Neurod1 Is Essential for the Primary Tonotopic Organization and Related Auditory Information Processing in the Midbrain.

Hearing depends on extracting frequency, intensity, and temporal properties from sound to generate an auditory map for acoustical signal processing. How physiology intersects with molecular specification to fine tune the developing properties of the auditory system that enable these aspects remains unclear. We made a novel conditional deletion model that eliminates the transcription factor NEUROD1 exclusively in the ear. These mice (both sexes) develop a truncated frequency range with no neuroanatomically recognizable mapping of spiral ganglion neurons onto distinct locations in the cochlea nor a cochleotopic map presenting topographically discrete projections to the cochlear nuclei. The disorganized primary cochleotopic map alters tuning properties of the inferior colliculus units, which display abnormal frequency, intensity, and temporal sound coding. At the behavioral level, animals show alterations in the acoustic startle response, consistent with altered neuroanatomical and physiological properties. We demonstrate that absence of the primary afferent topology during embryonic development leads to dysfunctional tonotopy of the auditory system. Such effects have never been investigated in other sensory systems because of the lack of comparable single gene mutation models.SIGNIFICANCE STATEMENT All sensory systems form a topographical map of neuronal projections from peripheral sensory organs to the brain. Neuronal projections in the auditory pathway are cochleotopically organized, providing a tonotopic map of sound frequencies. Primary sensory maps typically arise by molecular cues, requiring physiological refinements. Past work has demonstrated physiologic plasticity in many senses without ever molecularly undoing the specific mapping of an entire primary sensory projection. We genetically manipulated primary auditory neurons to generate a scrambled cochleotopic projection. Eliminating tonotopic representation to auditory nuclei demonstrates the inability of physiological processes to restore a tonotopic presentation of sound in the midbrain. Our data provide the first insights into the limits of physiology-mediated brainstem plasticity during the development of the auditory system.

Depth relationships and measures of tissue thickness in dorsal midbrain.

Dorsal human midbrain contains two nuclei with clear laminar organization, the superior and inferior colliculi. These nuclei extend in depth between the superficial dorsal surface of midbrain and a deep midbrain nucleus, the periaqueductal gray matter (PAG). The PAG, in turn, surrounds the cerebral aqueduct (CA). This study examined the use of two depth metrics to characterize depth and thickness relationships within dorsal midbrain using the superficial surface of midbrain and CA as references. The first utilized nearest-neighbor Euclidean distance from one reference surface, while the second used a level-set approach that combines signed distances from both reference surfaces. Both depth methods provided similar functional depth profiles generated by saccadic eye movements in a functional MRI task, confirming their efficacy for delineating depth for superficial functional activity. Next, the boundaries of the PAG were estimated using Euclidean distance together with elliptical fitting, indicating that the PAG can be readily characterized by a smooth surface surrounding PAG. Finally, we used the level-set approach to measure tissue depth between the superficial surface and the PAG, thus characterizing the variable thickness of the colliculi. Overall, this study demonstrates depth-mapping schemes for human midbrain that enables accurate segmentation of the PAG and consistent depth and thickness estimates of the superior and inferior colliculi.

Waxholm Space atlas of the rat brain auditory system: Three-dimensional delineations based on structural and diffusion tensor magnetic resonance imaging.

The mammalian auditory system comprises a complex network of brain regions. Interpretations and comparisons of experimental results from this system depend on appropriate anatomical identification of auditory structures. The Waxholm Space (WHS) atlas of the Sprague Dawley rat brain (Papp et al., Neuroimage 97:374-86, 2014) is an open access, three-dimensional reference atlas defined in an ex-vivo magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) volume. Version 2.0 of the atlas (Kjonigsen et al., Neuroimage 108:441-9, 2015) includes detailed delineations of the hippocampus and several major subcortical regions, but only few auditory structures. To amend this, we have delineated the complete ascending auditory system from the cochlea to the cerebral cortex. 40 new brain structure delineations have been added, and the delineations of 10 regions have been revised based on the interpretation of image features in the WHS rat brain MRI/DTI volumes. We here describe and validate the new delineations in relation to corresponding cell- and myelin-stained histological sections and previous literature. We found it possible to delineate all main regions and the majority of subregions and fibre tracts of the ascending auditory pathway, apart from the auditory cortex, for which delineations were extrapolated from a conventional two-dimensional atlas. By contrast, only parts of the descending pathways were discernible in the template. Version 3.0 of the atlas, with altogether 118 anatomical delineations, is shared via the NeuroImaging Tools and Resources Collaboratory (www.nitrc.org).

