Search

Before hearing onset (postnatal day 12 in mice), inner hair cells (IHCs) spontaneously fire action potentials, thereby driving pre-sensory activity in the ascending auditory pathway. The rate of IHC action potential bursts is modulated by inner supporting cells (ISCs) of Kölliker's organ through the activity of the Ca

The current study examines the modulation of the motion-onset response based on the frequency-range of sound stimuli. Delayed motion-onset and stationary stimuli were presented in a free-field by sequentially activating loudspeakers on an azimuthal plane keeping the natural percept of externalized sound presentation. The sounds were presented in low- or high-frequency ranges and had different motion direction within each hemifield. Difference waves were calculated by contrasting the moving and stationary sounds to isolate the motion-onset responses. Analyses carried out at the peak amplitudes and latencies on the difference waves showed that the early part of the motion response (cN1) was modulated by the frequency range of the sounds with stronger amplitudes elicited by stimuli with high frequency range. Subsequent post hoc analysis of the normalized amplitude of the motion response confirmed the previous finding by excluding the possibility that the frequency range had an overall effect on the waveform, and showing that this effect was instead limited to the motion response. These results support the idea of a modular organization of the motion-onset response with the processing of primary sound motion characteristics being reflected in the early part of the response. Also, the article highlights the importance of specificity in auditory stimulus design.

Synaptic refinement and strengthening are activity dependent processes that establish orderly arranged cochleotopic maps throughout the central auditory system. The maturation of auditory brainstem circuits is guided by action potentials (APs) arising from the inner hair cells in the developing cochlea. The AP firing of developing central auditory neurons can be modulated by paracrine ATP signaling, as shown for the cochlear nucleus bushy cells and principal neurons in the medial nucleus of the trapezoid body. However, it is not clear whether neuronal activity may be specifically regulated with respect to the nuclear tonotopic position, i.e. sound frequency selectivity. Using slice recordings before hearing onset and in vivo recordings with iontophoretic drug applications after hearing onset we show that cell-specific purinergic modulation follows a precise tonotopic pattern in the ventral cochlear nucleus of developing gerbils. In high-frequency regions, ATP responsiveness diminished before hearing onset. In low-to-mid frequency regions, ATP modulation persisted after hearing onset in a subset of low-frequency bushy cells (CF

Sound information is transduced into graded receptor potential by cochlear hair cells and encoded as discrete action potentials of auditory nerve fibers. In the cochlear nucleus, auditory nerve fibers convey this information through morphologically distinct synaptic terminals onto bushy cells (BCs) and stellate cells (SCs) for processing of different sound features. With expanding use of transgenic mouse models, it is increasingly important to understand thein vivofunctional development of these neurons in mice. We characterized the maturation of spontaneous and acoustically evoked activity in BCs and SCs by acquiring single-unit juxtacellular recordings between hearing onset (P12) and young adulthood (P30) of anesthetized CBA/J mice. In both cell types, hearing sensitivity and characteristic frequency (CF) range are mostly adult-like by P14, consistent with rapid maturation of the auditory periphery. In BCs, however, some physiological features like maximal firing rate, dynamic range, temporal response properties, recovery from post-stimulus depression, first spike latency (FSL) and encoding of sinusoid amplitude modulation undergo further maturation up to P18. In SCs, the development of excitatory responses is even more prolonged, indicated by a gradual increase in spontaneous and maximum firing rates up to P30. In the same cell type, broadly tuned acoustically evoked inhibition is immediately effective at hearing onset, covering the low- and high-frequency flanks of the excitatory response area. Together, these data suggest that maturation of auditory processing in the parallel ascending BC and SC streams engages distinct mechanisms at the first central synapses that may differently depend on the early auditory experience.

Broca's region is composed of two adjacent cytoarchitectonic areas, 44 and 45, which have distinct connectivity to superior temporal and inferior parietal regions in both macaque monkeys and humans. The current study aimed to make use of prior knowledge of sulcal anatomy and resting-state functional connectivity, together with a novel visualization technique, to manually parcellate areas 44 and 45 in individual brains in vivo. One hundred and one resting-state functional magnetic resonance imaging datasets from the Human Connectome Project were used. Left-hemisphere surface-based correlation matrices were computed and visualized in brainGL. By observation of differences in the connectivity patterns of neighbouring nodes, areas 44 and 45 were manually parcellated in individual brains, and then compared at the group-level. Additionally, the manual labelling approach was compared with parcellation results based on several data-driven clustering techniques. Areas 44 and 45 could be clearly distinguished from each other in all individuals, and the manual segmentation method showed high test-retest reliability. Group-level probability maps of areas 44 and 45 showed spatial consistency across individuals, and corresponded well to cytoarchitectonic probability maps. Group-level connectivity maps were consistent with previous studies showing distinct connectivity patterns of areas 44 and 45. Data-driven parcellation techniques produced clusters with varying degrees of spatial overlap with the manual labels, indicating the need for further investigation and validation of machine learning cortical segmentation approaches. The current study provides a reliable method for individual-level cortical parcellation that could be applied to regions distinguishable by even the most subtle differences in patterns of functional connectivity.

Inhibition plays a crucial role in neural signal processing, shaping and limiting responses. In the auditory system, inhibition already modulates second order neurons in the cochlear nucleus, e.g. spherical bushy cells (SBCs). While the physiological basis of inhibition and excitation is well described, their functional interaction in signal processing remains elusive. Using a combination of in vivo loose-patch recordings, iontophoretic drug application, and detailed signal analysis in the Mongolian Gerbil, we demonstrate that inhibition is widely co-tuned with excitation, and leads only to minor sharpening of the spectral response properties. Combinations of complex stimuli and neuronal input-output analysis based on spectrotemporal receptive fields revealed inhibition to render the neuronal output temporally sparser and more reproducible than the input. Overall, inhibition plays a central role in improving the temporal response fidelity of SBCs across a wide range of input intensities and thereby provides the basis for high-fidelity signal processing. DOI: http://dx.doi.org/10.7554/eLife.19295.001, eLife digest In humans and other animals, small differences in the time at which a sound arrives at each ear are crucial for determining the location of the sound. Neurons in the first processing station of the brain – the cochlear nucleus – receive information about sounds (or “inputs”) from the ears. They then produce electrical signals that relay this information to other areas of the brain. Some of these inputs increase the activity of the neurons and so are known as “excitatory” inputs, while other “inhibitory” inputs decrease the activity of the neurons. The balance between these two inputs determines what information is passed to other parts of the brain, but it is not clear how these inputs interact. Keine, Rübsamen and Englitz studied electrical activity in the brains of Mongolian gerbils while being exposed to sounds with more natural properties than previously studied. The experiments reveal that inhibitory inputs play an important role in controlling the activity of neurons in the cochlear nucleus. By decreasing the neurons’ activity, inhibitory inputs allow these cells to respond to many different levels of sound, from very loud to very quiet. The experiments also show that excitatory and inhibitory inputs are triggered by similar sounds so that the two processes quickly balance each other. This means that the brain is equally able to work out where a sound is coming from regardless of whether it is loud or quiet. Further work is now needed to understand responses to natural sounds and to determine how experimentally removing the inhibitory inputs affects hearing. DOI: http://dx.doi.org/10.7554/eLife.19295.002

