Permanent defects in rat peripheral auditory function following perinatal hypothyroidism: determination of a critical period

Rats were treated with propylthiouracil (PTU) for 10-day periods beginning at different ages. Daily injections of L-thyroxine (T4) were administered concurrently with PTU to a group of rats which served as one control group. Peripheral auditory function was evaluated by the brainstem response audiometry (BSRA) technique performed at 12, 16, 25 and 120 days of age. PTU treatment significantly increased wave I latency (cochlear nerve compound action potential) in adult rats when administered from 3 days before delivery through 6 days of age, but was without permanent effect (wave I latencies and thresholds) when administered for 10 days starting at 10 days after birth. T4 replacement during the first 10 postnatal days prevented permanent abnormalities. These data suggest that the period of greatest vulnerability to thyroid hormone depletion in the peripheral auditory system extends from at least 3 days before delivery through between 5 and 10 days of age.     

Murine auditory brainstem evoked response: putative two-channel differentiation of peripheral and central neural pathways

Standard noninvasive recordings of the auditory brainstem evoked response (ABR) from a single pair of obliquely oriented electrodes (typically midline vertex referenced to mastoid) confound inherently distinct signals propagating over peripheral and central neural pathways differing in location and spatial orientation. We describe here a technique for recording short-latency auditory evoked potentials that putatively differentiates peripheral and central neural activity in the mouse and rat. The technique involves recording from two orthogonally oriented electrode pairs using fast sample rates (100 k/s) to accurately measure differences in neural timing and waveform morphology. Electrodes oriented in a transverse plane (mastoid-to-mastoid) register an initial positive-going ABR peak (P1T) earlier than a series of peaks recorded from electrodes oriented along the midline (anterior and posterior to the inter-aural line). The absolute P1T latency is consistent with an origin in the primary auditory nerve, while the delayed midline latencies implicate activity farther along central neural pathways. Differences between these latencies (midline minus transverse) provide new and precise measures of central conduction time (CCT), which in one case is as brief as 0.10 ms. Results in wild type (WT) and knockout (KO) mice, as well as rats, show significant differences in absolute latencies as well as CCT.     

Effect of graded periods of congenital hypothyroidism on the peripheral auditory evoked activity of rats

Rats were treated with a goitrogen, propylthiouracil (PTU), from 3 days before delivery up to different ages postnatally. Peripheral auditory function was evaluated with the auditory brain-stem response (ABR) technique performed at 200 days of age. All groups of rats exposed consecutively pre- and postnatally to PTU displayed permanent auditory impairment for each stimulus modality used, as revealed by significantly prolonged wave I latencies and elevated thresholds, and the severity of these abnormalities was directly related to the duration of PTU treatment. The only congenitally hypothyroid animals not affected were those treated from 3 days before parturition up to birth and those treated for 10 days beginning at 35 days of age. These data underline the susceptibility of the developing auditory system since, while very brief perinatal PTU exposure resulted in permanent evoked response abnormalities, longer exposure in later life had no effect.     

Recording of brainstem evoked potentials and their association with gentamicin in neonates

Brainstem auditory evoked potential (BAEP) recording was used to screen presymptomatically the hearing of 200 neonates treated with ampicillin (100 mg/kg daily) and gentamicin sulfate (5 mg/kg daily). The study included 130 male and 70 female neonates; post-conceptional age ranged from 34 to 57 weeks (mean 42.36 weeks). We divided neonates into 2 groups according to duration of antibiotic treatment; group 1 consisted of 179 patients who were treated with antibiotic agents for 7 days. Although 15 (8.4%) in this group initially manifested abnormal BAEP recordings, only 8 of these brain-damaged neonates (4.5%) (6 with peripheral and 2 with central dysfunction) later manifested abnormal recordings. Group 2 consisted of 21 neonates who were treated for 10 to 30 days; BAEP recordings were abnormal in 7 patients (33.3%) (4 with peripheral and 3 with central dysfunction). We conclude that BAEP is indicated only for neonates treated with gentamicin sulfate for>10 days. In this group, infants so treated usually have underlying disease or severe infection, including birth asphyxia, hypoxia, sepsis, and meningoencephalitis, all of which are clinically significant indicators of high risk for auditory pathway dysfunction.     

