Stable bottom‐up processing during dynamic top‐down modulations in monkey auditory cortex

Characteristics of neurons in auditory cortex of monkeys performing a simple auditory task.

Multisensory connections of monkey auditory cerebral cortex

The effects of conditioning on the discharges of single neurons in primary auditory cortex (AI) were determined during acquisition of the pupillary conditioned response in chronically prepared cats. Acoustic stimuli (1-s white noise or tone) were presented with electrodermal stimulation unpaired during a sensitization control phase followed by pairing during a subsequent conditioning phase. Stimulus constancy at the periphery was ensured by the use of neuromuscular blockade. Discharge plasticity developed rapidly for both evoked and background activity, the former attaining criterion faster than the latter. The pupillary dilation conditioned response was acquired at the same rate as were changes in evoked activity (i.e., 10-15 trials) and faster than background activity (i.e., 20-25 trials). Increases in background activity were correlated with increasing level of tonic arousal, as indexed by pretrial size of the pupil.

Rats are born deaf and start hearing at the end of the second postnatal week, when the ear canals open and low-intensity sounds start to evoke responses in the auditory cortex. Here, using μECoG electrode arrays and intracortical silicon probe recordings, we found that bone-conducted (BC) sounds evoked biphasic responses in the auditory cortex starting from postnatal day (P) 8. The initial phase of these responses, generated by thalamocortical input, was followed by intracortical propagation within supragranular layers. BC-evoked responses co-localized with the responses evoked by electrical stimulation of the cochlea and the deepest layers of the inferior colliculus prior to onset of low-threshold hearing (P13), as well as with the responses evoked by high-frequency (30 kHz) low-intensity (70 dB) air-conducted sounds after that. Thus, BC signals reach high-frequency processing regions of the auditory cortex well before the onset of low-threshold hearing, reflecting early integrity of the auditory system.

Repetition of complex frequency-modulated sweeps enhances neuromagnetic responses in the human auditory cortex

Accumulating evidence demonstrates that responses in auditory cortex to auditory consequences of self-generated actions are modified relative to the responses evoked by identical sounds generated by an external source. Such modifications have been suggested to occur through a corollary discharge sent from the motor system, although the exact neuroanatomical origin is unknown. Furthermore, since tactile input has also been shown to modify responses in auditory cortex, it is not even clear whether the source of such modifications is motor output or somatosensory feedback. We recorded functional magnetic resonance imaging (fMRI) data from healthy human subjects (n = 11) while manipulating the rate at which they performed sound-producing actions with their right hand. In addition, we manipulated the amount of tactile feedback to examine the relative roles of motor and somatosensory cortices in modifying evoked activity in auditory cortex (superior temporal gyrus). We found an enhanced fMRI signal in left auditory cortex during perception of self-generated sounds relative to passive listening to identical sounds. Moreover, the signal difference between active and passive conditions in left auditory cortex covaried with the rate of sound-producing actions and was invariant to the amount of tactile feedback. Together with functional connectivity analysis, our results suggest motor output from supplementary motor area and left primary motor cortex as the source of signal modification in auditory cortex during perception of self-generated sounds. Motor signals from these regions could represent a predictive signal of the expected auditory consequences of the performed action.

How does attention modulate sensory representations? In order to probe the underlying neural mechanisms, we established a simple rodent model of modality-specific attention. Here we describe results of experiments in freely moving rats in which we have used tetrodes to record neural responses in primary auditory cortex (area A1) while subjects performed this behavior.Subjects were first trained to perform distinct auditory and olfactory two alternative forced-choice (2AFC) tasks. Training and testing were conducted in a custom three-poke computer-controlled behavioral apparatus. Subjects initiated trials with a center-poke, which triggered presentation of a tone (either 5 or 15 Hz), an odor (either R(-)-2-Octanol or S(+)-2-Octanol), or both. Subjects responded moving to the left or right poke. Correct responses were rewarded with water. Auditory and olfactory blocks (of 50 trials each) were interleaved in a single session. In auditory blocks, pure tones were either presented with or without a null odor (caproic acid, n=2 and 3 respectively), and subjects were cued to perform the task based on auditory stimuli. In olfactory blocks, both odors and pure tones were presented simultaneously, and subjects were cued to perform the task based on olfactory stimuli.After subjects reached consistent performance on the interleaved blocks, tetrode drives were implanted in primary auditory cortex of the left hemisphere. Single unit responses to tones were heterogeneous, and included transient, sustained, and suppressed. Among 304 responsive units recorded, 19% (58 units) showed modality-specific attentional modulation of at least one of the tone-evoked responses; in most cases, the responses to a particular auditory stimulus was enhanced in the auditory block (or, equivalently, suppressed in the olfactory block). In addition, we also observed modality-specific attentional modulation of the spontaneous activity in similar proportion of units (61 units). Our results suggest that shifting attention from audition to olfaction and back can modulate the activity of single neurons in primary auditory cortex.

