Anatomy of the auditory cortex then and now.

Using neuroanatomical investigations in the macaque, Deepak Pandya and his colleagues have established the framework for auditory cortex organization, with subdivisions into core and belt areas. This has aided subsequent neurophysiological and imaging studies in monkeys and humans, and a nomenclature building on Pandya's work has also been adopted by the Human Connectome Project. The foundational work by Pandya and his colleagues is highlighted here in the context of subsequent and ongoing studies on the functional anatomy and physiology of auditory cortex in primates, including humans, and their relevance for understanding cognitive aspects of speech and language.

Medial-lateral organization of primary auditory cortex and the question of sound localization.

Pandya made many important contributions to the understanding of the anatomy of the cortical auditory pathways beginning with his publication in 1969. This review focuses on the observation in that article on the transcallosal connections of the primary auditory cortex. The medial part of the cortex has such connections, but the lateral part does not. Pandya and colleagues speculated that this might have something to do with spatial localization of sound. Review of the subsequent literature shows that the primary auditory cortex anatomy is complex, but the original observation is likely correct. However, the physiological speculation was not.

Descriptive and functional anatomy of the Heschl Gyrus: historical review, manual labelling and current perspectives.

PURPOSE: The Heschl Gyrus (HG), which includes the Primary Auditory Cortex (PAC), lies on the upper surface of the superior temporal gyrus (T1). It has been the subject of growing interest in the fields of neuroscience over the past decade. Given the considerable interhemispheric and interindividual variability of its morphology, manual labelling remains the gold standard for its radio-anatomical study. The aim of this study was to revisit the original work of Richard L. Heschl, to provide a broad overview of the available anatomical knowledge and to propose a manually labelled 3D digital model. METHODS: We reviewed existing works on the HG, from Heschl's original publication of 1878, Dejerine neuroanatomical atlas of 1895 to the most recent digital atlases (Julich-Brain Cytoarchitectonic Atlas, the Human Connectome Project). Our segmentation work was based on data from the BigBrain Project and used the MRIcron 2019 software. RESULTS: The original publication by Heschl has been translated into French and English. We propose a correspondence of previous nomenclatures with the most recent ones, including the Terminologia Neuroanatomica. Finally, despite the notable anatomical variability of the HG, clear and coherent segmentation criteria allowed us to generate a 3D digital model of the HG. DISCUSSION AND CONCLUSION: Heschl's work is still relevant and could impulse further anatomical and functional studies. The segmentation criteria could serve as a reference for manual labelling of the HG. Furthermore, a thorough, and historically based understanding of the morphological, microstructural and functional characteristics of the HG could be useful for manual segmentation.

Evidence for Layer-Specific Connectional Heterogeneity in the Mouse Auditory Corticocollicular System.

The auditory cortex (AC) sends long-range projections to virtually all subcortical auditory structures. One of the largest and most complex of these-the projection between AC and inferior colliculus (IC; the corticocollicular pathway)-originates from layer 5 and deep layer 6. Though previous work has shown that these two corticocollicular projection systems have different physiological properties and network connectivities, their functional organization is poorly understood. Here, using a combination of traditional and viral tracers combined with in vivo imaging in both sexes of the mouse, we observed that layer 5 and layer 6 corticocollicular neurons differ in their areas of origin and termination patterns. Layer 5 corticocollicular neurons are concentrated in primary AC, while layer 6 corticocollicular neurons emanate from broad auditory and limbic areas in the temporal cortex. In addition, layer 5 sends dense projections of both small and large (>1 µm2 area) terminals to all regions of nonlemniscal IC, while layer 6 sends small terminals to the most superficial 50-100 µm of the IC. These findings suggest that layer 5 and 6 corticocollicular projections are optimized to play distinct roles in corticofugal modulation. Layer 5 neurons provide strong, rapid, and unimodal feedback to the nonlemniscal IC, while layer 6 neurons provide heteromodal and limbic modulation diffusely to the nonlemniscal IC. Such organizational diversity in the corticocollicular pathway may help to explain the heterogeneous effects of corticocollicular manipulations and, given similar diversity in corticothalamic pathways, may be a general principle in top-down modulation.SIGNIFICANCE STATEMENT We demonstrate that a major descending system in the brain is actually two systems. That is, the auditory corticocollicular projection, which exerts considerable influence over the midbrain, comprises two projections: one from layer 5 and the other from layer 6. The layer 6 projection is diffusely organized, receives multisensory inputs, and ends in small terminals; while the layer 5 projection is derived from a circumscribed auditory cortical area and ends in large terminals. These data suggest that the varied effects of cortical manipulations on the midbrain may be related to effects on two disparate systems. These findings have broader implications because other descending systems derive from two layers. Therefore, a duplex organization may be a common motif in descending control.