Peripheral auditory asymmetry in infantile autism

Difficulty in filtering relevant auditory information in background noise is one of the features of autism. Auditory filtering processes can be investigated at the peripheral level as they are hypothesized to involve active cochlear mechanisms which are regulated by the efferent activity of the medial olivocochlear (MOC) system. The aim of the present work was therefore to assess these peripheral auditory processes in 22 children and adolescents with autism compared with age- and gender-matched normal controls. Active cochlear mechanisms were evaluated with transiently evoked otoacoustic emissions (TEOAEs) and MOC system efficiency was assessed via TEOAEs which are decreased when stimulating the contralateral ear with noise. The MOC system evaluation was performed on 18 of the 22 children. In both studies, results were analysed according to age (from 4 to 10 years and from 11 to 20 years). The main result concerns the asymmetry of the efferent system which differs in individuals with autism. Several neural processes might be hypothesized as involved in the results obtained as the MOC system which originates in the brainstem received regulating controls from upper brain structures including auditory cortex. Lateralization abnormalities at the auditory periphery may reflect indirectly a problem at a higher level of auditory processing. A second important result shows a decrease in TEOAE amplitude with age, in patients, that may correspond to a decrease in hearing sensitivity.     

Abnormalities of multimodality evoked potentials in amyotrophic lateral sclerosis

Thirty-two patients with amyotrophic lateral sclerosis were studied with somatosensory evoked potentials (SEPs), visual evoked potentials, and brain-stem auditory evoked potentials. H-reflexes were used to screen for abnormalities of peripheral nerve conduction. Nineteen patients (59%) showed an abnormality of lower extremity SEPs. In 13 patients (40%) the delay was of central origin, while in six patients (19%) peripheral conduction delay was possible. Abnormality of upper limb SEPs was seen in 11 patients (34%), all but two of whom had abnormal lower limb SEPs as well. Four patients (12%) had abnormal brain-stem auditory evoked potentials, all of whom had abnormal SEPs from upper and lower limbs. Four patients had abnormal visual evoked potentials, which in three patients were of minor degree. These results give physiologic evidence to suggest that abnormalities in amyotrophic lateral sclerosis occur outside the motor system.     

Postnatal development of auditory function in the chicken revealed by auditory brain-stem responses (ABRs)

Auditory evoked brain-stem responses (ABRs) were recorded from the surfaces of the brain of lightly anesthetized newborn (1-7 days old) and adult (7-9 weeks old) chickens as a measure of the development of auditory processing. One-day-old and older chickens showed a series of waves within 5 msec after the stimulus onset. This precocity of the ABR in chickens contrasts with the first appearance of the ABR in cats at 4 days of age. The ABR onset latency was shorter in adult chickens than in newborns. This indicates that developmental modifications of mechanical transmission in the external and middle ear or cytodifferentiation of the sensory hair cells of the basillar papilla and the neurons of the acoustic nerve continue postnatally. Within the complex wave form of the response, most of the inter-wave latencies decreased with maturation, indicating that development of the central auditory pathway also continues postnatally. One inter-wave latency (N1 to P3-4) was significantly shorter (P less than 0.05) in adults than in newborns for intense click stimuli, and even among newborns, this inter-wave latency was significantly shorter in 6- and 7-day-old specimens than in 1-3-day-old specimens. It seems likely that changes in the N1 to P3-4 inter-wave latency reflect changes in evoked activity of second order auditory neurons that are located in the nucleus angularis and nucleus magnocellularis, and that intensive developmental changes occur in these neurons during the first postnatal week. The ABR recorded in chickens is a reliable measure of functional activity in the auditory system which is reproducible between individuals and capable of demonstrating developmental changes in specific segments of the wave form.     

