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Ultrasound has received widespread attention as an emerging technology for targeted, non-invasive neuromodulation based on its ability to evoke electrophysiological and motor responses in animals. However, little is known about the spatiotemporal pattern of ultrasound-induced brain activity that could drive these responses. Here, we address this question by combining focused ultrasound with wide-field optical imaging of calcium signals in transgenic mice. Surprisingly, we find cortical activity patterns consistent with indirect activation of auditory pathways rather than direct neuromodulation at the ultrasound focus. Ultrasound-induced activity is similar to that evoked by audible sound. Furthermore, both ultrasound and audible sound elicit motor responses consistent with a startle reflex, with both responses reduced by chemical deafening. These findings reveal an indirect auditory mechanism for ultrasound-induced cortical activity and movement requiring careful consideration in future development of ultrasonic neuromodulation as a tool in neuroscience research., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Ultrasound (US) can noninvasively activate intact brain circuits, making it a promising neuromodulation technique. However, little is known about the underlying mechanism. Here, we apply transcranial US and perform brain mapping studies in guinea pigs using extracellular electrophysiology. We find that US elicits extensive activation across cortical and subcortical brain regions. However, transection of the auditory nerves or removal of cochlear fluids eliminates the US-induced activity, revealing an indirect auditory mechanism for US neural activation. Our findings indicate that US activates the ascending auditory system through a cochlear pathway, which can activate other non-auditory regions through cross-modal projections. This cochlear pathway mechanism challenges the idea that US can directly activate neurons in the intact brain, suggesting that future US stimulation studies will need to control for this effect to reach reliable conclusions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The increasing use of mobile communication has triggered an interest in its possible effects on the regulation of neurotransmitter signals. Due to the close proximity of mobile phones to hearing-related brain regions during usage, its use may lead to a decrease in the ability to segregate sounds, leading to serious auditory dysfunction caused by the prolonged exposure to radiofrequency (RF) radiation. The interplay among auditory processing, excitation and inhibitory molecule interactions plays a major role in auditory function. In particular, inhibitory molecules, such a glycine, are predominantly localized in the auditory brainstem. However, the effects of exposure to RF radiation on auditory function have not been reported to date. Thus, the aim of the present study was to investigate the effects of exposure to RF radiation on glycine receptor (GlyR) immunoreactivity (IR) in the auditory brainstem region at 835 MHz with a specific absorption rate of 4.0 W/kg for three months using free-floating immunohistochemistry. Compared with the sham control (SC) group, a significant loss of staining intensity of neuropils and cells in the different subdivisions of the auditory brainstem regions was observed in the mice exposed to RF radiation (E4 group). A decrease in the number of GlyR immunoreactive cells was also noted in the cochlear nuclear complex [anteroventral cochlear nucleus (AVCN), 31.09%; dorsal cochlear nucleus (DCN), 14.08%; posteroventral cochlear nucleus (PVCN), 32.79%] and the superior olivary complex (SOC) [lateral superior olivary nucleus (LSO), 36.85%; superior paraolivary nucleus (SPN), 24.33%, medial superior olivary nucleus (MSO), 23.23%; medial nucleus of the trapezoid body (MNTB), 10.15%] of the mice in the E4 group. Auditory brainstem response (ABR) analysis also revealed a significant threshold elevation of in the exposed (E4) group, which may be associated with auditory dysfunction. The present study suggests that the auditory brainstem region is susceptible to chronic exposure to RF radiation, which may affect the function of the central auditory system.