The neocortex is the most complex part of the mammalian brain and as such it has undergone tremendous expansion during evolution, especially in primates. The majority of neocortical neurons originate from distinct neural stem and progenitor cells (NPCs) located in the ventricular and subventricular zone (SVZ). Previous studies revealed that the SVZ thickness as well as the abundance and distribution of NPCs, especially that of basal radial glia (bRG), differ markedly between the lissencephalic rodent and gyrencephalic primate neocortex. The northern tree shrew (Tupaia belangeri) is a rat-sized mammal with a high brain to body mass ratio, which stands phylogenetically mid-way between rodents and primates. Our study provides – for the first time – detailed data on the presence, abundance and distribution of bRG and other distinct NPCs in the developing neocortex of the northern tree shrew (Tupaia belangeri). We show that the developing tree shrew neocortex is characterized by an expanded SVZ, a high abundance of Pax6+ NPCs in the SVZ, and a relatively high percentage of bRG at peak of upper-layer neurogenesis. We further demonstrate that key features of tree shrew neocortex development, e.g., the presence, abundance and distribution of distinct NPCs, are closer related to those of gyrencephalic primates than to those of ferret and lissencephalic rodents. Together, our study provides novel insight into the evolution of bRG and other distinct NPCs in the neocortex development of Euarchontoglires and introduces the tree shrew as a potential novel model organism in the area of human brain development and developmental disorders.

Perineuronal nets (PNs) are a unique and complex meshwork of specific extracellular matrix molecules that ensheath a subset of neurons in many regions of the central nervous system (CNS). PNs appear late in development and are supposed to restrict synaptic plasticity and to stabilize functional neuronal connections. PNs were further hypothesized to create a charged milieu around the neurons and thus, might directly modulate synaptic activity. Although PNs were first described more than 120 years ago, their exact functions still remain elusive. The purpose of the present review is to propose the nuclei of the auditory system, which are highly enriched in PN-wearing neurons, as particularly suitable structures to study the functional significance of PNs. We provide a detailed description of the distribution of PNs from the cochlear nucleus to the auditory cortex considering distinct markers for detection of PNs. We further point to the suitability of specific auditory neurons to serve as promising model systems to study in detail the contribution of PNs to synaptic physiology and also more generally to the functionality of the brain.

Key points The proteoglycan brevican is a major component of the extracellular matrix of perineuronal nets and is highly enriched in the perisynaptic space suggesting a role for synaptic transmission. We have introduced the calyx of Held in the auditory brainstem as a model system to study the impact of brevican on dynamics and reliability of synaptic transmission. In vivo extracellular single-unit recordings at the calyx of Held in brevican-deficient mice yielded a significant increase in the action potential (AP) transmission delay and a prolongation of pre- and postsynaptic APs. The changes in dynamics of signal transmission were accompanied by the reduction of presynaptic vGlut1 and ultrastructural changes in the perisynaptic space. These data show that brevican is an important mediator of fast synaptic transmission at the calyx of Held. Abstract The extracellular matrix is an integral part of the neural tissue. Its most conspicuous manifestation in the brain are the perineuronal nets (PNs) which surround somata and proximal dendrites of distinct neuron types. The chondroitin sulfate proteoglycan brevican is a major component of PNs. In contrast to other PN-comprising proteoglycans (e.g. aggrecan and neurocan), brevican is mainly expressed in the perisynaptic space closely associated with both the pre- and postsynaptic membrane. This specific localization prompted the hypothesis that brevican might play a role in synaptic transmission. In the present study we specifically investigated the role of brevican in synaptic transmission at a central synapse, the calyx of Held in the medial nucleus of the trapezoid body, by the use of in vivo electrophysiology, immunohistochemistry, biochemistry and electron microscopy. In vivo extracellular single-unit recordings were acquired in brevican-deficient mice and the dynamics and reliability of synaptic transmission were compared to wild-type littermates. In knockout mice, the speed of pre-to-postsynaptic action potential (AP) transmission was reduced and the duration of the respective pre- and postsynaptic APs increased. The reliability of signal transmission, however, was not affected by the lack of brevican. The changes in dynamics of signal transmission were accompanied by the reduction of (i) presynaptic vGlut1 and (ii) the size of subsynaptic cavities. The present results suggest an essential role of brevican for the functionality of high-speed synaptic transmission at the calyx of Held.

Please find the peer-reviewed publisher version linked below.Signal processing in the auditory brainstem is based on an interaction of neuronal excitation and inhibition. To date, we have incomplete knowledge of how the dynamic interplay of both contributes to the processing power and temporal characteristics of signal coding. The spherical bushy cells (SBCs) of the anteroventral cochlear nucleus (AVCN) receive their primary excitatory input through auditory nerve fibers via large, axosomatic synaptic terminals called the endbulbs of Held and by additional, acoustically driven inhibitory inputs. SBCs provide the input to downstream nuclei of the brainstem sound source localization circuitry, such as the medial and lateral superior olive, which rely on temporal precise inputs. In this study, we used juxtacellular recordings in anesthetized Mongolian gerbils to assess the effect of acoustically evoked inhibition on the SBCs input-output function and on temporal precision of SBC spiking. Acoustically evoked inhibition proved to be strong enough to suppress action potentials (APs) of SBCs in a stimulus-dependent manner. Inhibition shows slow onset and offset dynamics and increasing strength at higher sound intensities. In addition, inhibition decreases the rising slope of the EPSP and prolongs the EPSP-to-AP transition time. Both effects can be mimicked by iontophoretic application of glycine. Inhibition also improves phase locking of SBC APs to low-frequency tones by acting as a gain control to suppress poorly timed EPSPs from generating postsynaptic APs to maintain precise SBC spiking across sound intensities. The present data suggest that inhibition substantially contributes to the processing power of second-order neurons in the ascending auditory system.