Phasic Off responses of auditory cortex underlie perception of sound duration.

It has been proposed that sound information is separately streamed into onset and offset pathways for parallel processing. However, how offset responses contribute to auditory perception remains unclear. Here, loose-patch and whole-cell recordings in awake mouse primary auditory cortex (A1) reveal that a subset of pyramidal neurons exhibit a transient "Off" response, with its onset tightly time-locked to the sound termination and its frequency tuning similar to that of the transient "On" response. Both responses are characterized by excitation briefly followed by inhibition, with the latter mediated by parvalbumin (PV) inhibitory neurons. Optogenetically manipulating sound-evoked A1 responses at different temporal phases or artificially creating phantom sounds in A1 further reveals that the A1 phasic On and Off responses are critical for perceptual discrimination of sound duration. Our results suggest that perception of sound duration is dependent on precisely encoding its onset and offset timings by phasic On and Off responses.

Corticostriatal control of defense behavior in mice induced by auditory looming cues.

Animals exhibit innate defense behaviors in response to approaching threats cued by the dynamics of sensory inputs of various modalities. The underlying neural circuits have been mostly studied in the visual system, but remain unclear for other modalities. Here, by utilizing sounds with increasing (vs. decreasing) loudness to mimic looming (vs. receding) objects, we find that looming sounds elicit stereotypical sequential defensive reactions: freezing followed by flight. Both behaviors require the activity of auditory cortex, in particular the sustained type of responses, but are differentially mediated by corticostriatal projections primarily innervating D2 neurons in the tail of the striatum and corticocollicular projections to the superior colliculus, respectively. The behavioral transition from freezing to flight can be attributed to the differential temporal dynamics of the striatal and collicular neurons in their responses to looming sound stimuli. Our results reveal an essential role of the striatum in the innate defense control.

Why do humans have unique auditory event-related fields? Evidence from computational modeling and MEG experiments.

Auditory event-related fields (ERFs) measured with magnetoencephalography (MEG) are useful for studying the neuronal underpinnings of auditory cognition in human cortex. They have a highly subject-specific morphology, albeit certain characteristic deflections (e.g., P1m, N1m, and P2m) can be identified in most subjects. Here, we explore the reason for this subject-specificity through a combination of MEG measurements and computational modeling of auditory cortex. We test whether ERF subject-specificity can predominantly be explained in terms of each subject having an individual cortical gross anatomy, which modulates the MEG signal, or whether individual cortical dynamics is also at play. To our knowledge, this is the first time that tools to address this question are being presented. The effects of anatomical and dynamical variation on the MEG signal is simulated in a model describing the core-belt-parabelt structure of the auditory cortex, and with the dynamics based on the leaky-integrator neuron model. The experimental and simulated ERFs are characterized in terms of the N1m amplitude, latency, and width. Also, we examine the waveform grand-averaged across subjects, and the standard deviation of this grand average. The results show that the intersubject variability of the ERF arises out of both the anatomy and the dynamics of auditory cortex being specific to each subject. Moreover, our results suggest that the latency variation of the N1m is largely related to subject-specific dynamics. The findings are discussed in terms of how learning, plasticity, and sound detection are reflected in the auditory ERFs. The notion of the grand-averaged ERF is critically evaluated.

Auditory and frontal anatomic correlates of pitch discrimination in musicians, non-musicians, and children without musical training.

Individual differences in pitch discrimination have been associated with the volume of both the bilateral Heschl's gyrus and the right inferior frontal gyrus (IFG). However, most of these studies used samples composed of individuals with different amounts of musical training. Here, we investigated the relationship between pitch discrimination and individual differences in the gray matter (GM) volume of these brain structures in 32 adult musicians, 28 adult non-musicians, and 32 children without musical training. The results showed that (i) the individuals without musical training (whether children or adults) who were better at pitch discrimination had greater volume of auditory regions, whereas (ii) musicians with better pitch discrimination had greater volume of the IFG. These results suggest that the relationship between pitch discrimination and the volume of auditory regions is innately established early in life, and that musical training modulates the volume of the IFG, probably improving audio-motor connectivity. This is the first study to detect a relationship between pitch discrimination ability and GM volume before beginning any musical training in children and adults.