Methods to control neural activity by light have been introduced to the field of neuroscience. During the last decade, several techniques have been established, including optogenetics, thermogenetics, and infrared neural stimulation. The techniques allow investigators to turn-on or turn-off neural activity. This review is an attempt to show the importance of the techniques for the auditory field and provide insight in the similarities, overlap, and differences of the techniques. Discussing the mechanism of each of the techniques will shed light on the abilities and challenges for each of the techniques. The field has been grown tremendously and a review cannot be complete. However, efforts are made to summarize the important points and to refer the reader to excellent papers and reviews to specific topics. This article is part of a Special Issue entitled ., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background and Purpose: Tinnitus is a frequent disorder which is very difficult to treat and there is compelling evidence that tinnitus is associated with functional alterations in the central nervous system. Targeted modulation of tinnitus-related cortical activity has been proposed as a promising new treatment approach. We aimed to investigate both immediate and long-term effects of low frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) in patients with tinnitus and normal hearing., Methods: Using a parallel design, 20 patients were randomized to receive either active or placebo stimulation over the left temporoparietal cortex for five consecutive days. Treatment results were assessed by using the Tinnitus Handicap Inventory. Ethyl cysteinate dimmer-single photon emission computed tomography (SPECT) imaging was performed before and 14 days after rTMS., Results: After active rTMS there was significant improvement of the tinnitus score as compared to sham rTMS for up to 6 months after stimulation. SPECT measurements demonstrated a reduction of metabolic activity in the inferior left temporal lobe after active rTMS., Conclusion: These results support the potential of rTMS as a new therapeutic tool for the treatment of chronic tinnitus, by demonstrating a significant reduction of tinnitus complaints over a period of at least 6 months and significant reduction of neural activity in the inferior temporal cortex, despite the stimulation applied on the superior temporal cortex.

Audio-visual stimuli typically yield faster responses than isolated modality-specific ones. This crossmodal speed advantage depends upon efficient multisensory integration mechanisms in the brain. Here, we used repetitive transcranial magnetic stimulation (rTMS) to address the role of the posterior parietal cortex, in particular of the inferior parietal lobule (IPL), in speeding up responses to crossmodal stimuli. The results show that rTMS over IPL impairs the response to contralateral modality-specific visual and auditory targets without affecting the response speed advantage following audio-visual targets. Furthermore, this speed advantage is subserved by a neural coactivation mechanism suggesting a summation in a given neural site. Control rTMS over V1 impaired only contralateral visual responses without affecting the response to auditory or audio-visual targets. These results suggest that the response speed advantage for crossmodal targets is maintained in spite of the IPL interference that impairs modality-specific responses. The possible role of alternative sites for the audio-visual advantage, such as the superior colliculus, is discussed.

The central auditory system creates various types of neurons tuned to different acoustic parameters other than a specific frequency. The response latency of auditory neurons typically shortens with an increase in stimulus intensity. However, approximately 10% of collicular neurons of the little brown bat show a "paradoxical latency-shift (PLS)": long latencies to intense sounds but short latencies to weak sounds. These neurons presumably are involved in the processing of target distance information carried by a pair of an intense biosonar pulse and its weak echo. Our current studies show that collicular PLS neurons of the big brown bat are modulated by the corticofugal (descending) system. Electric stimulation of cortical auditory neurons evoked two types of changes in the PLS neurons, depending on the relationship in the best frequency (BF) between the stimulated cortical and recorded collicular neurons. When the BF was matched between them, the cortical stimulation did not shift the BFs of the collicular neurons and shortened their response latencies at intense sounds so that the PLS became smaller. When the BF was unmatched, however, the cortical stimulation shifted the BFs of the collicular neurons and lengthened their response latencies at intense sounds, so that the PLS became larger. Cortical electric stimulation also modulated the response latencies of non-PLS neurons. It produced an inhibitory frequency tuning curve or curves. Our findings indicate that corticofugal feedback is involved in shaping the spectrotemporal patterns of responses of subcortical auditory neurons presumably through inhibition.

Previous psychological studies have shown that musical chords primed by Western musical scale in a tonal and modal schema are perceived in a hierarchy of stability. We investigated such priming effects on auditory magnetic responses to tonic-major and submediant-minor chords preceded by major scales and tonic-minor and submediant-major chords preceded by minor scales. Musically trained subjects participated in the experiment. During MEG recordings, subjects judged perceptual stability of the chords. The tonic chords were judged to be stable, whereas the submediant chords were judged to be unstable. Dipole moments of N1m response originating in the auditory cortex were larger in the left hemisphere for the submediant chords than for the tonic chords preceded by the major but not minor scales. No difference in the N1m or P2m moment was found for the chords presented without preceding scales. These results suggest priming effects of the tonal schema, interacting with contextual modality, on neural activity of the auditory cortex as well as perceptual stability of the chords. It is inferred that modulation of the auditory cortical activity is associated with attention induced by tonal instability and modality shift, which characterize the submediant chords.