Neuronal inhibition is crucial for temporally precise and reproducible signaling in the auditory brainstem. We showed previously (Keine et al., 2016) that for various synthetic stimuli, spherical bushy cell (SBC) activity in the Mongolian gerbil is rendered sparser and more reliable by subtractive inhibition. Employing environmental stimuli, we demonstrate here that the inhibitory gain control becomes even more effective, keeping stimulated response rates equal to spontaneous ones. However, what are the costs of this modulation? We performed dynamic stimulus reconstructions based on neural population responses for auditory nerve (ANF) input and SBC output to assess the influence of inhibition on signal representation. Compared to ANFs, reconstructions of natural stimuli based on SBC responses were temporally more precise, but the match between acoustic and represented signal decreased. Hence, for natural sounds, inhibition at SBCs plays an even stronger role in achieving sparse and reproducible neuronal activity, while compromising general signal representation., This article has been published in eLife on September 25, 2017 [DOI: 10.7554/eLife.29639]

Auditory processing disorder (APD) is defined as a processing deficit in the auditory modality and spans multiple processes. To date, APD diagnosis is mostly based on the utilization of speech material. Adequate nonspeech tests that allow differentiation between an actual central hearing disorder and related disorders such as specific language impairments are still not adequately available. In the present study, 84 children between 6 and 17 years of age (clinical group), referred to three audiological centers for APD diagnosis, were evaluated with standard audiological tests and additional auditory discrimination tests. Latter tests assessed the processing of basic acoustic features at two different stages of the ascending central auditory system: (1) auditory brainstem processing was evaluated by quantifying interaural frequency, level, and signal duration discrimination (interaural tests). (2) Diencephalic/telencephalic processing was assessed by varying the same acoustic parameters (plus signals with sinusoidal amplitude modulation), but presenting the test signals in conjunction with noise pulses to the contralateral ear (dichotic(signal/noise) tests). Data of children in the clinical group were referenced to normative data obtained from more than 300 normally developing healthy school children. The results in the audiological and the discrimination tests diverged widely. Of the 39 children that were diagnosed with APD in the audiological clinic, 30 had deficits in auditory performance. Even more alarming was the fact that of the 45 children with a negative APD diagnosis, 32 showed clear signs of a central hearing deficit. Based on these results, we suggest revising current diagnostic procedure to evaluate APD in order to more clearly differentiate between central auditory processing deficits and higher-order (cognitive and/or language) processing deficits.

Similarities have been observed in the localization of the final position of moving visual and moving auditory stimuli: Perceived endpoints that are judged to be farther in the direction of motion in both modalities likely reflect extrapolation of the trajectory, mediated by predictive mechanisms at higher cognitive levels. However, actual comparisons of the magnitudes of displacement between visual tasks and auditory tasks using the same experimental setup are rare. As such, the purpose of the present free-field study was to investigate the influences of the spatial location of motion offset, stimulus velocity, and motion direction on the localization of the final positions of moving auditory stimuli (Experiment 1 and 2) and moving visual stimuli (Experiment 3). To assess whether auditory performance is affected by dynamically changing binaural cues that are used for the localization of moving auditory stimuli (interaural time differences for low-frequency sounds and interaural intensity differences for high-frequency sounds), two distinct noise bands were employed in Experiments 1 and 2. In all three experiments, less precise encoding of spatial coordinates in paralateral space resulted in larger forward displacements, but this effect was drowned out by the underestimation of target eccentricity in the extreme periphery. Furthermore, our results revealed clear differences between visual and auditory tasks. Displacements in the visual task were dependent on velocity and the spatial location of the final position, but an additional influence of motion direction was observed in the auditory tasks. Together, these findings indicate that the modality-specific processing of motion parameters affects the extrapolation of the trajectory.

The medial nucleus of the trapezoid body (MNTB) is a vital structure of sound localization circuits in the auditory brainstem. Each principal cell of MNTB is contacted by a very large presynaptic glutamatergic terminal, the calyx of Held. The MNTB principal cells themselves are surrounded by extracellular matrix components forming prominent perineuronal nets (PNs). Throughout the CNS, PNs, which form lattice-like structures around the somata and proximal dendrites, are associated with distinct types of neurons. PNs are highly enriched in hyaluronan and chondroitin sulfate proteoglycans therefore providing a charged surface structure surrounding the cell body and proximal neurites of these neurons. The localization and composition of PNs have lead investigators to a number of hypotheses about their functions including: creating a specific extracellular ionic milieu around these neurons, stabilizing synapses, and influencing the outgrowth of axons. However, presently the precise functions of PNs are still quite unclear primarily due to the lack of an ideal experimental model system that is highly enriched in PNs and in which the synaptic transmission properties can be precisely measured. The MNTB principal cells could offer such a model, since they have been extensively characterized electrophysiologically. However, extracellular matrix (ECM) in these neurons has not yet been precisely detailed. The present study gives a detailed examination of the ECM organization and structural differences in PNs of the mouse MNTB. The different PN components and their distribution pattern are scrutinized throughout the MNTB. The data are complemented by electron microscopic investigations of the unique ultrastructural localization of PN-components and their interrelation with distinct pre- and postsynaptic MNTB cell structures. Therefore, we believe this work identifies the MNTB as an ideal system for studying PN function.

Aim The aim of this study was to characterize an alternative treatment for dilated cardiomyopathy (DCM) using a novel cardiac biological assist device created from engineered heart tissue (EHT). Methods and results The EHTs were constructed in vitro from matrigel, collagen, and neonatal rat cardiomyocytes as small ring-like spontaneously contracting devices. DCM was induced in 50 rats by 6 weeks doxorubicin treatment (2.5 mg/kg/week). After 38 drug-free days, rats underwent either implantation of EHT (DCM-EHT, n = 13), which was sutured around the ventricles, or sham operation (DCM-Sham, n = 12). Eleven untreated healthy rats served as the control group. Rats were investigated using a Millar catheter for pressure–volume loop recording, and by echocardiography 30 days after operation. Thereafter, the hearts were excised and investigated functionally, histologically, and biochemically. Doxorubicin led to the development of DCM with reduced fractional shortening (FS), reduced dP/dtmax, increased systolic and diastolic LV diameters, and reduced response to dobutamine. In DCM-Sham, these changes were further enhanced, while in DCM-EHT we found improved FS, dP/dtmax, and dobutamine responsiveness. In isolated hearts, electrical multielectrode mapping revealed that EHT was electrically activated synchronously to the recipient heart. Histologically, we found increased vascularization in the EHT and the recipient heart, and EHT vessels connected to the coronary system. Conclusions Implantation of EHT improves LV performance in rats with doxorubicin-induced DCM.