We tested the hypothesis that information is routed from one area of the auditory cortex (AC) to another via the dorsal division of the medial geniculate body (MGBd) by analyzing the degree of reciprocal connectivity between the auditory thalamus and cortex. Biotinylated dextran amine injected into the primary AC (AI) or anterior auditory field (AAF) of mice produced large, "driver-type" terminals primarily in the MGBd, with essentially no such terminals in the ventral MGB (MGBv). In contrast, small, "modulator-type" terminals were found primarily in the MGBv, and this coincided with areas of retrogradely labeled thalamocortical cell bodies. After MGBv injections, anterograde label was observed in layers 4 and 6 of the AI and AAF, which coincided with retrogradely labeled layer 6 cell bodies. After MGBd injections, thalamocortical terminals were seen in layers 1, 4, and 6 of the secondary AC and dorsoposterior AC, which coincided with labeled layer 6 cell bodies. Notably, after MGBd injection, a substantial number of layer 5 cells were labeled in all AC areas, whereas very few were seen after MGBv injection. Further, the degree of anterograde label in layer 4 of cortical columns containing labeled layer 6 cell bodies was greater than in columns containing labeled layer 5 cell bodies. These data suggest that auditory layer 5 corticothalamic projections are targeted to the MGBd in a nonreciprocal fashion and that the MGBd may route this information to the nonprimary AC.

The frequency resolution of neurons throughout the ascending auditory pathway is important for understanding how sounds are processed. In many animal studies, the frequency tuning widths are about 1/5th octave wide in auditory nerve fibers and much wider in auditory cortex neurons. Psychophysical studies show that humans are capable of discriminating far finer frequency differences. A recent study suggested that this is perhaps attributable to fine frequency tuning of neurons in human auditory cortex (Bitterman Y, Mukamel R, Malach R, Fried I, Nelken I. Nature 451: 197-201, 2008). We investigated whether such fine frequency tuning was restricted to human auditory cortex by examining the frequency tuning width in the awake common marmoset monkey. We show that 27% of neurons in the primary auditory cortex exhibit frequency tuning that is finer than the typical frequency tuning of the auditory nerve and substantially finer than previously reported cortical data obtained from anesthetized animals. Fine frequency tuning is also present in 76% of neurons of the auditory thalamus in awake marmosets. Frequency tuning was narrower during the sustained response compared to the onset response in auditory cortex neurons but not in thalamic neurons, suggesting that thalamocortical or intracortical dynamics shape time-dependent frequency tuning in cortex. These findings challenge the notion that the fine frequency tuning of auditory cortex is unique to human auditory cortex and that it is a de novo cortical property, suggesting that the broader tuning observed in previous animal studies may arise from the use of anesthesia during physiological recordings or from species differences.

How does attention modulate sensory representations? In order to probe the underlying neural mechanisms, we established a simple rodent model of modality-specific attention. Rats were trained to perform distinct auditory two-tone discrimination and olfactory odor discrimination in a two alternative choice (2AC) paradigm. To determine auditory cortex’s role in this frequency discrimination task, we used GABA-A receptor agonist muscimol to transiently and reversibly inactivate auditory cortexes bilaterally in rats performing simple interleaved auditory and olfactory discrimination. With olfactory discrimination performance serving as internal control for motivation and decision making capability, we found only auditory two-tone discrimination was selectively impaired in these rats. This shows the auditory cortex is involved in this two-tone discrimination task.To investigate the neural correlate of modality-specific attention in the auditory cortex, we trained rats to perform interleaved auditory and olfactory blocks (of 50~70 trials each) in a single session. In auditory blocks, pure tones were either presented with or without a neutral odor (caproic acid, n=2 and 3 respectively), and subjects were rewarded for discriminating auditory stimuli. In olfactory blocks, both task odors and pure tones were presented simultaneously, and subjects were rewarded for discriminating olfactory stimuli. We recorded neural responses in primary auditory cortex (area A1) in freely moving rats while subjects performed this behavior. Single unit responses to tones were heterogeneous, and included transient, sustained, and suppressed. We found 205 of 802 units recorded responsive to the stimuli we used. Of these 205 units, 18.5% showed modality-specific attentional modulation of the anticipatory activity before tone onset. In addition, we also observed in smaller proportion of units (11.2%) modality-specific attentional modulation of the tone-evoked responses; in most cases, the responses to a particular auditory stimulus was enhanced in the auditory block (or, equivalently, suppressed in the olfactory block). Attention increased choice probability of the population in the auditory block. We have also observed significant behavior choice probability in small proportions of units. Our results suggest that shifting attention between audition to olfaction tasks can modulate the activity of single neurons in primary auditory cortex.