Sleep duration is associated with auditory radiation microstructure.

OBJECTIVES: Although hearing has been shown to interact with sleep, the underlying mechanisms for the interaction remain largely unclear. In the absence of knowledge about the neural pathways that are associated with hearing-sleep interaction, this study aimed to examine whether the auditory radiation, the final portion of the auditory pathway from the cochlea to the cerebral cortex, shows association with sleep duration. METHODS: Using Diffusion Tensor Imaging (DTI) data from enhanced Nathan Kline Institute-Rockland Sample (NKI-RS), we isolated the white matter tracts between the medial geniculate nucleus of the thalamus and Heschl's gyrus in each individual subject (N = 465) using probabilistic tractography. As a measure of the white matter microstructure integrity, the mean fractional anisotropy (FA) of the whole auditory radiation was examined and tested for an association with sleep length in the Pittsburgh Sleep Assessment Index. RESULTS: A significant inverse-U shaped association was found between the auditory radiation FA and sleep duration. DISCUSSION: It is suggested that the auditory radiations are a part of the pathway mediating the sleep-hearing interaction. Although the current study does not resolve the causal relationship between hearing and sleep, it would be the first evidence that the auditory radiation is associated with sleep duration.

TASH: Toolbox for the Automated Segmentation of Heschl's gyrus.

Auditory cortex volume and shape differences have been observed in the context of phonetic learning, musicianship and dyslexia. Heschl's gyrus, which includes primary auditory cortex, displays large anatomical variability across individuals and hemispheres. Given this variability, manual labelling is the gold standard for segmenting HG, but is time consuming and error prone. Our novel toolbox, called 'Toolbox for the Automated Segmentation of HG' or TASH, automatically segments HG in brain structural MRI data, and extracts measures including its volume, surface area and cortical thickness. TASH builds upon FreeSurfer, which provides an initial segmentation of auditory regions, and implements further steps to perform finer auditory cortex delineation. We validate TASH by showing significant relationships between HG volumes obtained using manual labelling and using TASH, in three independent datasets acquired on different scanners and field strengths, and by showing good qualitative segmentation. We also present two applications of TASH, demonstrating replication and extension of previously published findings of relationships between HG volumes and (a) phonetic learning, and (b) musicianship. In sum, TASH effectively segments HG in a fully automated and reproducible manner, opening up a wide range of applications in the domains of expertise, disease, genetics and brain plasticity.

Heschl's gyrus fiber intersection area: a new insight on the connectivity of the auditory-language hub.

OBJECTIVE: The functional importance of the superior temporal lobe at the level of Heschl's gyrus is well known. However, the organization and function of these cortical areas and the underlying fiber tracts connecting them remain unclear. The goal of this study was to analyze the area formed by the organization of the intersection of Heschl's gyrus-related fiber tracts, which the authors have termed the "Heschl's gyrus fiber intersection area" (HGFIA). METHODS: The subcortical connectivity of Heschl's gyrus tracts was analyzed by white matter fiber dissection and by diffusion tensor imaging tractography. The white matter tracts organized in relation to Heschl's gyrus were isolated in 8 human hemispheres from cadaveric specimens and in 8 MRI studies in 4 healthy volunteers. In addition, these tracts and their functions were described in the surgical cases of left temporal gliomas next to the HGFIA in 6 patients who were awake during surgery and underwent intraoperative electrical stimulation mapping. RESULTS: Five tracts were observed to pass through the HGFIA: the anterior segment of the arcuate fasciculus, the middle longitudinal fasciculus, the acoustic radiation, the inferior fronto-occipital fasciculus, and the optic radiation. In addition, U fibers originating at the level of Heschl's gyrus and heading toward the middle temporal gyrus were identified. CONCLUSIONS: This investigation of the HGFIA, a region where 5 fiber tracts intersect in a relationship with the primary auditory area, provides new insights into the subcortical organization of Wernicke's area. This information is valuable when a temporal surgical approach is planned, in order to assess the surgical risk related to language disturbances.

Functional connectivity in human auditory networks and the origins of variation in the transmission of musical systems.