Our recent study has shown that somatosensory electrical stimulation may be useful to modulate sound-induced hyperactivity in the dorsal cochlear nucleus (DCN), a neural correlate of certain forms of tinnitus. Somatosensory electrical stimulation induced both suppressive and excitatory effects on neural activity in the DCN of both control and tone-exposed animals. However, it is unclear what neural pathways underlie the somatosensory electrical stimulation-induced effects on DCN activity. To address this issue, we conducted c-fos immunocytochemistry using hamsters and mapped neural activation in both auditory and non-auditory structures following transcutaneous electrical stimulation of the basal part of the pinna. We also conducted tracing experiments to investigate the anatomical relations between the DCN and structures that showed a significant increase in the number of Fos-positive neurons as a result of electrical stimulation. Electrical stimulation of the pinna induced significant increases in the number of Fos-positive neurons in the DCN, spinal trigeminal nucleus (Sp5), dorsal raphe nucleus (DR) and locus coeruleus (LC). Results of tracing experiments indicate that the DCN received inputs from the Sp5, DR and LC. The above results suggest that modulation of DCN activity through somatosensory electrical stimulation may involve both direct pathways via the Sp5 and indirect pathways via the DR and LC. Therefore, relieving tinnitus through somatosensory electrical stimulation may require manipulations of both auditory and non-auditory functions.

Neurons in the recipient layers of sensory cortices receive excitatory input from two major sources: the feedforward thalamocortical and recurrent intracortical inputs. To address their respective functional roles, we developed a new method for silencing cortex by competitively activating GABA(A) while blocking GABA(B) receptors. In the rat primary auditory cortex, in vivo whole-cell recording from the same neuron before and after local cortical silencing revealed that thalamic input occupied the same area of frequency-intensity tonal receptive field as the total excitatory input, but showed a flattened tuning curve. In contrast, excitatory intracortical input was sharply tuned with a tuning curve that closely matched that of suprathreshold responses. This can be attributed to a selective amplification of cortical cells' responses at preferred frequencies by intracortical inputs from similarly tuned neurons. Thus, weakly tuned thalamocortical inputs determine the subthreshold responding range, whereas intracortical inputs largely define the tuning. Such circuits may ensure a faithful conveyance of sensory information.

The ascending and descending projections of the central auditory system form multiple tonotopic loops. This study specifically examines the tonotopic pathway from the auditory thalamus to the auditory cortex and then to the auditory midbrain in mice. We observed the changes of receptive fields in the central nucleus of the inferior colliculus of the midbrain evoked by focal electrical stimulation of the ventral division of the medial geniculate body of the thalamus. The receptive field of an auditory neuron was characterized by five parameters: the best frequency, minimum threshold, bandwidth, size of receptive field, and average spike number. We found that focal thalamic stimulation changed the parametric values characterizing the recorded collicular receptive fields toward those characterizing the stimulated thalamic receptive fields. Cortical inactivation with muscimol prevented the development of the collicular plasticity induced by focal thalamic stimulation. Our data suggest that the intact colliculo-thalamo-cortico-collicular loops are important for the coordination of sound-guided plasticity in the central auditory system.

To investigate the corticofugal modulation of acoustic information ascending through the auditory pathway of the rat, immunohistochemical techniques were used to study the functional expression of Fos protein in neurons. With auditory stimulation at different frequencies, Fos expression in the medial geniculate body (MGB), inferior colliculus (IC), superior olivary complex, and cochlear nucleus was examined, and the extent of Fos expression on the two sides was compared. Strikingly, we found densely Fos-labeled neurons in all divisions of the MGB after both presentation of an auditory stimulus and administration of a gamma-aminobutyric acid type A (GABA(A)) antagonist (bicuculline methobromide; BIM) to the auditory cortex. The location of Fos-labeled neurons in the ventral division (MGv) after acoustic stimulation at different frequencies was in agreement with the known tonotopic organization. That no Fos-labeled neurons were found in the MGv with acoustic stimuli alone suggests that the transmission of ascending thalamocortical information is critically governed by corticofugal modulation. The dorsal (DCIC) and external cortices (ECIC) of the IC ipsilateral to the BIM-injected cortex showed a significantly higher number of Fos-labeled neurons than the contralateral IC. However, no difference in the number of Fos-labeled neurons was found between the central nucleus of the IC on either side, indicating that direct corticofugal modulation occurs only in the ECIC and DCIC. Further investigations are needed to assess the functional implications of the morphological differences observed between the descending corticofugal projections to the thalamus and the IC., ((c) 2007 Wiley-Liss, Inc.)