The spiral staircase: tonotopic microstructure and cochlear tuning.

Although usually assumed to be smooth and continuous, mammalian cochlear frequency-position maps are predicted to manifest a staircase-like structure comprising plateaus of nearly constant characteristic frequency separated by abrupt discontinuities. The height and width of the stair steps are determined by parameters of cochlear frequency tuning and vary with location in the cochlea. The step height is approximately equal to the bandwidth of the auditory filter (critical band), and the step width matches that of the spatial excitation pattern produced by a low-level pure tone. Stepwise tonotopy is an emergent property arising from wave reflection and interference within the cochlea, the same mechanisms responsible for the microstructure of the hearing threshold. Possible relationships between the microstructure of the cochlear map and the tiered tonotopy observed in the inferior colliculus are explored.

Input clustering in the normal and learned circuits of adult barn owls.

Experience-dependent formation of synaptic input clusters can occur in juvenile brains. Whether this also occurs in adults is largely unknown. We previously reconstructed the normal and learned circuits of prism-adapted barn owls and found that changes in clustering of axo-dendritic contacts (putative synapses) predicted functional circuit strength. Here we asked whether comparable changes occurred in normal and prism-removed adults. Across all anatomical zones, no systematic differences in the primary metrics for within-branch or between-branch clustering were observed: 95-99% of contacts resided within clusters (<10-20 µm from nearest neighbor) regardless of circuit strength. Bouton volumes, a proxy measure of synaptic strength, were on average larger in the functionally strong zones, indicating that changes in synaptic efficacy contributed to the differences in circuit strength. Bootstrap analysis showed that the distribution of inter-contact distances strongly deviated from random not in the functionally strong zones but in those that had been strong during the sensitive period (60-250 d), indicating that clusters formed early in life were preserved regardless of current value. While cluster formation in juveniles appeared to require the production of new synapses, cluster formation in adults did not. In total, these results support a model in which high cluster dynamics in juveniles sculpt a potential connectivity map that is refined in adulthood. We propose that preservation of clusters in functionally weak adult circuits provides a storage mechanism for disused but potentially useful pathways.

Anatomy of superior olivary complex and lateral lemniscus in Etruscan shrew.

Based on the auditory periphery and the small head size, Etruscan shrews (Suncus etruscus) approximate ancestral mammalian conditions. The auditory brainstem in this insectivore has not been investigated. Using labelling techniques, we assessed the structures of their superior olivary complex (SOC) and the nuclei of the lateral lemniscus (NLL). There, we identified the position of the major nuclei, their input pattern, transmitter content, expression of calcium binding proteins (CaBPs) and two voltage-gated ion channels. The most prominent SOC structures were the medial nucleus of the trapezoid body (MNTB), the lateral nucleus of the trapezoid body (LNTB), the lateral superior olive (LSO) and the superior paraolivary nucleus (SPN). In the NLL, the ventral (VNLL), a specific ventrolateral VNLL (VNLLvl) cell population, the intermediate (INLL) and dorsal (DNLL) nucleus, as well as the inferior colliculus's central aspect were discerned. INLL and VNLL were clearly separated by the differential distribution of various marker proteins. Most labelled proteins showed expression patterns comparable to rodents. However, SPN neurons were glycinergic and not GABAergic and the overall CaBPs expression was low. Next to the characterisation of the Etruscan shrew's auditory brainstem, our work identifies conserved nuclei and indicates variable structures in a species that approximates ancestral conditions.

Topographic distribution, frequency, and intensity dependence of stimulus-specific adaptation in the inferior colliculus of the rat.

