wave V latency can be accounted for by the higher incidence of otitis media in the prematurely born group.

Neurobehavioral and neurophysiological assessment of healthy and "at-risk" full-term infants.

The Neurological and Adaptive Capacity Score (NACS) and the auditory brainstem response (ABR) are measures that, respectively, provide neurobehavioral and neurophysiological information regarding the status of the central nervous system (CNS) in the neonatal period. We evaluated these measures as indices of CNS functioning in 15 neonates born at risk for neurological sequelae and 15 healthy controls. Significant group differences were observed on the NACS. The ABR failed to distinguish the groups, but abnormal responses were obtained from 1 severely asphyxiated infant. Measures used to define ABR abnormality were also correlated among risk infants. We concluded that the NACS is sensitive to mild but diffuse disturbances, whereas the ABR appears to reflect insults to the brainstem structures that are susceptible to damage from anoxia. Utilization of both tests provides more complete information regarding CNS integrity in neonates.

Maturation of contralateral brain-stem responses in preterm infants.

Average auditory brain-stem responses (ABRs) evoked by left and right ear stimulation of varying intensities were recorded from ipsilateral and contralateral scalp placements in human neonates. Subjects included pre-term infants, healthy full-term infants and high risk, full-term infants. Pre-term infants were classified into 4 age groups ranging from 29 to 41 weeks post-conceptional age (PCA). Significant ipsilateral/contralateral differences were observed. Further, this effect was highly dependent upon age. The youngest pre-term infants were devoid of contralateral activity despite robust ipsilateral responses. The emergence and evolution of the contralateral wave form could readily be visualized from 31 to 37 weeks PCA. The contralateral response was uninfluenced by stimulus intensity but appeared to be related to the amplitude of the ipsilateral response. No systematic ear differences were noted. Pre-term infants tested between 38 and 41 weeks PCA (term equivalence) showed some persisting immaturity in terms of the ABR. Healthy and sick full-term infants were indistinguishable with respect to ipsilateral or contralateral potentials. On the other hand, very ill 6-week-old infants showed specific contralateral abnormalities.

Failure of 5-hydroxytryptophan to modulate brain stem auditory evoked responses in myelin deficient mutant qk mice.

The effect of 5-hydroxytryptophan (5-HTP) on brain stem auditory evoked response (BAER) amplitude in Quaking (qk) and normal littermate mice was examined. Administration of 5-hydroxytryptophan (5-HTP) (75 mg/kg, i.p.) to normal mice increased the amplitude of BAER peaks I, II, and III but had no effect on peak IV. In qk mice, however, 5-HTP did not affect the amplitude of any BAER peaks. Our data indicate that although 5-HTP increased BAER amplitude in normal mice, it failed to modulate BAER in qk mice. These findings are consistent with the possibility that 5-HTP receptor sites associated with myelin basic protein may be reduced in the myelin-deficient mutant qk mice.

Maturation of the auditory brainstem response from birth through early childhood.

The various parameters of the auditory brainstem response (ABR) undergo distinct maturational transformations in early life. The multiplicity of observed changes suggests unique timetables for development of the contributing neural elements. Although the precise physioanatomic substrate of the ABR remains speculative, experimental manipulations and selective response measures have been utilized to elucidate the developmental process. Even at our current level of understanding, the ABR has proven to be a valuable tool for the study of functional development in the nervous system. In the perinatal period and early childhood, the ABR constitutes one of the most reliable measures of neural integrity in the cochlear and caudal brainstem pathway. As our knowledge expands, the ABR should continue to provide information on the neurological and audiological status of healthy and special risk populations.

Misonidazole neurotoxicity in rats: Part II. Effect of pre- and intermittent treatment with pentobarbital on misonidazole neurotoxicity in the rat.

Rats pretreated for 5 days with 50 mg/kg of pentobarbital tolerated statistically significant higher doses of misonidazole before the onset of misonidazole-induced neurotoxicity than rats treated intermittently with the same dose of pentobarbital. Presumably in pretreated rats, pentobarbital induced an increase in the activities of hepatic microsomal enzymes that led to a more rapid metabolism of misonidazole than in rats treated only intermittently.

Developmental profiles for the brainstem auditory evoked potential.

Brainstem auditory evoked potentials (BAEP's) were recorded from 641 subjects in eleven age groups ranging from birth through adulthood, including three levels of prematurity, in order to establish an age-specific normative data base. The amplitude and latency values for waves 1-6, interwave differences for 3-1, 5-3, 5-1 and the amplitude ratios for 5/3 and 5/1 were then converted to percentile scores to permit construction of age-related BAEP profile report forms. Visual inspection of the printed output reveals the proportion of subjects falling above and below a given individual across all BAEP measures. This simple format is useful for general screening purposes as well as plotting maturational changes in healthy or high risk infants.

Role of serotonin in the nicotine-induced depression of the brainstem auditory evoked response.

We have examined the role of serotonergic and/or dopaminergic mechanism in the mediation of the nicotine-induced depression of brainstem auditory evoked responses (BAER) to auditory stimuli. Nicotine produced dose- and time-dependent decreases in BAER amplitude. Administration of serotonin-depleting drugs (reserpine or p-chlorophenylalanine (PCPA), prevented this decrease. Administration of catecholamine-depleting drugs (alpha-methyl-p-tyrosine, disulfiram or Dopa), on the other hand, had no effect. These data thus suggest a role for serotonergic mechanisms in the mediation of nicotine-induced depression of the brainstem auditory pathway.

The theoretical distribution of evoked brainstem activity in preterm, high-risk, and healthy infants.

The observed scores for a number of parameters (amplitude, latency, interwave differences, and ratios) of the brainstem auditory evoked potential (BAEP) were plotted in order to ascertain the sampling distribution at selected ages. Comparisons between preterm and high-risk infants and healthy controls were also made. The cumulative frequency histograms for all but one BAEP variable were found to be normally distributed. Although this finding held across the age and diagnostic category, healthy and risk populations revealed distinct curves due primarily to the dispersion of scores rather than to the shape of the distributions. Only the amplitude ratio of waves 1 and 5 did not match the normal curve. The assumption of normality which underlies most "standard" statistical analyses can therefore be met for many BAEP measures.