Auditory Research publications

Noise-induced hearing loss (NIHL) affects millions of people worldwide and presents a large social and personal burden. Pharmacological activation of SIRT3, a regulator of the mitochondrial oxidative stress response, has a protective effect on hearing thresholds after traumatic noise damage in mice. In contrast, the role of endogenously activated SIRT3 in hearing recovery has not been established. Here we tested the hypothesis that SIRT3 is required in mice for recovery of auditory thresholds after a noise exposure that confers a temporary threshold shift (TTS). SIRT3-specific immunoreactivity is present in outer hair cells, around the post-synaptic regions of inner hair cells, and faintly within inner hair cells. Prior to noise exposure, homozygous Sirt3-KO mice have slightly but significantly higher thresholds than their wild-type littermates measured by the auditory brainstem response (ABR), but not by distortion product otoacoustic emissions (DPOAE). Moreover, homozygous Sirt3-KO mice display a significant reduction in the progression of their peak 1 amplitude at higher frequencies prior to noise exposure. After exposure to a single sub-traumatic noise dose that does not permanently reduce cochlear function, compromise cell survival, or damage synaptic structures in wild-type mice, there was no difference in hearing function between the two genotypes, measured by ABR and DPOAE. The numbers of hair cells and auditory synapses were similar in both genotypes before and after noise exposure. These loss-of-function studies complement previously published gain-of-function studies and help refine our understanding of SIRT3's role in cochlear homeostasis under different damage paradigms. They suggest that SIRT3 may promote spiral ganglion neuron function. They imply that cellular mechanisms of homeostasis, in addition to the mitochondrial oxidative stress response, act to restore hearing after TTS. Finally, we present a novel application of a biomedical statistical analysis for identifying changes between peak 1 amplitude progressions in ABR waveforms after damage.

Noise impairs signal perception and is a major source of selection on animal communication. Identifying adaptations that enable receivers to cope with noise is critical to discovering how animal sensory and communication systems evolve. We integrated biophysical and bioacoustic measurements with physiological modeling to demonstrate that the lungs of frogs serve a heretofore unknown noise-control function in vocal communication. Lung resonance enhances the signal-to-noise ratio for communication by selectively reducing the tympanum’s sensitivity at critical frequencies where the tuning of two inner ear organs overlaps. Social network analysis of citizen-science data on frog calling behavior indicates the calls of other frog species in multi-species choruses are a prominent source of environmental noise attenuated by the lungs. These data reveal that an ancient adaptation for detecting sound via the lungs has been evolutionarily co-opted to create spectral contrast enhancement that contributes to solving a multi-species cocktail party problem.

Introduction: In utero, exposure to sevoflurane (a commonly used inhalation anesthetic) can lead to hearing impairment in offspring mice, but the underlying impairment mechanism is not known. Materials and methods: Day-15 pregnant mice were treated with 2.5% sevoflurane for 2 h to investigate sevoflurane ototoxicity. Cochleae from offspring mice were harvested for hair-cell and ribbon-synapse assessments. Hearing in offspring mice was assessed at postnatal day 30 using an auditory brainstem-response (ABR) test. Cochlear-explant cultures from offspring mice were exposed to 2.5% sevoflurane for 6 h. Immediately after treatment, explants were assessed for hair-cell morphology, mitochondrial oxidative stress, and autophagy. Results: In utero, sevoflurane exposure impaired hearing in the offspring is demonstrated by a decrease in ABR wave I amplitudes, a marker for ribbon-synapse functionality. Sevoflurane exposure caused no obvious damage to hair cells, but cochlear ribbon synapses were reduced in postnatal day 15 offspring, and partially recovered by postnatal day 30. Sevoflurane treatment also increased mitochondrial reactive-oxygen species stress and decreased autophagy in the cochlear explants. Conclusion: These results suggest that oxidative stress and reduced autophagy may underly ribbon-synapse involvement in sevoflurane-induced hearing loss.

This study determined how well the “perceived spectrum,” estimated using a pitch similarity rating method, reflected the spectrum and pitch of seven different tonal sounds. The perceived spectrum well-matched the acoustic spectrum for pure tones ranging from 1 to 12 kHz, it also matched the broad frequency range for two complex tones with periodicity pitches of 1 and 2 kHz, but it did not reflect the pitch of the complex tones. These results suggest that while this method may not measure the pitch of sounds, it may be useful for measuring the general perceived frequency range of sounds.