The ability to detect unexpected sounds within the environment is an important function of the auditory system, as a rapid response may be required for the organism to survive. Previous studies found a decreased response to repetitive stimuli (standard), but an increased response to rare or less frequent sounds (deviant) in individual neurons in the inferior colliculus (IC) and at higher levels. This phenomenon, known as stimulus-specific adaptation (SSA) has been suggested to underpin change detection. Currently, it is not known how SSA varies within a single neuron receptive field, i.e., it is unclear whether SSA is a unique property of the neuron or a feature that is frequency and/or intensity dependent. In the present experiments, we used the common SSA index (CSI) to quantify and compare the degree of SSA under different stimulation conditions in the IC of the rat. We calculated the CSI at different intensities and frequencies for each individual IC neuron to map the neuronal CSI within the receptive field. Our data show that high SSA is biased toward the high-frequency and low-intensity regions of the receptive field. We also find that SSA is better represented in the earliest portions of the response, and there is a positive correlation between the width of the frequency response area of the neuron and the maximum level of SSA. The present data suggest that SSA in the IC is not mediated by the intrinsic membrane properties of the neurons and instead might be related to an excitatory and/or inhibitory input segregation.

Anatomical differences in the human inferior colliculus relate to the perceived valence of musical consonance and dissonance.

Helmholtz himself speculated about a role of the cochlea in the perception of musical dissonance. Here we indirectly investigated this issue, assessing the valence judgment of musical stimuli with variable consonance/dissonance and presented diotically (exactly the same dissonant signal was presented to both ears) or dichotically (a consonant signal was presented to each ear--both consonant signals were rhythmically identical but differed by a semitone in pitch). Differences in brain organisation underlying inter-subject differences in the percept of dichotically presented dissonance were determined with voxel-based morphometry. Behavioral results showed that diotic dissonant stimuli were perceived as more unpleasant than dichotically presented dissonance, indicating that interactions within the cochlea modulated the valence percept during dissonance. However, the behavioral data also suggested that the dissonance percept did not depend crucially on the cochlea, but also occurred as a result of binaural integration when listening to dichotic dissonance. These results also showed substantial between-participant variations in the valence response to dichotic dissonance. These differences were in a voxel-based morphometry analysis related to differences in gray matter density in the inferior colliculus, which strongly substantiated a key role of the inferior colliculus in consonance/dissonance representation in humans.

Mapping tonotopy in human auditory cortex.

Tonotopy is arguably the most prominent organizational principle in the auditory pathway. Nevertheless, the layout of tonotopic maps in humans is still debated. We present neuroimaging data that robustly identify multiple tonotopic maps in the bilateral auditory cortex. In contrast with some earlier publications, tonotopic gradients were not found to be collinearly aligned along Heschl's gyrus; instead, two tonotopic maps ran diagonally across the anterior and posterior banks of Heschl's gyrus, set at a pronounced angle. On the basis of the direction of the tonotopic gradient, distinct subdivisions of the auditory cortex could be clearly demarcated that suggest homologies with the tonotopic organization in other primates. Finally, we applied our method to tinnitus patients to show that - contradictory to some pathophysiological models - tinnitus does not necessarily involve large-scale tonotopic reorganization. Overall, we expect that tonotopic mapping techniques will significantly enhance our ability to study the hierarchical functional organization of distinct auditory processing centers in the healthy and diseased human brain.

Magnetic resonance imaging mesencephalic tectum dimensions according to age and gender.

OBJECTIVE: To analyze and classify normal MRI tectum length and colliculus dimensions according to age and gender. METHODS: Tectum length and colliculus diameters were measured on the T1 midsagittal and axial cranial MR images in the radiology archive of 532 (344 women, 188 men) patients aged 37.36+/-21.49 (range: 4-91) years old on average, and with no disorders affecting the mesencephalic tectum. All 532 patients underwent clinical MR imaging of the cranium at the MRI Unit of Sivas Numune Hospital and Sivas Cumhuriyet University Hospital, Sivas, Turkey between February and December 2011. RESULTS: Although there was a positive linear correlation between tectum length and age, there was a negative correlation between the anteroposterior diameter of the colliculus superior and colliculus inferior and age (p<0.01). While tectum length (M3) increases with age, the anteroposterior diameter of the colliculus superior and inferior (M1 and M2) decreased (p<0.01). The colliculi were larger, and the tectum was longer in men. Although there was no difference in size between right and left superior colliculi, the left colliculus inferior was larger than the right one. CONCLUSION: In addition to the fact that normal mesencephalic tectum dimensions provide information on the brain development of individuals, they may also be beneficial for the detection and treatment of related pathologies.

BOLD fMRI investigation of the rat auditory pathway and tonotopic organization.

