Two Prediction Error Systems in the Nonlemniscal Inferior Colliculus: "Spectral" and "Nonspectral".

According to the predictive processing framework, perception emerges from the reciprocal exchange of predictions and prediction errors (PEs) between hierarchically organized neural circuits. The nonlemniscal division of the inferior colliculus (IC) is the earliest source of auditory PE signals, but their neuronal generators, properties, and functional relevance have remained mostly undefined. We recorded single-unit mismatch responses to auditory oddball stimulation at different intensities, together with activity evoked by two sequences of alternating tones to control frequency-specific effects. Our results reveal a differential treatment of the unpredictable "many-standards" control and the predictable "cascade" control by lemniscal and nonlemniscal IC neurons that is not present in the auditory thalamus or cortex. Furthermore, we found that frequency response areas of nonlemniscal IC neurons reflect their role in subcortical predictive processing, distinguishing three hierarchical levels: (1) nonlemniscal neurons with sharply tuned receptive fields exhibit mild repetition suppression without signaling PEs, thereby constituting the input level of the local predictive processing circuitry. (2) Neurons with broadly tuned receptive fields form the main, "spectral" PE signaling system, which provides dynamic gain compensation to near-threshold unexpected sounds. This early enhancement of saliency reliant on spectral features was not observed in the auditory thalamus or cortex. (3) Untuned neurons form an accessory, "nonspectral" PE signaling system, which reports all surprising auditory deviances in a robust and consistent manner, resembling nonlemniscal neurons in the auditory cortex. These nonlemniscal IC neurons show unstructured and unstable receptive fields that could result from inhibitory input controlled by corticofugal projections conveying top-down predictions.

Prediction error signaling explains neuronal mismatch responses in the medial prefrontal cortex.

The mismatch negativity (MMN) is a key biomarker of automatic deviance detection thought to emerge from 2 cortical sources. First, the auditory cortex (AC) encodes spectral regularities and reports frequency-specific deviances. Then, more abstract representations in the prefrontal cortex (PFC) allow to detect contextual changes of potential behavioral relevance. However, the precise location and time asynchronies between neuronal correlates underlying this frontotemporal network remain unclear and elusive. Our study presented auditory oddball paradigms along with "no-repetition" controls to record mismatch responses in neuronal spiking activity and local field potentials at the rat medial PFC. Whereas mismatch responses in the auditory system are mainly induced by stimulus-dependent effects, we found that auditory responsiveness in the PFC was driven by unpredictability, yielding context-dependent, comparatively delayed, more robust and longer-lasting mismatch responses mostly comprised of prediction error signaling activity. This characteristically different composition discarded that mismatch responses in the PFC could be simply inherited or amplified downstream from the auditory system. Conversely, it is more plausible for the PFC to exert top-down influences on the AC, since the PFC exhibited flexible and potent predictive processing, capable of suppressing redundant input more efficiently than the AC. Remarkably, the time course of the mismatch responses we observed in the spiking activity and local field potentials of the AC and the PFC combined coincided with the time course of the large-scale MMN-like signals reported in the rat brain, thereby linking the microscopic, mesoscopic, and macroscopic levels of automatic deviance detection.

Dopamine modulates subcortical responses to surprising sounds.

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

The posterior auditory field is the chief generator of prediction error signals in the auditory cortex.