Despite the predominance of low-frequency hearing in anuran amphibians, a few frog species have evolved high-frequency communication within certain environmental contexts. Huia cavitympanum is the most remarkable anuran with regard to upper frequency limits; it is the first frog species known to emit exclusively ultrasonic signals. Characteristics of the Distortion Product Otoacoustic Emissions from the amphibian papilla and the basilar papilla were analysed to gain insight into the structures responsible for high-frequency/ultrasound sensitivity. Our results confirm the matching of vocalization spectra and inner ear tuning in this species. Compared to most anurans, H. cavitympanum has a hyperextended hearing range spanning from audible to ultrasonic frequencies, far above the previously established ‘spectral limits’ for the amphibian ear. The exceptional high-frequency sensitivity in the inner ear of H. cavitympanum illustrates the remarkable plasticity of the auditory system and the extent to which evolution can modify a sensory system to adapt it to its environment.

Background: Cisplatin is an alkylating agent that inhibits DNA replication and interferes with proliferation of cancer cells. However, the major limiting factor for its use is the possible development of adverse effects, including ototoxicity. Up till now, the mechanisms of this ototoxicity remain poorly understood. However, induction of oxidative stress and activation of the inflammatory cascade were suggested as contributing factors. Purpose: The aim of this study was to explore the effect of L-arginine on cisplatin-induced ototoxicity in rats. Methods: Thirty male adult Wistar rats were divided into three equal groups as follows: control group; cisplatin group and cisplatin + L-arginine group. Auditory brainstem response (ABR), tissue oxidative stress parameters, total nitrate/nitrite, nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase-1 (HO-1) content, transforming growth factor beta 1 (TGF-β1), tumor necrosis factor alpha (TNF-α) and interleukin 15 (IL-15) were assessed. Also, the cochlear tissues were subjected to histopathological and electron microscopic examination. Results: Administration of L-arginine to cisplatin-treated rats induced significant decrease in the average ABR threshold shifts at all frequencies, tissue TGF-β1, TNF-α and IL-15 associated with significant increase in tissue antioxidant enzymes, total nitrate/nitrite and Nrf2/HO-1 content compared to cisplatin group. Also, pretreatment of cisplatin-injected rats with L-arginine induced significant improvement of the histopathological and electron microscopic picture compared to cisplatin group. Conclusion: L-arginine may serve as a promising therapeutic modality for amelioration of cisplatin-induced ototoxicity. .

The “temporal effect” in simultaneous masking may be characterized by better probe detection thresholds for a short, tonal probe presented at the temporal center of a masker compared to at the onset of a masker. Energy-based models of masking have been used to interpret the temporal effect as evidence that the gain of the auditory system decreases during acoustic stimulation. This study shows that masking from temporal-envelope fluctuations of a precursor or from a temporal gap between stimuli violates the assumptions of energy-based models and complicates the interpretation of temporal effects in terms of a reduction in gain. Detection thresholds were measured for a 6-ms, 4000-Hz probe preceded by a narrowband precursor and presented 2-, 197-, or 392-ms after the onset of a narrowband masker. The delay between the precursor offset and masker onset ranged from −2 to 250 ms. Probe thresholds were elevated in the presence of precursors with fluctuating compared to flattened temporal envelopes and when a temporal gap was inserted between the precursor and masker. The results suggest that the interpretation and design of temporal-effect studies should consider the masking effects of temporal-envelope fluctuations. These findings are consistent with speech-perception experiments that show masking from temporal-envelope fluctuations.

Declining auditory spatial processing is hypothesized to contribute to the difficulty older adults have detecting, locating, and selecting a talker from among others in noisy listening environments. Though auditory spatial processing has been associated with several cortical structures, little is known regarding the underlying white matter architecture or how age-related changes in white matter microstructure may affect it. The arcuate fasciculus is a target for understanding age-related differences in auditory spatial attention based on normative spatial attention findings in humans. Similarly, animal and human clinical studies suggest that the corpus callosum plays a role in the cross-hemispheric integration of auditory spatial information important for spatial localization and attention. The current investigation used diffusion imaging to examine the extent to which age-group differences in the identification of spatially cued speech were accounted for by individual differences in the white matter microstructure of the right arcuate fasciculus and the corpus callosum. Higher right arcuate and callosal fractional anisotropy (FA) predicted better segregation and identification of spatially cued speech across younger and older listeners. Further, individual differences in callosal microstructure mediated age-group differences in auditory spatial processing. Follow-up analyses suggested that callosal tracts connecting left and right pre-frontal and posterior parietal cortex are particularly important for auditory spatial processing. The results are consistent with previous work in animals and clinical human samples and provide a cortical mechanism to account for age-related deficits in auditory spatial processing. Further, the results suggest that both intrahemispheric and interhemispheric mechanisms are involved in auditory spatial processing.