Rodents share general anatomical, physiological and behavioral features in the central auditory system with humans. In this study, monaural broadband noise and pure tone sounds are presented to normal rats and the resulting hemodynamic responses are measured with blood oxygenation level-dependent (BOLD) fMRI using a standard spin-echo echo planar imaging sequence (without sparse temporal sampling). The cochlear nucleus (CN), superior olivary complex, lateral lemniscus, inferior colliculus (IC), medial geniculate body and primary auditory cortex, all major auditory structures, are activated by broadband stimulation. The CN and IC BOLD signal changes increase monotonically with sound pressure level. Pure tone stimulation with three distinct frequencies (7, 20 and 40 kHz) reveals the tonotopic organization of the IC. The activated regions shift from dorsolateral to ventromedial IC with increasing frequency. These results agree with electrophysiology and immunohistochemistry findings, indicating the feasibility of auditory fMRI in rats. This is the first fMRI study of the rodent ascending auditory pathway.

Adaptation in the auditory midbrain of the barn owl (Tyto alba) induced by tonal double stimulation.

During hunting, the barn owl typically listens to several successive sounds as generated, for example, by rustling mice. As auditory cells exhibit adaptive coding, the earlier stimuli may influence the detection of the later stimuli. This situation was mimicked with two double-stimulus paradigms, and adaptation was investigated in neurons of the barn owl's central nucleus of the inferior colliculus. Each double-stimulus paradigm consisted of a first or reference stimulus and a second stimulus (probe). In one paradigm (second level tuning), the probe level was varied, whereas in the other paradigm (inter-stimulus interval tuning), the stimulus interval between the first and second stimulus was changed systematically. Neurons were stimulated with monaural pure tones at the best frequency, while the response was recorded extracellularly. The responses to the probe were significantly reduced when the reference stimulus and probe had the same level and the inter-stimulus interval was short. This indicated response adaptation, which could be compensated for by an increase of the probe level of 5-7 dB over the reference level, if the latter was in the lower half of the dynamic range of a neuron's rate-level function. Recovery from adaptation could be best fitted with a double exponential showing a fast (1.25 ms) and a slow (800 ms) component. These results suggest that neurons in the auditory system show dynamic coding properties to tonal double stimulation that might be relevant for faithful upstream signal propagation. Furthermore, the overall stimulus level of the masker also seems to affect the recovery capabilities of auditory neurons.

Comparative morphology and morphometry of the mesencephalic tectum in the African giant rat (Cricetomys gambianus).

The caudal colliculus serves as an integrative station and switchboard, controlling nucleus of lower auditory pathway and motor-auditory reflex production. The rostral colliculus coordinates reflexive movement of the head, neck, eye and focus the lens for visual tracking of objects. There is no information comparing mesencephalic tectum among neonates, juveniles and adults of African giant rat (AGR). Hence, this study aimed to compare the gross features and morphometric parameters of mesencephalic tectum postnatally in AGR. The following were found and reported: (a) Paired dorsal tips of caudal colliculi were observed through transverse fissure of the intact brain and so, corpora quadrigemina were partly occluded by cerebral cortex in neonates and juveniles. (b) The lateral and medial geniculate bodies were visible, though the lateral was grossly bigger than the medial in adults and juveniles but,  only the lateral was distinguishable in neonates. (c) Live body weight, absolute brain weight, caudal colliculus width, nose-rump and tail lengths increased as AGRs developed with age; mean values of rostral colliculus weight, caudal colliculus height and weight of caudal colliculus in neonates and juveniles were statistically same; while midbrain weight and rostral colliculus height tends to decrease as rats aged. (d) The mean weight of caudal colliculi and width of rostral colliculi were not affected by age. (e) Caudal colliculi were grossly wider than rostral in juveniles and adults, but not neonates. Established regression formulae are necessary to avoid future sacrifice of this rodent.

Differential patterns of inputs create functional zones in central nucleus of inferior colliculus.