The auditory cortex (AC) encompasses distinct fields subserving partly different aspects of sound processing. One essential function of the AC is the detection of unpredicted sounds, as revealed by differential neural activity to predictable and unpredictable sounds. According to the predictive coding framework, this effect can be explained by repetition suppression and/or prediction error signaling. The present study investigates functional specialization of the rat AC fields in repetition suppression and prediction error by combining a tone frequency oddball paradigm (involving high-probable standard and low-probable deviant tones) with two different control sequences (many-standards and cascade). Tones in the control sequences were comparable to deviant events with respect to neural adaptation but were not violating a regularity. Therefore, a difference in the neural activity between deviant and control tones indicates a prediction error effect, whereas a difference between control and standard tones indicates a repetition suppression effect. Single-unit recordings revealed by far the largest prediction error effects for the posterior auditory field, while the primary auditory cortex, the anterior auditory field, the ventral auditory field, and the suprarhinal auditory field were dominated by repetition suppression effects. Statistically significant repetition suppression effects occurred in all AC fields, whereas prediction error effects were less robust in the primary auditory cortex and the anterior auditory field. Results indicate that the non-lemniscal, posterior auditory field is more engaged in context-dependent processing underlying deviance-detection than the other AC fields, which are more sensitive to stimulus-dependent effects underlying differential degrees of neural adaptation.

Pattern-sensitive neurons reveal encoding of complex auditory regularities in the rat inferior colliculus.

A 'pattern alternation paradigm' has been previously used in human ERP recordings to investigate the brain encoding of complex auditory regularities, but prior studies on regularity encoding in animal models to examine mechanisms of adaptation of auditory neuronal responses have used primarily oddball stimulus sequences to study stimulus-specific adaptation alone. In order to examine the sensitivity of neuronal adaptation to expected and unexpected events embedded in a complex sound sequence, we used a similar patterned sequence of sounds. We recorded single unit activity and compared neuronal responses in the rat inferior colliculus (IC) to sound stimuli conforming to pattern alternation regularity with those to stimuli in which occasional sound repetitions violated that alternation. Results show that some neurons in the rat inferior colliculus are sensitive to the history of patterned stimulation and to violations of patterned regularity, demonstrating that there is a population of subcortical neurons, located as early as the level of the midbrain, that can detect more complex stimulus regularities than previously supposed and that are as sensitive to complex statistics as some neurons in primary auditory cortex. Our findings indicate that these pattern-sensitive neurons can extract temporal and spectral regularities between successive acoustic stimuli. This is important because the extraction of regularities from the sound sequences will result in the development of expectancies for future sounds and hence, the present results are compatible with predictive coding models. Our results demonstrate that some collicular neurons, located as early as in the midbrain level, are involved in the generation and shaping of prediction errors in ways not previously considered and thus, the present findings challenge the prevailing view that perceptual organization of sound only emerges at the auditory cortex level.

Topographic Distribution of Stimulus-Specific Adaptation across Auditory Cortical Fields in the Anesthetized Rat.

Stimulus-specific adaptation (SSA) in single neurons of the auditory cortex was suggested to be a potential neural correlate of the mismatch negativity (MMN), a widely studied component of the auditory event-related potentials (ERP) that is elicited by changes in the auditory environment. However, several aspects on this SSA/MMN relation remain unresolved. SSA occurs in the primary auditory cortex (A1), but detailed studies on SSA beyond A1 are lacking. To study the topographic organization of SSA, we mapped the whole rat auditory cortex with multiunit activity recordings, using an oddball paradigm. We demonstrate that SSA occurs outside A1 and differs between primary and nonprimary cortical fields. In particular, SSA is much stronger and develops faster in the nonprimary than in the primary fields, paralleling the organization of subcortical SSA. Importantly, strong SSA is present in the nonprimary auditory cortex within the latency range of the MMN in the rat and correlates with an MMN-like difference wave in the simultaneously recorded local field potentials (LFP). We present new and strong evidence linking SSA at the cellular level to the MMN, a central tool in cognitive and clinical neuroscience.

Cholinergic Modulation of Stimulus-Specific Adaptation in the Inferior Colliculus.