Amphibians are unique among extant vertebrates in having middle ear cavities that are internally coupled to each other and to the lungs. In frogs, the lung-to-ear sound transmission pathway can influence the tympanum’s inherent directionality, but what role such effects might play in directional hearing remain unclear. In this study of the American green treefrog ( Hyla cinerea ), we tested the hypothesis that the lung-to-ear sound transmission pathway functions to improve directional hearing, particularly in the context of interspecific sexual communication. Using laser vibrometry, we measured the tympanum’s vibration amplitude in females in response to a frequency modulated sweep presented from 12 sound incidence angles in azimuth. Tympanum directionality was determined across three states of lung inflation (inflated, deflated, reinflated) both for a single tympanum in the form of the vibration amplitude difference (VAD) and for binaural comparisons in the form of the interaural vibration amplitude difference (IVAD). The state of lung inflation had negligible effects (typically less than 0.5 dB) on both VADs and IVADs at frequencies emphasized in the advertisement calls produced by conspecific males (834 Hz and 2730 Hz). Directionality at the peak resonance frequency of the lungs (1558 Hz) was improved by ≅ 3 dB for a single tympanum when the lungs were inflated versus deflated, but IVADs were not impacted by the state of lung inflation. Based on these results, we reject the hypothesis that the lung-to-ear sound transmission pathway functions to improve directional hearing in frogs. SUMMARY STATEMENT Contrary to prevailing views on the mechanisms of hearing in frogs, the lung-to-ear pathway for sound transmission does not improve directional hearing in these vociferous vertebrates.

In vivo loose patch and breakthrough whole-cell recordings are useful tools for investigating the intrinsic and synaptic properties of neurons. However, the correlation among pipette resistance, seal condition, and recording time is not thoroughly clear. Presently, we investigated the recording time of different pipette resistances and seal conditions in loose patch and breakthrough whole-cell recordings. The recording time did not change with pipette resistance for loose patch recording (Rp-loose) and first increased and then decreased as seal resistance for loose patch recording (Rs-loose) increased. For a high probability of a recording time ≥30 min, the low and high cutoff values of Rs-loose were 21.5 and 36 MΩ, respectively. For neurons with Rs-loose values of 21.5-36 MΩ, the action potential (AP) amplitudes changed slightly 30 min after the seal. The recording time increased as seal resistance for whole-cell recording (Rs-tight) increased and the zero-current membrane potential for breakthrough whole-cell recording (MPzero-current) decreased. For a high probability of a recording time ≥30 min, the cutoff values of Rs-tight and MPzero-current were 2.35 GΩ and -53.5 mV, respectively. The area under the curve (AUC) of the MPzero-current receiver operating characteristic (ROC) curve was larger than that of the Rs-tight ROC curve. For neurons with MPzero-current values ≤ -53.5 mV, the inhibitory or excitatory postsynaptic current amplitudes did not show significant changes 30 min after the seal. In neurons with Rs-tight values ≥2.35 GΩ, the recording time gradually increased and then decreased as the pipette resistance for whole-cell recording (Rp-tight) increased. For the high probability of a recording time ≥30 min, the low and high cutoff values of Rp-tight were 6.15 and 6.45 MΩ, respectively. Together, we concluded that the optimal Rs-loose range is 21.5-36 MΩ, the optimal Rp-tight range is 6.15-6.45 MΩ, and the optimal Rs-tight and MPzero-current values are ≥2.35 GΩ and ≤ -53.5 mV, respectively. Compared with Rs-tight, the MPzero-current value can more accurately discriminate recording times ≥30 min and <30 min.