Serotonergic dysfunction in schizophrenia assessed by the loudness dependence measure of primary auditory cortex evoked activity

Increased serotonergic activity is discussed as an important pathogenetic factor in schizophrenia. Further support for this hypothesis is difficult to obtain due to the lack of valid indicators of the brain's serotonin system. A great deal of evidence discovered through human and animal studies suggests that a weak loudness dependence of auditory evoked potentials (LDAEP) indicates high serotonergic activity and vice versa. The LDAEP is a measure of auditory cortex activity, reflecting increase or decrease of auditory evoked potential amplitudes with increasing tone loudness, which is probably modulated by the serotonergic innervation there. This is true only for the LDAEP of the primary auditory cortex, since this region is more highly innervated by serotonergic fibers than the secondary auditory cortex. The LDAEP (N1/P2 component) of 25 inpatients with schizophrenia free of medication and 25 healthy controls matched by age and gender, were recorded. Using dipole source analysis, the LDAEP of primary (tangential dipole) and this of secondary auditory cortex (radial dipole) was separately analyzed. Following a 4-week treatment with the 5-HT(2) antagonists clozapine or olanzapine, patients were once again studied. The LDAEP of the primary, but not of the secondary auditory cortex, was significantly weaker in the patients with schizophrenia than in healthy volunteers, indicating enhanced serotonergic neurotransmission. After treatment with the 5-HT(2) antagonists, the LDAEP (of the right hemisphere) tended to be increased, indicating normalization of serotonergic function in the patients with schizophrenia. These results suggest that the loudness dependence of primary auditory cortex evoked activity is well suitable to assess serotonergic dysfunction in schizophrenia.     

Developmental impairment of auditory evoked N1/P2 component in rats undernourished in utero: its relation to brain serotonin activity

In utero undernourishment produces an elevation of L-tryptophan and serotonin in the brain, including the auditory cortex (A1), such changes seem to be related to an increase in the free fraction (FFT) of plasma L-tryptophan that is transported into the brain through the blood-brain barrier, where it is taken up by serotonergic neurons for serotonin synthesis. Our observations support that FFT has a positive correlation with L-tryptophan (L-Trp) and serotonin levels in the auditory cortex (r=0.95 and 0.82, respectively). Interestingly, a decreased intensity dependence of the auditory evoked N1/P2 component was found in gestationally undernourished animals during their postnatal development. The N1/P2 component had a negative correlation (r=0.81) with A1 serotonin, such that it reflects changes in the neurotransmitter concentration. The present observations suggest a relevant role of serotonin in modulating the activity of the auditory cortex. Since the N1/P2 component is mainly associated with the activity of A1 neurons, it may well be that perception of auditory information is impaired during this developmental period, in the early undernourished animals, possibly affecting cognitive processes. This may be relevant to humans since low birth weight babies that also suffered gestational undernourishment (fetal-placental insufficiency) present an increase in plasma FFT from birth up to 3 months of age. These findings support that the plasma FFT and the intensity dependence of the auditory evoked N1/P2 component relate one another and may be markers of changes of the brain serotonergic activity.     

Cognitive evoked potentials to anticipated oesophageal stimulus in humans: quantitative assessment of the cognitive aspects of visceral perception

Evoked potential studies provide an objective measure of the neural pathways involved with perception. The effects of cognitive factors, such as anticipation or awareness, on evoked potentials are not known. The aim was to compare the evoked potential response to oesophageal stimulation with the cortical activity associated with anticipation of the same stimulus. In 12 healthy men (23.5 +/- 4 years), oesophageal electrical stimulation (15 mA, 0.2 Hz, 0.2 msec) was applied, and the evoked potentials recorded using scalp electrodes. A computerized model of randomly skipped stimuli (4:1 ratio) was used to separately record the evoked potentials associated with stimulation and those associated with an anticipated stimulus. The electrical stimulus represented the nontarget stimulus and the skipped impulse the target (anticipatory) stimulus. This anticipatory evoked potential was also compared to auditory P300 evoked potentials. Reproducible evoked potentials and auditory P300 responses were elicited in all subjects. Anticipatory evoked potentials (peak latency 282.1 +/- 7.9 msec, amplitude 8.2 +/- 0.7 microV, P < 0.05 vs auditory P300 evoked potential) were obtained with the skipped stimulus. This anticipatory evoked potential was located frontocentrally, while the auditory P300 potential was located in the centro-parietal cortex. The anticipatory evoked potential associated with expectation of an oesophageal stimulus, although of similar latency to that of the auditory P300 evoked response, originates from a different cortical location. The recording of cognitive evoked potentials to an expected oesophageal stimulus depends on attention to, and awareness of, the actual stimulus. Anticipatory evoked potentials to GI stimuli may provide an objective electrophysiological tool for the assessment of the cognitive factors associated with visceral perception.     