Learning-induced or experience-dependent auditory cortical plasticity has often been characterized by frequency-specificity. Studies have revealed the critical role of the cholinergic basal forebrain and acoustic guidance. Cholinergic facilitation of specific thalamocortical inputs potentially determines such frequency-specificity but this issue requires further clarification. To examine the cholinergic effects on thalamocortical circuitry of specific frequency channels, we recorded the responses of cortical neurons while pairing basal forebrain activation or acetylcholine (ACh) microiontophoresis with tone presentations at 10 dB below the neuronal response threshold. We found that both basal forebrain activation and acetylcholine microiontophoresis paired with a tone induced a significant decrease in response threshold of the recorded cortical neurons to the frequency of the paired tone, and that this threshold decrease could be eliminated by atropine microiontophoresis. Our data suggest that cortical acetylcholine specifically facilitates thalamocortical circuitry tuned to the frequency of a presented tone; it is the first, fundamental step towards frequency-specific cortical plasticity evoked by auditory learning and experience.

Centrifugal olivocochlear (OC) pathways modulate cochlear hearing losses induced in cats by loud sounds varying in bandwidth from tones to clicks and noise bands, in a variety of conditions. The general effect, always to reduce hearing damage, can be a net effect resulting from complex interactions between OC subcomponents (crossed and uncrossed OC pathways). The interactions between these subcomponents vary with type of loud sound, suggesting that sound bandwidth may be important in determining how OC pathways modulate loud sound-induced hearing loss. This dependency was examined and here it is reported that OC pathways do not alter cochlear hearing losses caused by loud noise with a 2-kHz-wide bandwidth intermediate between the loud sounds of previous studies. Increasing stimulus bandwidth even slightly more, to use a loud 3.5-kHz-wide bandwidth noise as the damaging sound, once again revealed OC modulation of cochlear hearing loss. The fact that OC pathways do not modulate cochlear hearing losses induced by loud 2-kHz-wide noise was demonstrated in three very different test conditions in which OC pathways modulate hearing losses caused by narrower or broader bandwidth sounds. This confirmed that the absence of centrifugal modulation of hearing loss to this particular sound was a robust phenomenon not related to test condition. The absence of overall centrifugal effects was also true at the level of subcomponent pathways; neither crossed nor uncrossed OC pathways individually modulated cochlear hearing losses to the loud 2-kHz-wide noise. This surprising frequency dependency has general implications for centrifugal modulation of cochlear responses.

We conducted a study of the effects of mobile cellular telephone microwave radiation on the auditory system in 20 healthy men. After the subjects underwent baseline measurements of transient evoked otoacoustic emission (TEOAE) and auditory brainstem response (ABR), they participated in three sessions of exposure to an electromagnetic field of 900 to 1,800 MHz produced by a cellular phone. Sessions ranged from 15 to 30 minutes in length. TEOAE and ABR were again measured after or during each exposure. Throughout the study, no significant changes in either measurement were noted. We conclude that the use of cellular phones does not alter the auditory system in the short-term.

Focal electric stimulation of the auditory cortex, 30-min repetitive acoustic stimulation, and auditory fear conditioning each evoke shifts of the frequency-tuning curves [hereafter, best frequency (BF) shifts] of cortical and collicular neurons. The short-term collicular BF shift is produced by the corticofugal system and primarily depends on the relationship in BF between a recorded collicular and a stimulated cortical neuron or between the BF of a recorded collicular neuron and the frequency of an acoustic stimulus. However, it has been unknown whether focal electric stimulation of the inferior colliculus evokes the collicular BF shift and whether the collicular BF shift, if evoked, depends on corticofugal feedback. In our present research with the awake big brown bat, we found that focal electric stimulation of collicular neurons evoked the BF shifts of collicular neurons located near the stimulated ones; that there were two types of BF shifts: centripetal and centrifugal BF shifts, i.e., shifts toward and shifts away from the BF of stimulated neurons, respectively; and that the development of these collicular BF shifts was blocked by inactivation of the auditory cortex. Our data indicate that the collicular BF shifts (plasticity) evoked by collicular electric stimulation depended on corticofugal feedback. It should be noted that collicular BF shifts also depend on acetylcholine because it has been demonstrated that atropine (an antagonist of muscarinic acetylcholine receptors) applied to the IC blocks the development of collicular BF shifts.