Despite the apparent robustness of language learning in humans, a large number of children still fail to develop appropriate language skills despite adequate means and opportunity. Most cases of language impairment have a complex etiology, with genetic and environmental influences. In contrast, we describe a three-generation German family who present with an apparently simple segregation of language impairment. Investigations of the family indicate auditory processing difficulties as a core deficit. Affected members performed poorly on a nonword repetition task and present with communication impairments. The brain activation pattern for syllable duration as measured by event-related brain potentials showed clear differences between affected family members and controls, with only affected members displaying a late discrimination negativity. In conjunction with psychoacoustic data showing deficiencies in auditory duration discrimination, the present results indicate increased processing demands in discriminating syllables of different duration. This, we argue, forms the cognitive basis of the observed language impairment in this family. Genome-wide linkage analysis showed a haplotype in the central region of chromosome 12 which reaches the maximum possible logarithm of odds ratio (LOD) score and fully co-segregates with the language impairment, consistent with an autosomal dominant, fully penetrant mode of inheritance. Whole genome analysis yielded no novel inherited copy number variants strengthening the case for a simple inheritance pattern. Several genes in this region of chromosome 12 which are potentially implicated in language impairment did not contain polymorphisms likely to be the causative mutation, which is as yet unknown.

Spherical bushy cells (SBCs) in the anteroventral cochlear nucleus respond to acoustic stimulation with discharges that precisely encode the phase of low-frequency sound. The accuracy of spiking is crucial for sound localization and speech perception. Compared to the auditory nerve input, temporal precision of SBC spiking is improved through theengagement of acoustically evoked inhibition. Recently, the inhibition was shown to be less precise than previously understood. It shifts from predominantly glycinergic to synergistic GABA/glycine transmission in an activity-dependent manner. Concurrently, the inhibition attains a tonic character through temporal summation. The present study provides a comprehensive understanding of the mechanisms underlying this slow inhibitory input.We performed whole-cell voltage clamp recordings on SBCs from juvenile Mongolian gerbils and recorded evoked inhibitory postsynaptic currents (IPSCs) at physiological rates. The data reveal activity-dependent IPSC kinetics, i.e., the decay is slowed with increased input rates or recruitment. Lowering the release probability yielded faster decay kinetics of the single- and short train-IPSCs at 100 Hz, suggesting that transmitter quantity plays an important role in controlling the decay. Slow transmitter clearance from the synaptic cleft caused prolonged receptor binding and, in the case of glycine, spillover to nearby synapses. The GABAergic component prolonged the decay by contributing to the asynchronous vesicle release depending on the input rate. Hence, the different factors controlling the amount of transmitters in the synapse jointly slow the inhibition during physiologically relevant activity. Taken together, the slow time course is predominantly determined by the receptor kinetics and transmitter clearance during short stimuli, whereas long duration or high frequency stimulation additionally engage asynchronous release to prolong IPSCs.[This Document is Protected by copyright and was first published by Frontiers. All rights reserved, it is reproduced with permission.]

eNeuro / Society for Neuroscience 3(5), e0186-16.2016 (2016). doi:10.1523/ENEURO.0186-16.2016, Published by Society for Neuroscience, Washington, DC

In the developing nervous system, spontaneous neuronal activity arises independently of experience or any environmental input. This activity may play a major role in axonal pathfinding, refinement of topographic maps, dendritic morphogenesis, and the segregation of axonal terminal arbors. In the auditory system, endogenously released ATP in the cochlea activates inner hair cells to trigger bursts of action potentials (APs), which are transferred to the central auditory system. Here we show the modulatory role of purinergic signaling beyond the cochlea, i.e., the developmentally regulated and cell-type-specific depolarizing effects on auditory brainstem neurons of Mongolian gerbil. We assessed the effects of P2X receptors (P2XRs) on neuronal excitability from prehearing to early stages of auditory signal processing. Our results demonstrate that in neurons expressing P2XRs, extracellular ATP can evoke APs in sync with Ca(2+) signals. In cochlear nucleus (CN) bushy cells, ATP increases spontaneous and also acoustically evoked activity in vivo, but these effects diminish with maturity. Moreover, ATP not only augmented glutamate-driven firing, but it also evoked APs in the absence of glutamatergic transmission. In vivo recordings also revealed that endogenously released ATP in the CN contributes to neuronal firing activity by facilitating AP generation and prolonging AP duration. Given the enhancing effect of ATP on AP firing and confinement of P2XRs to certain auditory brainstem nuclei, and to distinct neurons within these nuclei, it is conceivable that purinergic signaling plays a specific role in the development of neuronal brainstem circuits.

Motion perception can be altered by information received through multiple senses. So far, the interplay between the visual and the auditory modality in peripheral motion perception is scarcely described. The present free-field study investigated audio-visual motion perception for different azimuthal trajectories in space. To disentangle effects related to crossmodal interactions (the influence of one modality on signal processing in another modality) and multisensory integration (binding of bimodal streams), we manipulated the subjects' attention in two experiments on a single set of moving audio-visual stimuli. Acoustic and visual signals were either congruent or spatially and temporally disparate at motion offset. (i) Crossmodal interactions were studied in a selective attention task. Subjects were instructed to attend to either the acoustic or the visual stream and to indicate the perceived final position of motion. (ii) Multisensory integration was studied in a divided attention task in which subjects were asked to report whether they perceived unified or separated audio-visual motion offsets. The results indicate that crossmodal interactions in motion perception do not depend on the integration of the audio-visual stream. Furthermore, in the crossmodal task, both visual and auditory motion perception were susceptible to modulation by irrelevant streams, provided that temporal disparities did not exceed a critical range. Concurrent visual streams modulated auditory motion perception in the central field, whereas concurrent acoustic streams attracted visual motion information in the periphery. Differential abilities between the visual and auditory system when attempting to accurately track positional information along different trajectories account for the observed biasing effects.