Time-dependent frequency trajectories are an inherent feature of many behaviorally relevant sounds, such as species-specific vocalizations. Dynamic frequency trajectories, even in short sounds, often convey meaningful information, which may be used to differentiate sound categories. However, it is not clear what and where neural responses in the auditory cortical pathway are critical for conveying information about behaviorally relevant frequency trajectories, and how these responses change with experience. Here, we uncover tuning to subtle variations in frequency trajectories in auditory cortex of female mice. We found that auditory cortical responses could be modulated by variations in a pure tone trajectory as small as 1/24th of an octave, comparable to what has been reported in primates. In particular, late spiking after the end of a sound stimulus was more often sensitive to the sound's subtle frequency variation compared with spiking during the sound. Such “Off” responses in the adult A2, but not those in core auditory cortex, were plastic in a way that may enhance the representation of a newly acquired, behaviorally relevant sound category. We illustrate this with the maternal mouse paradigm for natural vocalization learning. By using an ethologically inspired paradigm to drive auditory responses in higher-order neurons, our results demonstrate that mouse auditory cortex can track fine frequency changes, which allows A2 Off responses in particular to better respond to pitch trajectories that distinguish behaviorally relevant, natural sound categories.SIGNIFICANCE STATEMENT A whistle's pitch conveys meaning to its listener, as when dogs learn that distinct pitch trajectories whistled by their owner differentiate specific commands. Many species use pitch trajectories in their own vocalizations to distinguish sound categories, such as in human languages, such as Mandarin. How and where auditory neural activity encodes these pitch trajectories as their meaning is learned but not well understood, especially for short-duration sounds. We studied this in mice, where infants use ultrasonic whistles to communicate to adults. We found that late neural firing after a sound ends can be tuned to how the pitch changes in time, and that this response in a secondary auditory cortical field changes with experience to acquire a pitch change's meaning.

Primary auditory cortex is a critical stage in the human auditory pathway, a gateway between subcortical and higher-level cortical areas. Receiving the output of all subcortical processing, it sends its output on to higher-level cortex. Non-invasive physiological recordings of primary auditory cortex using electroencephalography (EEG) and magnetoencephalography (MEG), however, may not have sufficient specificity to separate responses generated in primary auditory cortex from those generated in underlying subcortical areas or neighboring cortical areas. This limitation is important for investigations of effects of top-down processing (e.g., selective-attention-based) on primary auditory cortex: higher-level areas are known to be strongly influenced by top-down processes, but subcortical areas are often assumed to perform strictly bottom-up processing. Fortunately, recent advances have made it easier to isolate the neural activity of primary auditory cortex from other areas. In this perspective, we focus on time-locked responses to stimulus features in the high gamma band (70-150 Hz) and with early cortical latency (∼40 ms), intermediate between subcortical and higher-level areas. We review recent findings from physiological studies employing either repeated simple sounds or continuous speech, obtaining either a frequency following response (FFR) or temporal response function (TRF). The potential roles of top-down processing are underscored, and comparisons with invasive intracranial EEG (iEEG) and animal model recordings are made. We argue that MEG studies employing continuous speech stimuli may offer particular benefits, in that only a few minutes of speech generates robust high gamma responses from bilateral primary auditory cortex, and without measurable interference from subcortical or higher-level areas.

Sequences of repeating tones can be masked by other tones of different frequency. When these tone sequences are perceived, nevertheless, a prominent neural response in the auditory cortex is evoked by each tone of the sequence. When the targets are detected based on their isochrony, participants know that they are listening to the target once they detected it. To explore if the neural activity is more closely related to this detection task or to perceptual awareness, this magnetoencephalography (MEG) study used targets that could only be identified with cues provided after or before the masked target. In experiment 1, multiple mono-tone streams with jittered inter-stimulus interval were used, and the tone frequency of the target was indicated by a cue. Results showed no differential auditory cortex activity between hit and miss trials with post-stimulus cues. A late negative response for hit trials was only observed for pre-stimulus cues, suggesting a task-related component. Since experiment 1 provided no evidence for a link of a difference response with tone awareness, experiment 2 was planned to probe if detection of tone streams was linked to a difference response in auditory cortex. Random-tone sequences were presented in the presence of a multi-tone masker, and the sequence was repeated without masker thereafter. Results showed a prominent difference wave for hit compared to miss trials in experiment 2 evoked by targets in the presence of the masker. These results suggest that perceptual awareness of tone streams is linked to neural activity in auditory cortex.

Sensory perception is a product of interactions between the internal state of an organism and the physical attributes of a stimulus. It has been shown across the animal kingdom that perception and sensory-evoked physiological responses are modulated depending on whether or not the stimulus is the consequence of voluntary actions. These phenomena are often attributed to motor signals sent to relevant sensory regions that convey information about upcoming sensory consequences. However, the neurophysiological signature of action-locked modulations in sensory cortex, and their relationship with perception, is still unclear. In the current study, we recorded neurophysiological (using Magnetoencephalography) and behavioral responses from 16 healthy subjects performing an auditory detection task of faint tones. Tones were either generated by subjects' voluntary button presses or occurred predictably following a visual cue. By introducing a constant temporal delay between button press/cue and tone delivery, and applying source-level analysis, we decoupled action-locked and auditory-locked activity in auditory cortex. We show action-locked evoked-responses in auditory cortex following sound-triggering actions and preceding sound onset. Such evoked-responses were not found for button-presses that were not coupled with sounds, or sounds delivered following a predictive visual cue. Our results provide evidence for efferent signals in human auditory cortex that are locked to voluntary actions coupled with future auditory consequences.

Formation of associations in auditory cortex by slow changes of tonic firing