Objectives: The cochlea may be damaged by modern conventional radiotherapy (RT) for head and neck cancers when the ear is included in the radiation field. It is unclear however, if the retro-cochlear auditory pathways are affected as well, which has clinical significance in cochlear implantation. This study aims to investigate the integrity of the retro-cochlear auditory pathways in patients who had received RT for nasopharyngeal carcinoma., Study Design: Prospective study., Methods: Patients who were newly diagnosed with nasopharyngeal carcinoma and treated by RT alone were studied. Evoked response audiometry and PTAs were carried out prior to and after RT (at 3, 18, and 48 months postRT). In addition, evoked response audiometry was also performed during the 3rd, 5th, and 7th week of RT. Waves 1 to 5, 1 to 3, and 3 to 5 latencies were measured. The values recorded during and postRT were compared with those recorded before RT. In addition, a subset of ears that demonstrated postRT sensorineural hearing loss were identified so that their respective wave 1 to 5 interwave latencies could be similarly compared. Wilcoxon signed ranks test was used in the statistical analysis. To confirm that the cochlea and internal auditory meatus receive significant doses of radiation, the RT treatment plans of nine other nasopharyngeal carcinoma patients treated by the same RT technique were analyzed to derive dose-volume histograms of these structures., Results: Twenty-seven patients (20 males and 7 females) with a mean age of 51.2 (range 36-75) years participated in the study. There was no statistically significant difference in waves 1 to 5, 1 to 3, and 3 to 5 interwave latencies recorded during RT and postRT as compared with those recorded before RT (P > .05). Pre- and postRT wave 1 to 5 latencies of the 16 ears that had postRT hearing deterioration were also not statistically significant (P = .366). The mean radiation doses delivered to the cochlea and internal auditory meatus ranged from 24.1 to 62.2 Gy and 14.4 to 43.4 Gy, respectively., Conclusion: This study suggests in patients who have had RT for nasopharyngeal carcinoma, the retro-cochlear auditory pathways are functionally intact even in the longer term.

A major cue for the localization of sound in space is the interaural time difference (ITD). We examined the role of inhibition in the shaping of ITD responses in the inferior colliculus (IC) by iontophoretically ejecting gamma-aminobutyric acid (GABA) antagonists and GABA itself using a multibarrel pipette. The GABA antagonists block inhibition, whereas the applied GABA provides a constant level of inhibition. The effects on ITD responses were evaluated before, during and after the application of the drugs. If GABA-mediated inhibition is involved in shaping ITD tuning in IC neurons, then applying additional amounts of this inhibitory transmitter should alter ITD tuning. Indeed, for almost all neurons tested, applying GABA reduced the firing rate and consequently sharpened ITD tuning. Conversely, blocking GABA-mediated inhibition increased the activity of IC neurons, often reduced the signal-to-noise ratio and often broadened ITD tuning. Blocking GABA could also alter the shape of the ITD function and shift its peak suggesting that the role of inhibition is multifaceted. These effects indicate that GABAergic inhibition at the level of the IC is important for ITD coding.

Plasticity of the auditory cortex can be induced by conditioning or focal cortical stimulation. The latter was used here to measure how stimulation in the tonotopy of the mouse primary auditory cortex influences frequency tuning in the midbrain central nucleus of the inferior colliculus (ICC). Shapes of collicular frequency tuning curves (FTCs) were quantified before and after cortical activation by measuring best frequencies, FTC bandwidths at various sound levels, level tolerance, Q-values, steepness of low- and high-frequency slopes, and asymmetries. We show here that all of these measures were significantly changed by focal cortical activation. The changes were dependent not only on the relationship of physiological properties between the stimulated cortical neurons and recorded collicular neurons but also on the tuning curve class of the collicular neuron. Cortical activation assimilated collicular FTC shapes; sharp and broad FTCs were changed to the shapes comparable to those of auditory nerve fibers. Plasticity in the ICC was organized in a center (excitatory)-surround (inhibitory) way with regard to the stimulated location (i.e., the frequency) of cortical tonotopy. This ensures, together with the spatial gradients of distribution of collicular FTC shapes, a sharp spectral filtering at the core of collicular frequency-band laminae and an increase in frequency selectivity at the periphery of the laminae. Mechanisms of FTC plasticity were suggested to comprise both corticofugal and local ICC components of excitatory and inhibitory modulation leading to a temporary change of the balance between excitation and inhibition in the ICC.