This study represents the first effort to obtain a comprehensive library of adult Mongolian gerbil (Meriones unguiculatus) vocalizations recorded in a variety of behavioural contexts. In Phase I of the study, a gerbil colony was introduced into a seminatural enclosure and allowed to breed naturally over an observation period of 19 months. During this period, detailed observations of gerbil social and vocal behaviour were made. In Phase II, this knowledge was used to stage natural behavioural scenarios among adult gerbils in which high-quality recordings of vocalizations could be obtained, and the spectro-temporal properties of these vocalizations analysed. Calls generally occurred in interactive social situations, such as same-sex aggression, mating, food dispute, alarm, and disturbance by conspecifics. Additionally, brief ultrasonic calls were associated with investigation of a new setting and were named ‘contact calls’. Vocalizations were classified by behavioural context and analysed with respect to spectral and temporal characteristics. Calls encompassed a broad range of frequencies (approx. 3-45 kHz); most calls possessed significant energy at two or more harmonics in addition to the fundamental frequency. Calls generally lasted approx. 4-500 ms and were emitted in sequences of 3-20 variants with silent intervals. Such natural call series had significant low-frequency AM content below 8 Hz. Calls within an individual behavioural class had substantial variability in both spectral and temporal properties, but were significantly different from all other call classes in one or more of average fundamental frequency, frequency sweep range, duration, or frequency sweep direction.

The development of the auditory system has received increasing attention since the mechanisms of patterned, spontaneous activity in prehearing mammals were discovered. This early activity originates in the cochlea and is assumed to be of importance for the establishment and refinement of synaptic connections in the auditory system. In the present study we investigate synaptic transmission and its interplay with spontaneous discharges in the developing auditory system. We used the calyx of Held as a model system, where this question can be investigatedin vivoover a broad range of ages [postnatal day 8 (P8)–P28]. To precisely quantify the timing and reliability of synaptic transmission, we developed a novel fitting approach which decomposes the extracellularly recorded signal into its presynaptic and postsynaptic components. In prehearing mice, we found signal transmission to be unreliable, with high variability in the transmission delay and in the amplitude of postsynaptic components. These timing and amplitude changes were strongly correlated with the preceding activity. Around hearing onset (P12–P14), the properties of signal transmission converged to the adult-like state which was characterized by high transmission reliability as well as high consistency in timing and amplitude. Although activity-dependent depression was still found in action potentials, EPSP depression no longer played a prominent role. In conclusion, the maturation of synaptic transmission at the calyx of Held seems to be precisely timed to achieve its adult potential by the time acoustically evoked signal processing commences.

Non-technical summary Voltage-gated potassium channels control excitability throughout the nervous system and their dysfunction (or mutation) is associated with epilepsy and movement disorders. Loss of the insulating myelin sheath around nerve fibres (axons) in multiple sclerosis causes transmission failure by exposing too many potassium channels. We show that too few potassium channels also causes errors in information transmission as measured by the ability to localize the source of a sound, and suggests a general role for potassium channels along myelinated nerve fibres. These results give insights into normal neuronal function and into neurodegenerative disease mechanisms for patients with ataxia and multiple sclerosis.Voltage-gated potassium (Kv) channels containing Kv1.1 subunits are strongly expressed in neurons that fire temporally precise action potentials (APs). In the auditory system, AP timing is used to localize sound sources by integrating interaural differences in time (ITD) and intensity (IID) using sound arriving at both cochleae. In mammals, the first nucleus to encode IIDs is the lateral superior olive (LSO), which integrates excitation from the ipsilateral ventral cochlear nucleus and contralateral inhibition mediated via the medial nucleus of the trapezoid body. Previously we reported that neurons in this pathway show reduced firing rates, longer latencies and increased jitter in Kv1.1 knockout (Kcna1-/-) mice. Here, we investigate whether these differences have direct impact on IID processing by LSO neurons. Single-unit recordings were made from LSO neurons of wild-type (Kcna1+/+) and from Kcna1-/- mice. IID functions were measured to evaluate genotype-specific changes in integrating excitatory and inhibitory inputs. In Kcna1+/+ mice, IID sensitivity ranged from +27 dB (excitatory ear more intense) to -20 dB (inhibitory ear more intense), thus covering the physiologically relevant range of IIDs. However, the distribution of IID functions in Kcna1-/- mice was skewed towards positive IIDs, favouring ipsilateral sound positions. Our computational model revealed that the reduced performance of IID encoding in the LSO of Kcna1-/- mice is mainly caused by a decrease in temporal fidelity along the inhibitory pathway. These results imply a fundamental role for Kv1.1 in temporal integration of excitation and inhibition during sound source localization.

The phase of low-frequency sinusoids is encoded in phase-coupled discharges of spherical bushy cells (SBCs) of the anteroventral cochlear nucleus and transmitted to the medial superior olive, where binaural input-coincidence is used for processing of sound source localization. SBCs are innervated by auditory nerve fibers through large, excitatory synapses (endbulbs of Held) and by inhibitory inputs, which effectively reduce SBC discharge rates. Here we monitor presynaptic potentials of endbulb-terminals and postsynaptic spikes of SBCs in extracellular single unit recordings in vivo. We compare postsynaptic phase-coupling of SBCs and their presynaptic immediate auditory nerve input. In all but one SBC discharge rates at the characteristic frequency were reduced pre-to-postsynaptically and phase-coupling accuracy was increased in one-third of them. We investigated the contribution of systemic inhibition on spike timing in SBCs by iontophoretic application of glycine- and GABA-receptor antagonists (strychnine, bicuculline). Discharge rate increased in one-third of the units during antagonist application, which was accompanied by a deterioration of phase-coupling accuracy in half of those units. These results suggest that the phase-coupling accuracy is improved in a subpopulation of SBCs during transmission from the auditory nerve to the SBCs by reduction of spike rates.

The representation of acoustic stimuli in the brainstem forms the basis for higher auditory processing. While some characteristics of this representation (e.g. tuning curve) are widely accepted, it remains a challenge to predict the firing rate at high temporal resolution in response to complex stimuli. In this study we explore models for in vivo, single cell responses in the medial nucleus of the trapezoid body (MNTB) under complex sound stimulation. We estimate a family of models, the multilinear models, encompassing the classical spectrotemporal receptive field and allowing arbitrary input-nonlinearities and certain multiplicative interactions between sound energy and its short-term auditory context. We compare these to models of more traditional type, and also evaluate their performance under various stimulus representations. Using the context model, 75% of the explainable variance could be predicted based on a cochlear-like, gamma-tone stimulus representation. The presence of multiplicative contextual interactions strongly reduces certain inhibitory/suppressive regions of the linear kernels, suggesting an underlying nonlinear mechanism, e.g. cochlear or synaptic suppression, as the source of the suppression in MNTB neuronal responses. In conclusion, the context model provides a rich and still interpretable extension over many previous phenomenological models for modeling responses in the auditory brainstem at submillisecond resolution.