2-Hydroxypropyl-β-cyclodextrin (HPβCD), a cholesterol chelator, is being used to treat diseases associated with abnormal cholesterol metabolism such as Niemann-Pick C1 (NPC1). However, the high doses of HPβCD needed to slow disease progression may cause hearing loss. Previous studies in mice have suggested that HPβCD ototoxicity results from selective outer hair cell (OHC) damage. However, it is unclear if HPβCD causes the same type of damage or is more or less toxic to other species such as rats, which are widely used in toxicity research. To address these issues, rats were given a subcutaneous injection of HPβCD between 500 and 4000 mg/kg. Distortion product otoacoustic emissions (DPOAE), the cochlear summating potential (SP), and compound action potential (CAP) were used to assess cochlear function followed by quantitative analysis of OHC and inner hair cell (IHC) loss. The 3000- and 4000-mg/kg doses abolished DPOAE and greatly reduced SP and CAP amplitudes. These functional deficits were associated with nearly complete loss of OHC as well as ~ 80% IHC loss over the basal two thirds of the cochlea. The 2000-mg/kg dose abolished DPOAE and significantly reduced SP and CAP amplitudes at the high frequencies. These deficits were linked to OHC and IHC losses in the high-frequency region of the cochlea. Little or no damage occurred with 500 or 1000 mg/kg of HPβCD. The HPβCD-induced functional and structural deficits in rats occurred suddenly, involved damage to both IHC and OHC, and were more severe than those reported in mice.

Auditory dysfunction is the most prevalent injury associated with blast overpressure exposure (BOP) in Warfighters and civilians, yet little is known about the underlying pathophysiological mechanisms. To gain insights into these injuries, an advanced blast simulator was used to expose rats to BOP and assessments were made to identify structural and molecular changes in the middle/inner ears utilizing otoscopy, RNA sequencing (RNA-seq), and histopathological analysis. Deficits persisting up to 1 month after blast exposure were observed in the distortion product otoacoustic emissions (DPOAEs) and the auditory brainstem responses (ABRs) across the entire range of tested frequencies (4–40 kHz). During the recovery phase at sub-acute time points, low frequency (e.g. 4–8 kHz) hearing improved relatively earlier than for high frequency (e.g. 32–40 kHz). Perforation of tympanic membranes and middle ear hemorrhage were observed at 1 and 7 days, and were restored by day 28 post-blast. A total of 1,158 differentially expressed genes (DEGs) were significantly altered in the cochlea on day 1 (40% up-regulated and 60% down-regulated), whereas only 49 DEGs were identified on day 28 (63% up-regulated and 37% down-regulated). Seven common DEGs were identified at both days 1 and 28 following blast, and are associated with inner ear mechanotransduction, cytoskeletal reorganization, myelin development and axon survival. Further studies on altered gene expression in the blast-injured rat cochlea may provide insights into new therapeutic targets and approaches to prevent or treat similar cases of blast-induced auditory damage in human subjects.

Our understanding of nonlinear stimulus transformations by neural circuits is hindered by the lack of comprehensive yet interpretable computational modeling frameworks. Here, we propose a data-driven approach based on deep neural networks to directly model arbitrarily nonlinear stimulus-response mappings. Reformulating the exact function of a trained neural network as a collection of stimulus-dependent linear functions enables a locally linear receptive field interpretation of the neural network. Predicting the neural responses recorded invasively from the auditory cortex of neurosurgical patients as they listened to speech, this approach significantly improves the prediction accuracy of auditory cortical responses, particularly in nonprimary areas. Moreover, interpreting the functions learned by neural networks uncovered three distinct types of nonlinear transformations of speech that varied considerably from primary to nonprimary auditory regions. The ability of this framework to capture arbitrary stimulus-response mappings while maintaining model interpretability leads to a better understanding of cortical processing of sensory signals.

Cisplatin is a widely used anti-cancer drug used to treat a variety of cancer types. One of the side effects of this life-saving drug is irreversible ototoxicity, resulting in permanent hearing loss in many patients. In order to understand why cisplatin is particularly toxic to the inner ear, we compared the hearing loss and cochlear uptake of cisplatin to that of two related drugs, carboplatin and oxaliplatin. These three drugs are similar in that each contains a core platinum atom; however, carboplatin and oxaliplatin are considered less ototoxic than cisplatin. We delivered these three drugs to mice using a 6-week cyclic drug administration protocol. We performed the experiment twice, once using equimolar concentrations of the drugs and once using concentrations of the drugs more proportional to those used in the clinic. For both concentrations, we detected a significant hearing loss caused by cisplatin and no hearing loss caused by carboplatin or oxaliplatin. Cochlear uptake of each drug was measured using inductively coupled plasma mass spectrometry (ICP-MS) to detect platinum. Cochlear platinum levels were highest in mice treated with cisplatin followed by oxaliplatin, while carboplatin was largely excluded from the cochlea. Even when the drug doses were increased, cochlear platinum remained low in mice treated with oxaliplatin or carboplatin. We also examined drug clearance from the inner ear by measuring platinum levels at 1 h and 24 h after drug administration. Our findings suggest that the reduced cochlear platinum we observed with oxaliplatin and carboplatin were not due to increased clearance of these drugs relative to cisplatin. Taken together, our data indicate that the differential ototoxicity among cisplatin, carboplatin, and oxaliplatin is attributable to differences in cochlear uptake of these three drugs.