Distinct pathways carry monaural and binaural information from the lower auditory brainstem to the central nucleus of the inferior colliculus (ICC). Previous anatomical and physiological studies suggest that differential ascending inputs to regions of the ICC create functionally distinct zones. Here, we provide direct evidence of this relationship by combining recordings of single unit responses to sound in the ICC with focal, iontophoretic injections of the retrograde tracer Fluoro-Gold at the physiologically characterized sites. Three main patterns of anatomical inputs were observed. One pattern was identified by inputs from the cochlear nucleus and ventral nucleus of the lateral lemniscus in isolation, and these injection sites were correlated with monaural responses. The second pattern had inputs only from the ipsilateral medial and lateral superior olive, and these sites were correlated with interaural time difference (ITD)-sensitive responses to low frequency (<500 Hz). A third pattern had inputs from a variety of olivary and lemniscal sources, notably the contralateral lateral superior olive and dorsal nucleus of the lateral lemniscus. These were correlated with high-frequency ITD sensitivity to complex acoustic stimuli. These data support the notion of anatomical regions formed by specific patterns of anatomical inputs to the ICC. Such synaptic domains may represent functional zones in ICC.

Morphological and functional midbrain phenotypes in Fibroblast Growth Factor 17 mutant mice detected by Mn-enhanced MRI.

With increasing efforts to develop and utilize mouse models of a variety of neuro-developmental diseases, there is an urgent need for sensitive neuroimaging methods that enable in vivo analysis of subtle alterations in brain anatomy and function in mice. Previous studies have shown that the brains of Fibroblast Growth Factor 17 null mutants (Fgf17(-/-)) have anatomical abnormalities in the inferior colliculus (IC)-the auditory midbrain-and minor foliation defects in the cerebellum. In addition, changes in the expression domains of several cortical patterning genes were detected, without overt changes in forebrain morphology. Recently, it has also been reported that Fgf17(-/-) mutants have abnormal vocalization and social behaviors, phenotypes that could reflect molecular changes in the cortex and/or altered auditory processing / perception in these mice. We used manganese (Mn)-enhanced magnetic resonance imaging (MEMRI) to analyze the anatomical phenotype of Fgf17(-/-) mutants in more detail than achieved previously, detecting changes in IC, cerebellum, olfactory bulb, hypothalamus and frontal cortex. We also used MEMRI to characterize sound-evoked activity patterns, demonstrating a significant reduction of the active IC volume in Fgf17(-/-) mice. Furthermore, tone-specific (16- and 40-kHz) activity patterns in the IC of Fgf17(-/-) mice were observed to be largely overlapping, in contrast to the normal pattern, separated along the dorsal-ventral axis. These results demonstrate that Fgf17 plays important roles in both the anatomical and functional development of the auditory midbrain, and show the utility of MEMRI for in vivo analyses of mutant mice with subtle brain defects.

Neural coding of echo-envelope disparities in echolocating bats.

The effective use of echolocation requires not only measuring the delay between the emitted call and returning echo to estimate the distance of an ensonified object. To locate an object in azimuth and elevation, the bat's auditory system must analyze the returning echoes in terms of their binaural properties, i.e., the echoes' interaural intensity and time differences (IIDs and ITDs). The effectiveness of IIDs for echolocation is undisputed, but when bats ensonify complex objects, the temporal structure of echoes may facilitate the analysis of the echo envelope in terms of envelope ITDs. Using extracellular recordings from the auditory midbrain of the bat, Phyllostomus discolor, we found a population of neurons that are sensitive to envelope ITDs of echoes of their sonar calls. Moreover, the envelope-ITD sensitivity improved with increasing temporal fluctuations in the echo envelopes, a sonar parameter related to the spatial statistics of complex natural reflectors like vegetation. The data show that in bats envelope ITDs may be used not only to locate external, prey-generated rustling sounds but also in the context of echolocation. Specifically, the temporal fluctuations in the echo envelope, which are created when the sonar emission is reflected from a complex natural target, support ITD-mediated echolocation.

Multiple mechanisms shape selectivity for FM sweep rate and direction in the pallid bat inferior colliculus and auditory cortex.

The inferior colliculus and auditory cortex of the pallid bat contain a large percentage of neurons that are highly selective for the direction and rate of the downward frequency modulated (FM) sweep of the bat's echolocation pulse. Approximately 25% of neurons tuned to the echolocation pulse respond exclusively to downward FM sweeps. This review focuses on the finding that this selectivity is generated by multiple mechanisms that may act alone or in concert. In the inferior colliculus, selectivity for sweep rate is shaped by at least three mechanisms: shortpass or bandpass tuning for signal duration, delayed high-frequency inhibition that prevents responses to slow sweep rates, and asymmetrical facilitation that occurs only when two tones are presented at appropriate delays. When acting alone, the three mechanisms can produce essentially identical rate selectivity. Direction selectivity can be produced by two mechanisms: an early low-frequency inhibition that prevents responses to upward sweeps, and the same asymmetrical two-tone inhibition that shapes rate tuning. All mechanisms except duration tuning are also present in the auditory cortex. Discussion centers on whether these mechanisms are redundant or complementary.