Music producers, whether original composers or performers, vary in their ability to acquire and faithfully transmit music. This form of variation may serve as a mechanism for the emergence of new traits in musical systems. In this study, we aim to investigate whether individual differences in the social learning and transmission of music relate to intrinsic neural dynamics of auditory processing systems. We combined auditory and resting-state functional magnetic resonance imaging (fMRI) with an interactive laboratory model of cultural transmission, the signaling game, in an experiment with a large cohort of participants (N=51). We found that the degree of interhemispheric rs-FC within fronto-temporal auditory networks predicts-weeks after scanning-learning, transmission, and structural modification of an artificial tone system. Our study introduces neuroimaging in cultural transmission research and points to specific neural auditory processing mechanisms that constrain and drive variation in the cultural transmission and regularization of musical systems.

Divergence in the functional organization of human and macaque auditory cortex revealed by fMRI responses to harmonic tones.

We report a difference between humans and macaque monkeys in the functional organization of cortical regions implicated in pitch perception. Humans but not macaques showed regions with a strong preference for harmonic sounds compared to noise, measured with both synthetic tones and macaque vocalizations. In contrast, frequency-selective tonotopic maps were similar between the two species. This species difference may be driven by the unique demands of speech and music perception in humans.

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).

CACNA1C risk variant affects microstructural connectivity of the amygdala.

Deficits in perception of emotional prosody have been described in patients with affective disorders at behavioral and neural level. In the current study, we use an imaging genetics approach to examine the impact of CACNA1C, one of the most promising genetic risk factors for psychiatric disorders, on prosody processing on a behavioral, functional and microstructural level. Using functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) we examined key areas involved in prosody processing, i.e. the amygdala and voice areas, in a healthy population. We found stronger activation to emotional than neutral prosody in the voice areas and the amygdala, but CACNA1C rs1006737 genotype had no influence on fMRI activity. However, significant microstructural differences (i.e. mean diffusivity) between CACNA1C rs1006737 risk allele carriers and non carriers were found in the amygdala, but not the voice areas. These modifications in brain architecture associated with CACNA1C might reflect a neurobiological marker predisposing to affective disorders and concomitant alterations in emotion perception.

Optimal features for auditory categorization.

Humans and vocal animals use vocalizations to communicate with members of their species. A necessary function of auditory perception is to generalize across the high variability inherent in vocalization production and classify them into behaviorally distinct categories ('words' or 'call types'). Here, we demonstrate that detecting mid-level features in calls achieves production-invariant classification. Starting from randomly chosen marmoset call features, we use a greedy search algorithm to determine the most informative and least redundant features necessary for call classification. High classification performance is achieved using only 10-20 features per call type. Predictions of tuning properties of putative feature-selective neurons accurately match some observed auditory cortical responses. This feature-based approach also succeeds for call categorization in other species, and for other complex classification tasks such as caller identification. Our results suggest that high-level neural representations of sounds are based on task-dependent features optimized for specific computational goals.

Larger Auditory Cortical Area and Broader Frequency Tuning Underlie Absolute Pitch.

Absolute pitch (AP), the ability of some musicians to precisely identify and name musical tones in isolation, is associated with a number of gross morphological changes in the brain, but the fundamental neural mechanisms underlying this ability have not been clear. We presented a series of logarithmic frequency sweeps to age- and sex-matched groups of musicians with or without AP and controls without musical training. We used fMRI and population receptive field (pRF) modeling to measure the responses in the auditory cortex in 61 human subjects. The tuning response of each fMRI voxel was characterized as Gaussian, with independent center frequency and bandwidth parameters. We identified three distinct tonotopic maps, corresponding to primary (A1), rostral (R), and rostral-temporal (RT) regions of auditory cortex. We initially hypothesized that AP abilities might manifest in sharper tuning in the auditory cortex. However, we observed that AP subjects had larger cortical area, with the increased area primarily devoted to broader frequency tuning. We observed anatomically that A1, R and RT were significantly larger in AP musicians than in non-AP musicians or control subjects, which did not differ significantly from each other. The increased cortical area in AP in areas A1 and R were primarily low frequency and broadly tuned, whereas the distribution of responses in area RT did not differ significantly. We conclude that AP abilities are associated with increased early auditory cortical area devoted to broad-frequency tuning and likely exploit increased ensemble encoding.SIGNIFICANCE STATEMENT Absolute pitch (AP), the ability of some musicians to precisely identify and name musical tones in isolation, is associated with a number of gross morphological changes in the brain, but the fundamental neural mechanisms have not been clear. Our study shows that AP musicians have significantly larger volume in early auditory cortex than non-AP musicians and non-musician controls and that this increased volume is primarily devoted to broad-frequency tuning. We conclude that AP musicians are likely able to exploit increased ensemble representations to encode and identify frequency.