Neural encoding of an ever-changing acoustic environment is a complex and demanding process that depends on modulation by neuroactive substances. Some neurons of the inferior colliculus (IC) exhibit "stimulus-specific adaptation" (SSA), i.e., a decrease in their response to a repetitive sound, but not to a rare one. Previous studies have demonstrated that acetylcholine (ACh) alters the frequency response areas of auditory neurons and therefore is important in the encoding of spectral information. Here, we address how microiontophoretic application of ACh modulates SSA in the IC of the anesthetized rat. We found that ACh decreased SSA in IC neurons by increasing the response to the repetitive tone. This effect was mainly mediated by muscarinic receptors. The strength of the cholinergic modulation depended on the baseline SSA level, exerting its greatest effect on neurons with intermediate SSA responses across IC subdivisions. Our data demonstrate that the increased availability of ACh exerts transient functional changes in partially adapting IC neurons, enhancing the sensory encoding of the ongoing stimulation. This effect potentially contributes to the propagation of ascending sensory-evoked afferent activity through the thalamus en route to the cortex. SIGNIFICANCE STATEMENT: Neural encoding of an ever-changing acoustic environment is a complex and demanding task that may depend on the available levels of neuroactive substances. We explored how the cholinergic inputs affect the responses of neurons in the auditory midbrain that exhibit different degrees of stimulus-specific adaptation (SSA), i.e., a specific decrease in their response to a repeated sound that does not generalize to other, rare sounds. This work addresses the role of cholinergic synaptic inputs as well as the contribution of the muscarinic and nicotinic receptors on SSA. This is the first report on the role of neuromodulation on SSA, and the results contribute to our understanding of the cellular bases for processing low- and high-probability sounds.

Deviance detection in auditory subcortical structures: what can we learn from neurochemistry and neural connectivity?

A remarkable ability of animals that is critical for survival is to detect and respond to to unexpected stimuli in an ever-changing world. Auditory neurons that show stimulus-specific adaptation (SSA), i.e., a decrease in their response to frequently occurring stimuli while maintaining responsiveness when different stimuli are presented, might participate in the coding of deviance occurrence. Traditionally, deviance detection is measured by the mismatch negativity (MMN) potential in studies of evoked local field potentials. We present a review of the state-of-the-art of SSA in auditory subcortical nuclei, i.e., the inferior colliculus and medial geniculate body of the thalamus, and link the differential receptor distribution and neural connectivity of those regions in which extreme SSA has been found. Furthermore, we review both SSA and MMN-like responses in auditory and non-auditory areas that exhibit multimodal sensitivities that we suggest conform to a distributed network encoding for deviance detection. The understanding of the neurochemistry and response similarities across these different regions will contribute to a better understanding of the neural mechanism underlying deviance detection.

Modulation of stimulus-specific adaptation by GABA(A) receptor activation or blockade in the medial geniculate body of the anaesthetized rat.

Stimulus-specific adaptation (SSA), which describes adaptation to repeated sounds concurrent with the maintenance of responsiveness to uncommon ones, may be an important neuronal mechanism for the detection of and attendance to rare stimuli or for the detection of deviance. It is well known that GABAergic neurotransmission regulates several different response properties in central auditory system neurons and that GABA is the major inhibitory neurotransmitter acting in the medial geniculate body (MGB). The mechanisms underlying SSA are still poorly understood; therefore, the primary aim of the present study was to examine what role, if any, MGB GABAergic circuits play in the generation and/or modulation of SSA. Microiontophoretic activation of GABA(A) receptors (GABA(A)Rs) with GABA or with the selective GABA(A)R agonist gaboxadol significantly increased SSA (computed with the common SSA index, CSI) by decreasing responses to common stimuli while having a lesser effect on responses to novel stimuli. In contrast, GABA(A)R blockade using gabazine resulted in a significant decrease in SSA. In all cases, decreases in the CSI during gabazine application were accompanied by an increase in firing rate to the stimulus paradigm. The present findings, in conjunction with those of previous studies, suggest that GABA(A)-mediated inhibition does not generate the SSA response, but can regulate the level of SSA sensitivity in a gain control manner. The existence of successive hierarchical levels of processing through the auditory system suggests that the GABAergic circuits act to enhance mechanisms to reduce redundant information.

An overview of stimulus-specific adaptation in the auditory thalamus.