Dopamine guides behavior and learning through pleasure, according to classic understanding. Dopaminergic neurons are traditionally thought to signal positive or negative prediction errors (PEs) when reward expectations are, respectively, exceeded or not matched. These signed PEs are quite different from the unsigned PEs, which report surprise during sensory processing. But mounting theoretical accounts from the predictive processing framework postulate that dopamine, as a neuromodulator, could potentially regulate the postsynaptic gain of sensory neurons, thereby scaling unsigned PEs according to their expected precision or confidence. Despite ample modeling work, the physiological effects of dopamine on the processing of surprising sensory information are yet to be addressed experimentally. In this study, we tested how dopamine modulates midbrain processing of unexpected tones. We recorded extracellular responses from the rat inferior colliculus to oddball and cascade sequences, before, during, and after the microiontophoretic application of dopamine or eticlopride (a D2-like receptor antagonist). Results demonstrate that dopamine reduces the net neuronal responsiveness exclusively to unexpected sensory input without significantly altering the processing of expected input. We conclude that dopaminergic projections from the thalamic subparafascicular nucleus to the inferior colliculus could encode the expected precision of unsigned PEs, attenuating via D2-like receptors the postsynaptic gain of sensory inputs forwarded by the auditory midbrain neurons. This direct dopaminergic modulation of sensory PE signaling has profound implications for both the predictive coding framework and the understanding of dopamine function.

Listeners differ in their ability to attend to a speech stream in the presence of a competing sound. Differences in speech intelligibility in noise cannot be fully explained by the hearing ability which suggests the involvement of additional cognitive factors. A better understanding of the temporal fluctuations in the ability to pay selective auditory attention to a desired speech stream may help in explaining these variabilities. In order to better understand the temporal dynamics of selective auditory attention, we developed an online auditory attention decoding (AAD) processing pipeline based on speech envelope tracking in the electroencephalogram (EEG). Participants had to attend to one audiobook story while a second one had to be ignored. Online AAD was applied to track the attention toward the target speech signal. Individual temporal attention profiles were computed by combining an established AAD method with an adaptive staircase procedure. The individual decoding performance over time was analyzed and linked to behavioral performance as well as subjective ratings of listening effort, motivation, and fatigue. The grand average attended speaker decoding profile derived in the online experiment indicated performance above chance level. Parameters describing the individual AAD performance in each testing block indicated significant differences in decoding performance over time to be closely related to the behavioral performance in the selective listening task. Further, an exploratory analysis indicated that subjects with poor decoding performance reported higher listening effort and fatigue compared to good performers. Taken together our results show that online EEG based AAD in a complex listening situation is feasible. Adaptive attended speaker decoding profiles over time could be used as an objective measure of behavioral performance and listening effort. The developed online processing pipeline could also serve as a basis for future EEG based near real-time auditory neurofeedback systems.

Brain injury affecting the isocortical frontal cortex is a common pathological occurrence. Many patients report severe deficits to functions of daily living. However, there is a variable degree of motor recovery that occurs with some individuals recovering astounding degrees of motor recovery while others have not. This variability has led researchers into investigating the possible mechanisms for this variability. Recently, several non-human primate studies have shed light on the possibility of spared, ipsilesional motor area taken over the lost function to the damaged cortex. Unfortunately, these studies have focused on long-term adaption ranging from 5months to one year post injury. In this present study, we are the first use rigorous stereological quantification to show that significant neuroplastic changes in the form of changes to neuroanatomical connections between distant cortical area occurs at a very early time point of 4 weeks post injury. Much like the Dancause study in 2005, we found that ishemic damage to the distal forelimb area (DFL) of the primary motor cortex (M1) induced plastic changes between the DFL of the ventral premotor cortex (PMv) and area 1/2 of the somatosensory cortex. Indeed, we found a nearly 2 fold increase in the number of boutons between PMV and area 1/2. Additionally, labeled fibers from PMv change direction from their normal termination within M1 and traveled in a ventral posterior direction toward the somatosensory cortex. Also of interest, several labeled fibers actually traveled through the glial scar of M1 toward the somatosensory cortex. These data demonstrate that a massive neuroplastic response has occurred following an ischemic insult to the DFL of M1. These data may suggest that the brain may be undergoing an attempt to re-establish a degree of motor and or sensory control to compensate for the lost function due to the injury.