Evaluation of medial division of the medial geniculate (MGM) and posterior intralaminar nucleus (PIN) inputs to the rat auditory cortex, amygdala, and striatum.

The medial division of the medial geniculate (MGM) and the posterior intralaminar nucleus (PIN) are association nuclei of the auditory thalamus. We made tracer injections in these nuclei to evaluate/compare their presynaptic terminal and postsynaptic target features in auditory cortex, amygdala and striatum, at the light and electron microscopic levels. Cortical labeling was concentrated in Layer 1 but in other layers distribution was location-dependent. In cortical areas designated dorsal, primary and ventral (AuD, Au1, AuV) terminals deep to Layer 1 were concentrated in infragranular layers and sparser in the supragranular and middle layers. In ectorhinal cortex (Ect), distributions below Layer 1 changed with concentrations in supragranular and middle layers. In temporal association cortex (TeA) terminal distributions below Layer 1 was intermediate between AuV/1/D and Ect. In amygdala and striatum, terminal concentrations were higher in striatum but not as dense as in cortical Layer 1. Ultrastructurally, presynaptic terminal size was similar in amygdala, striatum or cortex and in all cortical layers. Postsynaptically MGM/PIN terminals everywhere synapsed on spines or small distal dendrites but as a population the postsynaptic structures in cortex were larger than those in the striatum. In addition, primary cortical targets of terminals were larger in primary cortex than in area Ect. Thus, although postsynaptic size may play some role in changes in synaptic influence between areas it appears that terminal size is not a variable used for that purpose. In auditory cortex, cortical subdivision-dependent changes in the terminal distribution between cortical layers may also play a role.

Differential responses to spectrally degraded speech within human auditory cortex: An intracranial electrophysiology study.

Understanding cortical processing of spectrally degraded speech in normal-hearing subjects may provide insights into how sound information is processed by cochlear implant (CI) users. This study investigated electrocorticographic (ECoG) responses to noise-vocoded speech and related these responses to behavioral performance in a phonemic identification task. Subjects were neurosurgical patients undergoing chronic invasive monitoring for medically refractory epilepsy. Stimuli were utterances /aba/ and /ada/, spectrally degraded using a noise vocoder (1-4 bands). ECoG responses were obtained from Heschl's gyrus (HG) and superior temporal gyrus (STG), and were examined within the high gamma frequency range (70-150 Hz). All subjects performed at chance accuracy with speech degraded to 1 and 2 spectral bands, and at or near ceiling for clear speech. Inter-subject variability was observed in the 3- and 4-band conditions. High gamma responses in posteromedial HG (auditory core cortex) were similar for all vocoded conditions and clear speech. A progressive preference for clear speech emerged in anterolateral segments of HG, regardless of behavioral performance. On the lateral STG, responses to all vocoded stimuli were larger in subjects with better task performance. In contrast, both behavioral and neural responses to clear speech were comparable across subjects regardless of their ability to identify degraded stimuli. Findings highlight differences in representation of spectrally degraded speech across cortical areas and their relationship to perception. The results are in agreement with prior non-invasive results. The data provide insight into the neural mechanisms associated with variability in perception of degraded speech and potentially into sources of such variability in CI users.

Architectonic features and relative locations of primary sensory and related areas of neocortex in mouse lemurs.

Mouse lemurs are the smallest of the living primates, and are members of the understudied radiation of strepsirrhine lemurs of Madagascar. They are thought to closely resemble the ancestral primates that gave rise to present day primates. Here we have used multiple histological and immunochemical methods to identify and characterize sensory areas of neocortex in four brains of adult lemurs obtained from a licensed breeding colony. We describe the laminar features for the primary visual area (V1), the secondary visual area (V2), the middle temporal visual area (MT) and area prostriata, somatosensory areas S1(3b), 3a, and area 1, the primary motor cortex (M1), and the primary auditory cortex (A1). V1 has "blobs" with "nonblob" surrounds, providing further evidence that this type of modular organization might have evolved early in the primate lineage to be retained in all extant primates. The laminar organization of V1 further supports the view that sublayers of layer 3 of primates have been commonly misidentified as sublayers of layer 4. S1 (area 3b) is proportionately wider than the elongated area observed in anthropoid primates, and has disruptions that may distinguish representations of the hand, face, teeth, and tongue. Primary auditory cortex is located in the upper temporal cortex and may include a rostral area, R, in addition to A1. The resulting architectonic maps of cortical areas in mouse lemurs can usefully guide future studies of cortical connectivity and function.