Postnatal development of the hamster coclea. I. Growth of hair cells and the organ of Corti

A morphometric analysis of the developing organ of Corti and its component hair cells was carried out in an age-graded series of Syrian golden hamsters with the aid of scanning electron microscopy. The purpose was to establish a quantitative framework that would provide insight into the rules and principles by which the mammalian cochlea attains its adult proportions. This study examined postnatal development at two day intervals from birth to 22 days after birth. Our analysis included measures of cochlear length and hair cell numbers as well as measures of hair cell sizes in each of five sectors along the cochlear spiral. Our results demonstrate several principles of cochlear development: (1) The full two and one-fourths turns seen in the adult cochlea are already present at birth, but the cochlea continues to elongate for the next 10–12 days. (2) Development of hair cells in the apex generally lags behind that in the base. Whereas the stereocilia and apical margins of hair cells are clearly defined in the basal turn, they become well defined in the apex only postnatally. (3) Growth in cochlear length occurs mainly by increases in cell size rather than in cell numbers; although hair cells do increase in numbers during the first 4 days of cochlear growth, this increase involves addition of hair cells only to preexisting regions of the cochlear apex. Moreover, the full complement of hair cells is established 6 days before the full size of the cochlea is attained; in contrast, hair cell growth occurs at all positions along the cochlear spiral and spans the entire period of cochlear elongation. (4) The period of hair cell growth exceeds the period of organ of Corti growth and appears to be possible by decreases in intercellular spacing, primarily in the apical region of the cochlea; inner and outer hair cell growth was complete between 16 and 18 days after birth. (5) Inner and outer hair cell neighbors remain virtually constant at different ages indicating that the spatial relationships between the two hair cell populations is preserved as the cochlea grows. (6) Comparison with previous developmental studies of auditory function in the hamster reveals that the age of 16 days after birth, when hair cells attain their mature sizes, coincides with the onset of brainstem auditory evoked responses. Growth of hair cell somas alone, however, cannot explain either the subsequent maturation of evoked potential thresholds or changes in frequency representation in the developing cochlea. © Wiley-Liss, Inc.     

Auditory brainstem evoked potentials in early-treated congenital hypothyroidism

To evaluate the effect of early treatment of congenital hypothyroidism on central nervous system development, auditory brainstem evoked potentials were determined in 32 patients with hyperthyrotropinemia diagnosed during neonatal screening. The patients included 27 with congenital hypothyroidism and 5 with transient hypothyroidism. Abnormal auditory brainstem evoked potential tracings were found in 8 patients (congenital hypothyroidism in 7 and transient hypothyroidism in 1). Four of these patients had increased peripheral conduction time (wave I prolongation), and the other 4 had increased central conduction time (wave III or V prolongation). The patients with abnormal auditory brainstem evoked potentials did not show increased initial manifestations, yet 6 of them had lower initial thyroxine levels. Specific auditory brainstem evoked potential abnormalities were found in 25% of early-treated patients with congenital hypothyroidism. The possible causal relationship between deviant auditory brainstem evoked potential patterns and later neurodevelopment demands further clarification. This study suggests the usefulness of auditory brainstem evoked potential assessment to provide information about electrophysiologic deviation of the auditory pathway in patients with early-treated congenital hypothyroidism.     

Elimination of peripheral auditory pathway activation does not affect motor responses from ultrasound neuromodulation