Glycine is an inhibitory neurotransmitter activating a chloride conductance in the mammalian CNS. In vitro studies from brain slices revealed a novel presynaptic site of glycine action in the medial nucleus of the trapezoid body (MNTB) which increases the release of the excitatory transmitter glutamate from the calyx of Held. Here, we investigate the action of glycine on action potential firing of single MNTB neurons from the gerbil under acoustic stimulation in vivo. Iontophoretic application of the glycine receptor antagonist strychnine caused a significant decrease in spontaneous and sound-evoked firing rates throughout the neurons' excitatory response areas, with the largest changes at the respective characteristic frequency (CF). The decreased firing rate was accompanied by longer and more variable onset latencies of sound-evoked responses. Outside the neurons' excitatory response areas, firing rates increased during the application of strychnine due to a reduction of inhibitory sidebands, causing a broadening of frequency tuning. These results indicate that glycine enhances the efficacy for on-CF stimuli, while simultaneously suppressing synaptic transmission for off-CF stimuli. These in vivo results provide evidence of multiple excitatory and inhibitory glycine effects on the same neuronal population in the mature mammalian CNS.

The neuronal representation of acoustic amplitude modulations is an important prerequisite for understanding the processing of natural sounds. We investigated this representation in the medial nucleus of the trapezoid body (MNTB) of the Mongolian gerbil using sinusoidal amplitude modulations (SAM). Depending on the SAM's carrier frequency (f(C)) MNTB cells either increase or decrease their discharge rates, indicating underlying excitatory and inhibitory/suppressive mechanisms. As natural sounds typically are composed of multiple spectral components we investigated how stimuli containing two spectral components are represented in the MNTB, especially when they have opposing effects on the discharge rate. Three conditions were compared: SAM stimuli (1) with rate-increasing f(C), (2) with rate-increasing f(C) and an additional unmodulated rate-decreasing pure tone, and (3) with rate-decreasing f(C) and an unmodulated, rate-increasing pure tone. We found that responses under all three conditions showed comparable strength of phase-locking. Adding a rate-decreasing tone to a rate-increasing SAM increased phase-locking for modulation frequencies (f(AM)) of < or = 600 Hz. A comparison of two possible coding strategies--phase-locking vs. envelope reproduction--indicates that both strategies are realized to different degrees depending on the f(AM). We measured latencies for following modulations in rate-increasing and rate-decreasing SAMs using a modified reverse correlation approach. Although latencies varied between 2.5 and 5 ms between cells, a decrease in rate consistently followed an increase in rate with a delay of about 0.2 ms in each cell. These results suggest a temporally precise representation of rate-increasing and rate-decreasing stimuli at the level of the MNTB during dynamic stimulation.

Antibodies directed against calcium-binding proteins (CaBPs) parvalbumin, calbindin-D28k and calretinin were used as neuronal markers to identify and characterize different principal cell types in the mammalian cochlear nucleus. For this purpose, double immunofluorescence labeling and the combination of CaBP-labeling with pan-neuronal markers were applied to analyze the CaBPs distribution in neurons of the cochlear nucleus (CN) of the Mongolian gerbil (Meriones unguiculatus) and the gray short-tailed opossum (Monodelphis domestica). Despite of the fact, that these two mammalian species are not closely related, principal cell types in the CN of the two species showed many corresponding morphological features and similarities in immunolabeling of the CaBPs. Parvalbumin seems not to be suited as a differential neuronal marker in the CN since it is expressed by almost all neurons. In contrast, calbindin and calretinin were more restricted to specific cell types and showed a mostly complementary labeling pattern. As one of the most interesting findings, calbindin and calretinin were predominantly found in subpopulations of globular bushy cells and octopus cells in the ventral CN. Such a neuron-specific CaBP-expression in subpopulations of morphologically defined cell types argues for a more refined classification of CN cell types in Meriones and Monodelphis. Additionally, other cell types (cartwheel cells, unipolar brush cells, fusiform cells) were marked with calbindin or calretinin as well. Calretinin staining was predominantly observed in auditory nerve fibers and their endings including endbulbs of Held in Meriones. Spherical bushy cells showed a different calretinin-immunolabeling in Meriones and Monodelphis. This species-specific difference may be related to adaptive differences in auditory function.

Localization of sounds by the auditory system is based on the analysis of three sources of information: interaural level differences (ILD, caused by an attenuation of the sound as it travels to the more distant ear), interaural time differences (ITD, caused by the additional amount of time it takes for the sound to arrive at the more distant ear), and spectral cues (caused by direction-specific spectral filter properties of the pinnae). Although in a number of psychophysiological studies cortical processes of ITD and ILD analysis were investigated, there is hitherto no evidence on the cortical processing of spectral cues for sound localization. The objective of the present experiment was to test whether it is possible to observe electrophysiological correlates of sound localization based on spectral cues. In an auditory oddball experiment, 80 ms of broadband noise from varying free field locations were presented to inattentive participants. Mismatch negativities (MMNs) were observed for pairs of standards and location deviants located symmetrically with respect to the interaural axis. As interaural time and level differences are identical for such pairs of sounds, the observed MMNs most likely reflect cognitive processes of sound localization utilizing the spectral filter properties of the pinnae. MMN latencies suggest that sound localization based on spectral cues is slower than ITD- or ILD-based localization.