The regional distribution of T2-relaxation times in MR images of the substantia nigra and crus cerebri.

INTRODUCTION: When scanning the size of the substantia nigra (SN), for example in Parkinson's disease, it is important to precisely locate its true anatomic location. The hypointense areas on T2-weighted magnetic resonance images (T2w) at the level of the upper midbrain are usually labeled as the SN. Recent studies showed that the line of demarcation between the SN and the crus cerebri (CC) in T2w images seems not to be clear. The purpose of our study was to evaluate the depiction of the SN and the CC on calculated R2 maps by analyzing the regional distribution of T2 values in both regions. METHODS: In 36 healthy subjects, triple echo turbo spin echo were obtained at 1.5 T and R2 maps calculated. Proton density-weighted turbo spin echo images (PDw) were used as reference. The CC and SN were manually traced on PDw sections (CCP and SNP) and also the hyperintense areas on the R2 maps, suggestive of the SN (DT2). The obtained volumes were evaluated in terms of total size, intersections size, and residual areas, as well as the corresponding T2 values. RESULTS: DT2 corresponded to anterolateral parts of the SNP and showed an extension to anteromedial part of the CC. The intersections between DT2 and CCP and DT2 and SNP presented both decreased but different T2 values (102 +/- 5 and 95 +/- 4 ms). CONCLUSION: An exact differentiation of the SN from the CC is not possible on the basis of T2w images but rather on the basis of the underlying calculated T2 values from the triple echo sequence.

Diffusion tensor imaging of the inferior colliculus and brainstem auditory-evoked potentials in preterm infants.

BACKGROUND: Preterm and low-birth-weight infants have an increased risk of sensorineural hearing loss. Brainstem auditory-evoked potentials (BAEP) are an effective method to detect subtle deficits in impulse conduction in the auditory pathway. Abnormalities on diffusion tensor imaging (DTI) have been shown to be associated with perinatal white-matter injury and reduced fractional anisotropy (FA) has been reported in patients with sensorineural hearing loss. OBJECTIVES: To evaluate the possibility of a correlation between BAEP and DTI of the inferior colliculus in preterm infants. MATERIALS AND METHODS: DTI at term age and BAEP measurements were performed on all very-low-birth-weight or very preterm study infants (n=56). FA and apparent diffusion coefficient (ADC) of the inferior colliculus were measured from the DTI. RESULTS: Shorter BAEP wave I, III, and V latencies and I-III and I-V intervals and higher wave V amplitude correlated with higher FA of the inferior colliculus. CONCLUSION: The association between the DTI findings of the inferior colliculus and BAEP responses suggests that DTI can be used to assess the integrity of the auditory pathway in preterm infants.

Lateralization of stimuli with independent fine-structure and envelope-based temporal disparities.

Psychoacoustic experiments were conducted to investigate the role and interaction of fine-structure and envelope-based interaural temporal disparities. A computational model for the lateralization of binaural stimuli, motivated by recent physiological findings, is suggested and evaluated against the psychoacoustic data. The model is based on the independent extraction of the interaural phase difference (IPD) from the stimulus fine-structure and envelope. Sinusoidally amplitude-modulated 1-kHz tones were used in the experiments. The lateralization from either carrier (fine-structure) or modulator (envelope) IPD was matched with an interaural level difference, revealing a nearly linear dependence for both IPD types up to 135 degrees , independent of the modulation frequency. However, if a carrier IPD was traded with an opposed modulator IPD to produce a centered sound image, a carrier IPD of 45 degrees required the largest opposed modulator IPD. The data could be modeled assuming a population of binaural neurons with a physiological distribution of the best IPDs clustered around 45 degrees -50 degrees . The model was also used to predict the perceived lateralization of previously published data. Subject-dependent differences in the perceptual salience of fine-structure and envelope cues, also reported previously, could be modeled by individual weighting coefficients for the two cues.