BackgroundRecent studies in a variety of animal models including rodents, monkeys, and humans suggest that transcranial focused ultrasound (tFUS) has considerable promise for non-invasively modulating neural activity with the ability to target deep brain structures. However, concerns have been raised that motor responses evoked by tFUS may be due to indirect activation of the auditory pathway rather than direct activation of motor circuits.ObjectiveIn this study, we sought to examine the involvement of peripheral auditory system activation from tFUS stimulation applied to elicit motor responses. The purpose was to determine to what extent ultrasound induced auditory artifact could be a factor in ultrasound motor neuromodulation.MethodsIn this study, tFUS-induced electromyography (EMG) signals were recorded and analyzed in wild-type (WT) normal hearing mice and two strains of genetically deaf mice to examine the involvement of the peripheral auditory system in tFUS-stimulated motor responses. In addition, auditory brainstem responses (ABRs) were measured to elucidate the effect of the tFUS stimulus envelope on auditory and motor responses. We also varied the tFUS stimulation duration to measure its effect on motor response duration.ResultsWe show, first, that the sharp edges in a tFUS rectangular envelope stimulus activate the peripheral afferent auditory pathway and, second, that smoothing these edges eliminates the auditory responses without affecting the motor responses in normal hearing WT mice. We further show that by eliminating peripheral auditory activity using two different strains of deaf knockout mice, motor responses are the same as in normal hearing WT mice. Finally, we demonstrate a high correlation between tFUS pulse duration and EMG response duration.ConclusionThese results support the concept that tFUS-evoked motor responses are not a result of stimulation of the peripheral auditory system.     

Changes in subcortical visual and auditory evoked potentials following amygdaloid kindling in cats

In this study we dealt with the changes in visual and auditory evoked potentials following kindling, to reveal the distant effects of epileptic activity. The experiments were performed using cats. Visual and auditory evoked potentials were obtained initially. Daily stimulation of 60 Hz (rectangular wave, 1 ms in duration, 500 microA in peak current, 2-s train) was given to the right amygdala, for kindling. After the completion of kindling, evoked responses were recorded again. In the auditory system the changes of responses in the cortex, medial geniculate nucleus, and cochlear nucleus were distinguished. The changes of potentials in the subcortex were larger than those at the cortical level. For visual evoked potentials there was a discrepancy between stimulation with light and electrical stimulation of the optic chiasm. There was no significant change in amplitude of visual evoked potentials by flash. In the case of optic chiasm stimulation, an enlargement of evoked responses was obtained. These results indicate modality-specific change of the auditory system and widespread subcortical change. These results might be caused by some vulnerability of the auditory system in the case of amygdaloid kindling, as a result of the epileptogenic process.     

Chronic blockade of bioelectric activity in neonatal rat neocortex in vitro:Physiological effects

We have examined what effect the loss of spontaneous bioelectric activity has on neural network formation in organotypic rat neocortical explants grown under serum-free culture conditions. Explants were taken from dorsal midline (presumptive visual) and lateral (presumptive auditory) occipital cortex and chronically exposed to tetrodotoxin which blocked all measurable bioelectric activity between change of medium. Extracellular recordings revealed complex, rhythmic spontaneous and evoked multiunit discharges in all explants examined (following tetrodotoxin washout in the experimental group). Control auditory explants had significantly more sites from which electric activity could be recorded compared with control visual explants. Auditory cultures showed no effect of the tetrodotoxin treatment, whereas visual explants showed significant increases over control values, equalling the auditory values. This increased level of spontaneous bioelectric activity was maintained for at least 10 days following transfer of the cultures to control growth medium. There was no significant difference between control visual and auditory explants regarding the number of sites from which evoked activity was seen. Nor did either cortex group show an effect of tetrodotoxin on the number of sites from which evoked activity was seen. The frequency with which spontaneous bioelectric discharges occurred per site increased with age in auditory vs visual cortex. These differences, however, were abolished in the tetrodotoxin-treated groups. It was concluded that neocortical explants which have experienced chronic suppression of spontaneous electric activity did not suffer deficits in neural network formation, though there is an effect on the incidence and frequency with which such activity is given.     

Effects of reaction time performance on single-unit activity in the central auditory pathway of the rhesus macaque

The activity of single units at various locations in the central auditory pathway of rhesus macaques was recorded during the monkeys' performance and nonperformance in an auditory reaction time task. Evoked unit responses during performance were compared with those observed during passive delivery of identical stimuli. Single units were recorded from the cochlear nucleus, superior olivary complex, lateral lemniscus, inferior colliculus, medial geniculate nucleus, and auditory cortex. Significant effects of task performance on unit discharge patterns were observed at all levels of the central auditory pathway: Spontaneous discharge rates in the more peripheral auditory nuclei tended to be higher during performance. Evoked discharge that occurred relatively late during a stimulus presentation (greater than 75 msec after stimulus onset) was increased during performance, compared with the nonperformance condition, in nuclei above the cochlear nucleus. The initial latency of evoked discharge was increased during performance for subcortical nuclei but was decreased for units in auditory cortex. These results suggest that the effects of performance may be mediated by a tonic increase in the excitability of auditory units which operates primarily at peripheral auditory stations, and a descending, stimulus-evoked increase in excitability which primarily influences the cells of higher auditory nuclei. At the cortical level, these changes lead to increased signal-to-noise ratio of the evoked response during performance in the auditory task.     