The objective of this study was to explore the molecular mechanisms of acute noise-induced hearing loss and recovery of steady-state noise-induced hearing loss using miniature pigs. We used miniature pigs exposed to white noise at 120 dB (A) as a model. Auditory brainstem response (ABR) measurements were made before noise exposure, 1 day and 7 days after noise exposure. Proteomic Isobaric Tags for Relative and Absolute Quantification (iTRAQ) was used to observe changes in proteins of the miniature pig inner ear following noise exposure. Western blot and immunofluorescence were performed for further quantitative and qualitative analysis of proteomic changes. The average ABR-click threshold of miniature pigs before noise exposure, 1 day and 7 days after noise exposure, were 39.4 dB SPL, 67.1 dB SPL, and 50.8 dB SPL, respectively. In total, 2,158 proteins were identified using iTRAQ. Both gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) database analyses showed that immune and metabolic pathways were prominently involved during the impairment stage of acute hearing loss. During the recovery stage of acute hearing loss, most differentially expressed proteins were related to cholesterol metabolism. Western blot and immunofluorescence showed accumulation of reactive oxygen species and nuclear translocation of NF- κ B (p65) in the hair cells of miniature pig inner ears during the acute hearing loss stage after noise exposure. Nuclear translocation of NF- κ B (p65) may be associated with overexpression of downstream inflammatory factors. Apolipoprotein (Apo) A1 and Apo E were significantly upregulated during the recovery stage of hearing loss and may be related to activation of cholesterol metabolic pathways. This is the first study to use proteomics analysis to analyze the molecular mechanisms of acute noise-induced hearing loss and its recovery in a large animal model (miniature pigs). Our results showed that activation of metabolic, inflammatory, and innate immunity pathways may be involved in acute noise-induced hearing loss, while cholesterol metabolic pathways may play an important role in recovery of hearing ability following noise-induced hearing loss.

The brain combines information from multiple sensory modalities to interpret the environment. Multisensory integration is often modeled by ideal Bayesian causal inference, a model proposing that perceptual decisions arise from a statistical weighting of information from each sensory modality based on its reliability and relevance to the observer’s task. However, ideal Bayesian causal inference fails to describe human behavior in a simultaneous auditory spatial discrimination task in which spatially aligned visual stimuli improve performance despite providing no information about the correct response. This work tests the hypothesis that humans weight auditory and visual information in this task based on their relative reliabilities, even though the visual stimuli are task-uninformative, carrying no information about the correct response, and should be given zero weight. Listeners perform an auditory spatial discrimination task with relative reliabilities modulated by the stimulus durations. By comparing conditions in which task-uninformative visual stimuli are spatially aligned with auditory stimuli or centrally located (control condition), listeners are shown to have a larger multisensory effect when their auditory thresholds are worse. Even in cases in which visual stimuli are not task-informative, the brain combines sensory information that is scene-relevant, especially when the task is difficult due to unreliable auditory information.

Speech motor control requires integration of sensory and motor information. Bidirectional communication between frontal and auditory cortices is crucial for speech production, self-monitoring and motor control. We used cortical direct electrical stimulation (DES) to functionally dissect audio-motor interactions underlying speech production and motor control. Eleven neurosurgical patients performed a visually cued vocal task in which a short auditory feedback perturbation was introduced during vocalization. We evaluated the effect of DES on vocal initiation, voice fundamental frequency (F0) and feedback-dependent motor control. DES of frontal sites modulated vocal onset latencies. Stimulation of different inferior frontal gyrus sites elicited either shortening or prolongation of vocal latencies. DES distinctly modulated voice F0 at different vocalization stages. Frontal and temporal areas played an important role in setting voice F0 in the first 250 ms of an utterance, while Heschl’s gyrus was involved later when auditory input is available for self-monitoring. Vocal responses to pitch-shifted auditory feedback were mostly reduced by DES of non-core auditory cortices. Overall, we demonstrate that vocal planning and initiation are driven by frontal cortices, while feedback-dependent control relies predominantly on non-core auditory cortices. Our findings represent direct evidence of the role played by different auditory and frontal regions in vocal motor control.