The current study evaluated changes in [14C]-2-deoxyglucose (2-DG) uptake along the auditory pathways of hamsters that were exposed unilaterally to intense sound. The measurement of the acoustically evoked auditory brainstem responses indicated that intense sound exposure caused asymmetrical hearing loss. The 2-DG results revealed some changes in metabolic activity in exposed animals, as compared to unexposed animals. Significant decreases in 2-DG uptake were found in the ipsilateral anteroventral and posteroventral cochlear nucleus, with respect to the exposed left ears. Exposed animals also showed significant increases in the ipsilateral nucleus of the lateral lemniscus, central nucleus of inferior colliculus and medial geniculate body. No significant changes in uptake were observed in the ipsilateral dorsal cochlear nucleus, superior olivary complex, auditory cortex and any contralateral structures. The mechanisms for the observed changes in 2-DG uptake are discussed.

Objective: To investigate whether pulsed high-frequency electromagnetic field (pulsed EM field) emitted by a mobile phone for 30 min has short-term adverse effects on the human central auditory system., Methods: We studied the auditory brainstem response (ABR), the ABR recovery function and middle latency response (MLR) before and after using a mobile phone for 30 min in 15 normal hearing volunteers., Results: None of the 3 measures were affected by exposure to pulsed EM field emitted by a mobile phone for 30 min., Conclusions: Based on the ABR and MLR methods utilized in the study, we conclude that 30 min mobile phone use has no short-term adverse effects on the human auditory system.

Two experiments were carried out to investigate the consequences of exposure to proton radiation, such as might occur for astronauts during space flight. C57BL/6 mice were exposed, either with or without 15-g/cm2 aluminum shielding, to 0-, 3-, or 4-Gy proton irradiation mimicking features of a solar particle event. Irradiation produced transient direct deficits in open-field exploratory behavior and acoustic startle habituation. Rotorod performance at 18 rpm was impaired by exposure to proton radiation and was impaired at 26 rpm, but only for mice irradiated with shielding and at the 4-Gy dose. Long-term (>2 weeks) indirect deficits in open-field activity appeared as a result of impaired experiential encoding immediately following exposure. A 2-week recovery prior to testing decreased most of the direct effects of exposure, with only rotorod performance at 26 rpm being impaired. These results suggest that the performance deficits may have been mediated by radiation damage to hippocampal, cerebellar, and possibly, forebrain dopaminergic function.

Although radiation damage to the inner ear can be induced experimentally in animals, its incidence in humans as a complication of therapy for nasopharyngeal carcinoma (NPC) remains a matter of conjecture due to inadequate histological validation. A case of advanced NPC with a mixed conductive and neurosensory hearing loss is presented that at necropsy showed tumour invasion of the VIIIth cranial nerve in the internal auditory meatus with associated infection. The architecture of the organ of Corti was well-preserved despite heavy doses of radiation but degeneration, the cause of which could not be substantiated, was present in the auditory nerve pathway. A diagnosis of radiation damage to the end-organ of hearing in the absence of supporting histological evidence should be made with caution.

Autoradiographic maps of brain activity in rats exposed to pulsed or continuous-wave (CW) microwave radiation were made using [14C]2-deoxy-D-glucose ([14C]2-DG). Special emphasis was given to measurements of activity in the auditory system because previous work had shown that pulsed microwave radiation can elicit auditory responses in man and other animals. In particular, one middle ear was ablated in nine rats to attenuate the transmission of air-borne sound to one cochlea. The resulting imbalance in auditory input for four animals not exposed to microwave radiation was reflected as a bilateral asymmetry of [14C]2-DG uptake at the inferior colliculus and medial geniculate body. In contrast, a symmetrical pattern of uptake at these structures in an animal exposed to pulsed microwave radiation showed that this stimulus bypasses the middle ear in eliciting auditory responses. This result established the utility of the [14C]2-DG method for demonstrating a known effect of microwave radiation on brain activity. The results also revealed responses at auditory nuclei in 4 animals exposed to CW microwave radiation. These responses, which have not been observed with other methods, were evident at the power densities of 2.5 and 10 mW/sq. cm. To exclude the possibility that CW microwave radiation produced this result by direct action on brain tissue, additional data were obtained from two rats with one cochlea destroyed. In both animals, the uptake of [14C]2-DG at the inferior colliculus and medial geniculate body was virtually identical to the uptake in animals not exposed to microwave radiation, i.e. greatest on the side of the brain contralateral to the intact cochlea. This finding, coupled with the finding of a bilateral symmetry of [14C]2-DG uptake in the auditory pathways of animals with one middle ear ablated, confirmed the hypothesis that auditory responses to CW microwave radiation originate within the cochlea. Effects on brain activity outside of the auditory system were not found in qualitative analyses of autoradiographs for the conditions of exposure to CW microwave radiation noted above or for exposure to pulsed microwave radiation at the average power density of 2.5 mW/sq. cm.