Chronic blockade of bioelectric activity in neonatal rat neocortex in vitro: physiological effects

We have examined what effect the loss of spontaneous bioelectric activity has on neural network formation in organotypic rat neocortical explants grown under serum-free culture conditions. Explants were taken from dorsal midline (presumptive visual) and lateral (presumptive auditory) occipital cortex and chronically exposed to tetrodotoxin which blocked all measurable bioelectric activity between change of medium. Extracellular recordings revealed complex, rhythmic spontaneous and evoked multiunit discharges in all explants examined (following tetrodotoxin washout in the experimental group). Control auditory explants had significantly more sites from which electric activity could be recorded compared with control visual explants. Auditory cultures showed no effect of the tetrodotoxin treatment, whereas visual explants showed significant increases over control values, equalling the auditory values. This increased level of spontaneous bioelectric activity was maintained for at least 10 days following transfer of the cultures to control growth medium. There was no significant difference between control visual and auditory explants regarding the number of sites from which evoked activity was seen. Nor did either cortex group show an effect of tetrodotoxin on the number of sites from which evoked activity was seen. The frequency with which spontaneous bioelectric discharges occurred per site increased with age in auditory vs visual cortex. These differences, however, were abolished in the tetrodotoxin-treated groups. It was concluded that neocortical explants which have experienced chronic suppression of spontaneous electric activity did not suffer deficits in neural network formation, though there is an effect on the incidence and frequency with which such activity is given.     

Brain stem auditory evoked fields in response to clicks

Magnetoencephalographic correlates of brain stem auditory evoked potentials (BAEP) have been identified by applying the model of a current dipole with invariant location and orientation (fixed dipole) to data recorded with a 37-channel first-order gradiometer system. In all three subjects studied, the dominating wave of the recorded brain stem auditory evoked field (BAEF) coincided exactly with wave V in the contralateral BAEP (maximal field amplitude of the order of 2-3 fT). In one subject, also a wave preceding wave V was observed, which was associated with basically the same spatial pattern as wave V itself, but had an opposite polarity. The study suggests that the supplementary information provided by BAEF measurements could be decisive for a better understanding of human auditory evoked brain stem activity.     

Multimodality evoked potentials in closed head trauma

Patients with closed head injuries who had Glasgow coma scale scores of 7 or less were studied with evoked potentials soon after trauma. Of the patients, 39 had brain-stem auditory evoked potentials (BAEPs); 12, stroboscopic visual evoked potentials (VEPs); and 23, short-latency somatosensory evoked potentials (SSEPs). Evoked potential results were graded from 1 (normal) to 4 (most abnormal). Outcomes were categorized by the Glasgow outcome scale, with good outcome and moderate disability further classified as "favorable" and severe disability, vegetative state, and death as "unfavorable." The BAEPs and VEPs were reliable predictors of an unfavorable but not a favorable outcome. The SSEPs reliably predicted both kinds of outcomes. No instances of "false pessimism" were encountered in any modality. Evoked potential results were more reliable than intracranial pressure, pupillary light reaction, or motor findings in predicting outcome. Frequent occurrence of peripheral auditory injuries was shown.     

Comparison of the developmental changes of the brainstem auditory evoked response (BAER) in taurine-supplemented and taurine-deficient kittens

A similar development of the brainstem auditory evoked response is present in taurine-supplemented and taurine-deficient kittens between the second postnatal week and the third month of life. Between birth and the second postnatal week kittens from mothers fed the 1% taurine diet showed earlier maturation of the brainstem auditory evoked response as indicated by lower threshold, shorter P1 latency and shorter central conduction time when compared to the kittens from mothers fed the 0.05% taurine diet. These results suggest an important role of taurine in the anatomical and functional development of the auditory system.