In the auditory brain, some populations of neurons exhibit stimulus-specific adaptation (SSA), whereby they adapt to frequently occurring stimuli but retain sensitivity to stimuli that are rare. SA has been observed in auditory structures from the midbrain to the primary auditory cortex (A1) and has been proposed to be a precursor to the generation of deviance detection. SSA is strongly expressed in non-lemniscal regions of the medial geniculate body (MGB), the principal nucleus of the auditory thalamus. In this account we review the state of the art of SSA research in the MGB, highlighting the importance of this auditory centre in detecting sounds that may be relevant for survival.

Physiological properties of auditory neurons responding to omission deviants in the anesthetized rat.

The detection of novel, low probability events in the environment is critical for survival. To perform this vital task, our brain is continuously building and updating a model of the outside world; an extensively studied phenomenon commonly referred to as predictive coding. Predictive coding posits that the brain is continuously extracting regularities from the environment to generate predictions. These predictions are then used to supress neuronal responses to redundant information, filtering those inputs, which then automatically enhances the remaining, unexpected inputs. We have recently described the ability of auditory neurons to generate predictions about expected sensory inputs by detecting their absence in an oddball paradigm using omitted tones as deviants. Here, we studied the responses of individual neurons to omitted tones by presenting individual sequences of repetitive pure tones, using both random and periodic omissions, presented at both fast and slow rates in the inferior colliculus and auditory cortex neurons of anesthetized rats. Our goal was to determine whether feature-specific dependence of these predictions exists. Results showed that omitted tones could be detected at both high (8 Hz) and slow repetition rates (2 Hz), with detection being more robust at the non-lemniscal auditory pathway.

Acetylcholine modulates the precision of prediction error in the auditory cortex.

A fundamental property of sensory systems is their ability to detect novel stimuli in the ambient environment. The auditory brain contains neurons that decrease their response to repetitive sounds but increase their firing rate to novel or deviant stimuli; the difference between both responses is known as stimulus-specific adaptation or neuronal mismatch (nMM). Here, we tested the effect of microiontophoretic applications of ACh on the neuronal responses in the auditory cortex (AC) of anesthetized rats during an auditory oddball paradigm, including cascade controls. Results indicate that ACh modulates the nMM, affecting prediction error responses but not repetition suppression, and this effect is manifested predominantly in infragranular cortical layers. The differential effect of ACh on responses to standards, relative to deviants (in terms of averages and variances), was consistent with the representational sharpening that accompanies an increase in the precision of prediction errors. These findings suggest that ACh plays an important role in modulating prediction error signaling in the AC and gating the access of these signals to higher cognitive levels.

How 'hidden hearing loss' noise exposure affects neural coding in the inferior colliculus of rats.

Exposure to brief, intense sound can produce profound changes in the auditory system, from the internal structure of inner hair cells to reduced synaptic connections between the auditory nerves and the inner hair cells. Moreover, noisy environments can also lead to alterations in the auditory nerve or to processing changes in the auditory midbrain, all without affecting hearing thresholds. This so-called hidden hearing loss (HHL) has been shown in tinnitus patients and has been posited to account for hearing difficulties in noisy environments. However, much of the neuronal research thus far has investigated how HHL affects the response characteristics of individual fibres in the auditory nerve, as opposed to higher stations in the auditory pathway. Human models show that the auditory nerve encodes sound stochastically. Therefore, a sufficient reduction in nerve fibres could result in lowering the sampling of the acoustic scene below the minimum rate necessary to fully encode the scene, thus reducing the efficacy of sound encoding. Here, we examine how HHL affects the responses to frequency and intensity of neurons in the inferior colliculus of rats, and the duration and firing rate of those responses. Finally, we examined how shorter stimuli are encoded less effectively by the auditory midbrain than longer stimuli, and how this could lead to a clinical test for HHL.

Neural correlates of novelty detection in the primary auditory cortex of behaving monkeys.