The proteoglycan brevican is a major component of the extracellular matrix of perineuronal nets and is highly enriched in the perisynaptic space suggesting a role for synaptic transmission. We have introduced the calyx of Held in the auditory brainstem as a model system to study the impact of brevican on dynamics and reliability of synaptic transmission. In vivo extracellular single-unit recordings at the calyx of Held in brevican-deficient mice yielded a significant increase in the action potential (AP) transmission delay and a prolongation of pre- and postsynaptic APs. The changes in dynamics of signal transmission were accompanied by the reduction of presynaptic vGlut1 and ultrastructural changes in the perisynaptic space. These data show that brevican is an important mediator of fast synaptic transmission at the calyx of Held.The extracellular matrix is an integral part of the neural tissue. Its most conspicuous manifestation in the brain are the perineuronal nets (PNs) which surround somata and proximal dendrites of distinct neuron types. The chondroitin sulfate proteoglycan brevican is a major component of PNs. In contrast to other PN-comprising proteoglycans (e.g. aggrecan and neurocan), brevican is mainly expressed in the perisynaptic space closely associated with both the pre- and postsynaptic membrane. This specific localization prompted the hypothesis that brevican might play a role in synaptic transmission. In the present study we specifically investigated the role of brevican in synaptic transmission at a central synapse, the calyx of Held in the medial nucleus of the trapezoid body, by the use of in vivo electrophysiology, immunohistochemistry, biochemistry and electron microscopy. In vivo extracellular single-unit recordings were acquired in brevican-deficient mice and the dynamics and reliability of synaptic transmission were compared to wild-type littermates. In knockout mice, the speed of pre-to-postsynaptic action potential (AP) transmission was reduced and the duration of the respective pre- and postsynaptic APs increased. The reliability of signal transmission, however, was not affected by the lack of brevican. The changes in dynamics of signal transmission were accompanied by the reduction of (i) presynaptic vGlut1 and (ii) the size of subsynaptic cavities. The present results suggest an essential role of brevican for the functionality of high-speed synaptic transmission at the calyx of Held.

Auditory spatial processing is an important ability in everyday life and allows the processing of omnidirectional information. In this review, we report and compare data from psychoacoustic and electrophysiological experiments on sound localisation accuracy and auditory spatial discrimination in infants, children, and young and older adults. The ability to process auditory spatial information changes over lifetime: the perception of the acoustic space develops from an initially imprecise representation in infants and young children to a concise representation of spatial positions in young adults and the respective performance declines again in older adults. Localisation accuracy shows a strong deterioration in older adults, presumably due to declined processing of binaural temporal and monaural spectro-temporal cues. When compared to young adults, the thresholds for spatial discrimination were strongly elevated both in young children and older adults. Despite the consistency of the measured values the underlying causes for the impaired performance might be different: (1) the effect is due to reduced cognitive processing ability and is thus task-related; (2) the effect is due to reduced information about the auditory space and caused by declined processing in auditory brain stem circuits; and (3) the auditory space processing regime in young children is still undergoing developmental changes and the interrelation with spatial visual processing is not yet established. In conclusion, we argue that for studying auditory space processing over the life course, it is beneficial to investigate spatial discrimination ability instead of localisation accuracy because it more reliably indicates changes in the processing ability.

Frontiers in neural circuits 9, - (2015). doi:10.3389/fncir.2015.00014, Published by Frontiers Research Foundation, Lausanne

We report evidence for a context- and not stimulus-dependent functional asymmetry in the left and right human auditory midbrain, thalamus, and cortex in response to monaural sounds. Neural activity elicited by left- and right-ear stimulation was measured simultaneously in the cochlear nuclei, inferior colliculi (ICs), medial geniculate bodies (MGBs), and auditory cortices (ACs) in 2 functional magnetic resonance imaging experiments. In experiment 1, pulsed noise was presented monaurally to either ear, or binaurally, simulating a moving sound source. In experiment 2, only monaural sounds were presented. The results show a modulation of the neural responses to monaural sounds by the presence of binaural sounds at a time scale of tens of seconds: In the absence of binaural stimulation, the left and right ICs, MGBs, and ACs responded stronger to stimulation of the contralateral ear. When blocks of binaural stimuli were interspersed in the sound sequence, the contralateral preference vanished in those structures in the right hemisphere. The resulting hemispheric asymmetry was similar to the asymmetry demonstrated for spatial sound processing. Taken together, the data demonstrate that functional asymmetries in auditory processing are modulated by context. The observed long time constant suggests that this effect results from a "top-down" mechanism.

The present study investigates the acoustic basis of the hemispheric asymmetry for the processing of speech and music. Experiments on this question ideally involve stimuli that are perceptually unrelated to speech and music, but contain acoustic characteristics of both. Stimuli in previous studies were derived from speech samples or tonal sequences. Here we introduce a new class of noise-like sound stimuli with no resemblance of speech or music that permit independent parametric variation of spectral and temporal acoustic complexity. Using these stimuli in a functional MRI experiment, we test the hypothesis of a hemispheric asymmetry for the processing of spectral and temporal sound structure by seeking cortical areas in which the blood oxygen level dependent (BOLD) signal covaries with the number of simultaneous spectral components (spectral complexity) or the temporal modulation rate (temporal complexity) of the stimuli. BOLD-responses from the left and right Heschl's gyrus (HG) and part of the right superior temporal gyrus covaried with the spectral parameter, whereas covariation analysis for the temporal parameter highlighted an area on the left superior temporal gyrus. The portion of superior temporal gyrus in which asymmetrical responses are apparent corresponds to the antero-lateral auditory belt cortex, which has been implicated with spectral integration in animal studies. Our results support a similar function of the anterior auditory belt in humans. The findings indicate that asymmetrical processing of complex sounds in the cerebral hemispheres does not depend on semantic, but rather on acoustic stimulus characteristics.

The localization of low-frequency sounds mainly relies on the processing of microsecond temporal disparities between the ears, since low frequencies produce little or no interaural energy differences. The overall auditory cortical response to low-frequency sounds is largely symmetrical between the two hemispheres, even when the sounds are lateralized. However, the effects of unilateral lesions in the superior temporal cortex suggest that the spatial information mediated by lateralized sounds is distributed asymmetrically across the hemispheres. This paper describes a functional magnetic resonance imaging experiment, which shows that the interaural temporal processing of lateralized sounds produces an enhanced response in the contralateral planum temporale (PT). The response is stronger and extends further into adjacent regions of the inferior parietal lobe (IPL) when the sound is moving than when it is stationary. This suggests that the interaural temporal information mediated by lateralized sounds is projected along a posterior pathway comprising the PT and IPL of the respective contralateral hemisphere. The differential responses to moving sounds further revealed that the left hemisphere responded predominantly to sound movement within the right hemifield, whereas the right hemisphere responded to sound movement in both hemifields. This rightward asymmetry parallels the asymmetry associated with the allocation of visuo-spatial attention and may underlie unilateral auditory neglect phenomena.