Pregnant CBA/CBA mice were whole body irradiated with 2 Gy on the 13th or 16th day of gestation, respectively. The exposed fetuses were raised to an age of 21 postnatal days. Auditory brainstem recordings of threshold levels showed a considerable elevation independent of if irradiation had been performed on either the 13th gestational day or the 16th gestational day. In exposed animals a latency difference occurs in the peaks that increases from peak 1 to peak 5, measuring in peak 5 up to 1.16 ms. Also the peak-to-peak length of waves 1-5 increases in irradiated animals. Scanning electron microscopy of the cochleae showed varying degrees of stereociliary derangement of both outer and inner hair cells, particularly in cochleae where irradiation had been performed on the 13th gestational day, but not loss of hair cells. Light microscopic analysis of auditory brainstem nuclei revealed normal conditions except that in inner ears exposed on the 16th gestational day the flocculus was fused to the lateral surface of the anterior ventral cochlear nucleus. It is concluded that the elevated threshold levels in irradiated animals are most likely due to pathological changes in the peripheral receptor organ whereas the increased latencies and the increased peak-to-peak length likewise reflect functional changes in the brainstem auditory nuclei.

The function and morphology of the vestibular and cochlear parts of the inner ear have been examined after prenatal irradiation on the 12th, 13th and 16th gestational days in the CBA/CBA mouse. Irradiation was performed with a 0.5, 1 or 2 Gy single dose, whole body irradiation of the pregnant female. The irradiated fetuses were born after full term pregnancies and reached maturity (were 1--2 months old) before inner ears were analyzed with regard to vestibular tests, auditory thresholds and morphology. Morphology was studied by light microscopy (LM), transmission electron microscopy (TEM) and scanning electron microscopy (SEM). Auditory function was analyzed by frequency specific auditory brainstem response (ABR). Irradiation doses exceeding 2 Gy caused death to the pregnant female, abortion or malformed litters which were eaten by their mothers. Doses of 0.5, 1 and 2 Gy caused malformed cristae ampullares and maculae utriculi, in particular after exposure on the 12th or 13th gestational days. After those doses no abnormality of clinical behaviour of the animals was found. Ultrastructurally, type I hair cells (HC) of the vestibular part seemed more vulnerable to irradiation than the type II HC while the outer (OHC) and inner (IHC) hair cells appeared equally vulnerable. The ultrastructural changes of hair cells were predominantly localized to the hair cell surface showing a defect cuticle which was sometimes malformed and bulging. Sensory hair fusion occurred with a resulting poor maturation of sensory hair rootlets. The efferent nerve endings were estimated to be reduced in number but, if present, they had a normal ultrastructure. Otoconia showed severe morphological damage following irradiation particularly if exposed on the 16th gestational day. Malformed and fused otoconia were frequent having a disarrayed matrix. The irradiation induced morphological alterations in vivo could be reproduced in the in vitro systems. In addition, a retarded growth of the in vitro developing inner ear anlage was estimated to be the same for the vestibular and cochlear parts. The cochlear part of the inner ear showed a dose and age dependent hearing loss following irradiation. A shift of the ABR threshold was recorded in all exposed groups that were irradiated with 2 Gy. A correlation was found between the individual ABR-audiograms and the degree of morphological HC damage in the cochlea along the basilar membrane. The 12th gestational day inner ear anlage was most vulnerable to irradiation. The 13th gestational day inner ear was almost equally vulnerable and showed a dose-response relationship.(ABSTRACT TRUNCATED AT 400 WORDS)