The neural mechanisms underlying novelty detection are not well understood, especially in relation to behavior. Here, we present single-unit responses from the primary auditory cortex (A1) from two monkeys trained to detect deviant tones amid repetitive ones. Results show that monkeys can detect deviant sounds, and there is a strong correlation between late neuronal responses (250-350 ms after deviant onset) and the monkeys' perceptual decisions. The magnitude and timing of both neuronal and behavioral responses are increased by larger frequency differences between the deviant and standard tones and by increasing the number of standard tones preceding the deviant. This suggests that A1 neurons encode novelty detection in behaving monkeys, influenced by stimulus relevance and expectations. This study provides evidence supporting aspects of predictive coding in the sensory cortex.

Protocol for behavioral and neural recording in macaques during a novelty detection task.

The neural mechanisms of novelty detection, especially in relation to behavior, are currently poorly understood. Here, we present a protocol for recording neuronal activity in macaque auditory cortex during novelty detection tasks. We describe steps for behavioral training, surgical headpost implantation, MRI-based electrode targeting, and electrophysiological recording. These steps allow direct assessment of the correlation between novelty detection behavior and neuronal activity. For complete details on the use and execution of this protocol, please refer to Gong et al.1.

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.

Novelty detection in an auditory oddball task on freely moving rats.

The relative importance or saliency of sensory inputs depend on the animal's environmental context and the behavioural responses to these same inputs can vary over time. Here we show how freely moving rats, trained to discriminate between deviant tones embedded in a regular pattern of repeating stimuli and different variations of the classic oddball paradigm, can detect deviant tones, and this discriminability resembles the properties that are typical of neuronal adaptation described in previous studies. Moreover, the auditory brainstem response (ABR) latency decreases after training, a finding consistent with the notion that animals develop a type of plasticity to auditory stimuli. Our study suggests the existence of a form of long-term memory that may modulate the level of neuronal adaptation according to its behavioural relevance, and sets the ground for future experiments that will help to disentangle the functional mechanisms that govern behavioural habituation and its relation to neuronal adaptation.

Neuronal responses to omitted tones in the auditory brain: A neuronal correlate for predictive coding.

Prediction provides key advantages for survival, and cognitive studies have demonstrated that the brain computes multilevel predictions. Evidence for predictions remains elusive at the neuronal level because of the complexity of separating neural activity into predictions and stimulus responses. We overcome this challenge by recording from single neurons from cortical and subcortical auditory regions in anesthetized and awake preparations, during unexpected stimulus omissions interspersed in a regular sequence of tones. We find a subset of neurons that responds reliably to omitted tones. In awake animals, omission responses are similar to anesthetized animals, but larger and more frequent, indicating that the arousal and attentional state levels affect the degree to which predictions are neuronally represented. Omission-sensitive neurons also responded to frequency deviants, with their omission responses getting emphasized in the awake state. Because omission responses occur in the absence of sensory input, they provide solid and empirical evidence for the implementation of a predictive process.

Effect of auditory cortex deactivation on stimulus-specific adaptation in the medial geniculate body.

An animal's survival may depend on detecting new events or objects in its environment, and it is likely that the brain has evolved specific mechanisms to detect such changes. In sensory systems, neurons often exhibit stimulus-specific adaptation (SSA) whereby they adapt to frequently occurring stimuli, but resume firing when "surprised" by rare or new ones. In the auditory system, SSA has been identified in the midbrain, thalamus, and auditory cortex (AC). It has been proposed that the SSA observed subcortically originates in the AC as a higher-order property that is transmitted to the subcortical nuclei via corticofugal pathways. Here we report that SSA in the auditory thalamus of the rat remains intact when the AC is deactivated by cooling, thus demonstrating that the AC is not necessary for the generation of SSA in the thalamus. The AC does, however, modulate the responses of thalamic neurons in a way that strongly indicates a gain modulation mechanism. The changes imposed by the AC in thalamic neurons depend on the level of SSA that they exhibit.