The voltage-gated potassium (Kv) channel subunit Kv1.1, encoded by theKcna1gene, is expressed strongly in the ventral cochlear nucleus (VCN) and the medial nucleus of the trapezoid body (MNTB) of the auditory pathway. To examine the contribution of the Kv1.1 subunit to the processing of auditory information,in vivosingle-unit recordings were made from VCN neurons (bushy cells), axonal endings of bushy cells at MNTB cells (calyces of Held), and MNTB neurons ofKcna1-null (-/-) mice and littermate control (+/+) mice. Thresholds and spontaneous firing rates of VCN and MNTB neurons were not different between genotypes. At higher sound intensities, however, evoked firing rates of VCN and MNTB neurons were significantly lower in -/- mice than +/+ mice. The SD of the first-spike latency (jitter) was increased in VCN neurons, calyces, and MNTB neurons of -/- mice compared with +/+ controls. Comparison along the ascending pathway suggests that the increased jitter found in -/- MNTB responses arises mostly in the axons of VCN bushy cells and/or their calyceal terminals rather than in the MNTB neurons themselves. At high rates of sinusoidal amplitude modulations, -/- MNTB neurons maintained high vector strength values but discharged on significantly fewer cycles of the amplitude-modulated stimulus than +/+ MNTB neurons. These results indicate that inKcna1-null mice the absence of the Kv1.1 subunit results in a loss of temporal fidelity (increased jitter) and the failure to follow high-frequency amplitude-modulated sound stimulationin vivo.

Detection of mistuned partials in otherwise harmonic complex tones was investigated in naïve subjects of three different age groups. Signals were presented at constant sensation level to compensate for differences in hearing sensitivity and to specifically examine age-related changes in inharmonicity perception. Performance was measured under two conditions, monaural signal presentation and dichotic signal-noise presentation, with the latter aiming at the influence of contralateral distractor sounds. Stimuli were complex tones with ten harmonics and 125-Hz fundamental frequency. Mistuning detection was measured for the first, second, fourth, and eighth harmonic. In a three-interval, three-alternative forced-choice procedure, subjects were required to distinguish a complex tone containing one mistuned partial from two reference tones, with all partials at their harmonic frequencies. Thresholds were measured as the amount of frequency shift necessary for the mistuning to be detected. Performance deteriorated moderately with age for the two higher partials tested, but not for the lower ones. Thresholds for dichotic signal/noise presentation did not differ significantly from monaural ones in any of the age groups. Results are discussed in relation to hypotheses of harmonicity perception in auditory scene analysis and with respect to the investigation of patients suffering form respective deficits due to acquired brain lesions.

This study provides a morphologic characterization of the human superior olivary complex as revealed by immunohistochemistry by using antibodies against the calcium binding proteins parvalbumin, calbindin, calretinin, and the nonphosphorylated neurofilament H SMI-32. By combining these markers, it was possible to establish the neuronal architecture and details of the morphologic organization (including axonal terminals) of the different nuclei. The medial superior olivary nucleus is formed by a sheet of parallel-oriented cells. A clear segregation of axon terminals was noticed on the medially and laterally oriented dendrites of the mostly bipolar neurons. The lateral superior olivary nucleus lacked a distinct nuclear shape but was formed by several patches of rather irregularly arranged neurons. Calretinin or parvalbumin immunoreactive afferent terminals were observed which contacted somata or dendrites of these neurons. The immunolabeling also revealed the boundaries of the dorsal periolivary nucleus and morphologic detail of its neurons. A coherent nuclear structure that could be addressed as the medial nucleus of the trapezoid body was not identified by any single one or by combinations of the markers used. The data were also used to establish a three-dimensional-reconstruction of the three major subnuclei of the superior olivary complex. The results are discussed with respect to the possible role of the superior olivary complex in the processing of spatial acoustic information in the azimuthal plane.

Spherical bushy cells (SBCs) of the anteroventral cochlear nucleus (AVCN) receive their main excitatory input from auditory nerve fibers (ANFs) through large synapses, endbulbs of Held. These cells are also the target of inhibitory inputs whose function is not well understood. The present study examines the role of inhibition in the encoding of low-frequency sounds in the gerbil's AVCN. The presynaptic action potentials of endbulb terminals and postsynaptic action potentials of SBCs were monitored simultaneously in extracellular single-unit recordings in vivo. An input-output analysis of presynaptic and postsynaptic activity was performed for both spontaneous and acoustically driven activity. Two-tone stimulation and neuropharmacological experiments allowed the effects of neuronal inhibition and cochlear suppression on SBC activity to be distinguished. Ninety-one percent of SBCs showed significant neuronal inhibition. Inhibitory sidebands enclosed the high- or low-frequency, or both, sides of the excitatory areas of these units; this was reflected as a presynaptic to postsynaptic increase in frequency selectivity of up to one octave. Inhibition also affected the level-dependent responses at the characteristic frequency. Although in all units the presynaptic recordings showed monotonic rate-level functions, this was the case in only half of the postsynaptic recordings. In the other half of SBCs, postsynaptic inhibitory areas overlapped the excitatory areas, resulting in nonmonotonic rate-level functions. The results demonstrate that the sound-evoked spike activity of SBCs reflects the integration of acoustically driven excitatory and inhibitory input. The inhibition specifically affects the processing of the spectral, temporal, and intensity cues of acoustic signals.

In this functional MRI study the frequency-dependent localization of acoustically evoked BOLD responses within the human auditory cortex was investigated. A blocked design was employed, consisting of periods of tonal stimulation (random frequency modulations with center frequencies 0.25, 0.5, 4.0, and 8.0 kHz) and resting periods during which only the ambient scanner noise was audible. Multiple frequency-dependent activation sites were reliably demonstrated on the surface of the auditory cortex. The individual gyral pattern of the superior temporal plane (STP), especially the anatomy of Heschl's gyrus (HG), was found to be the major source of interindividual variability. Considering this variability by tracking the frequency responsiveness to the four stimulus frequencies along individual Heschl's gyri yielded medio-lateral gradients of responsiveness to high frequencies medially and low frequencies laterally. It is, however, argued that with regard to the results of electrophysiological and cytoarchitectonical studies in humans and in nonhuman primates, the multiple frequency-dependent activation sites found in the present study as well as in other recent fMRI investigations are no direct indication of tonotopic organization of cytoarchitectonical areas. An alternative interpretation is that the activation sites correspond to different cortical fields, the topological organization of which cannot be resolved with the current spatial resolution of fMRI. In this notion, the detected frequency selectivity of different cortical areas arises from an excess of neurons engaged in the processing of different acoustic features, which are associated with different frequency bands. Differences in the response properties of medial compared to lateral and frontal compared to occipital portions of HG strongly support this notion.