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.

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.

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.

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.

Alzheimer's Disease, Hearing Loss, and Deviance Detection.

Age-related hearing loss is a widespread condition among the elderly, affecting communication and social participation. Given its high incidence, it is not unusual that individuals suffering from age-related hearing loss also suffer from other age-related neurodegenerative diseases, a scenario which severely impacts their quality of life. Furthermore, recent studies have identified hearing loss as a relevant risk factor for the development of dementia due to Alzheimer's disease, although the underlying associations are still unclear. In order to cope with the continuous flow of auditory information, the brain needs to separate repetitive sounds from rare, unexpected sounds, which may be relevant. This process, known as deviance detection, is a key component of the sensory perception theory of predictive coding. According to this framework, the brain would use the available incoming information to make predictions about the environment and signal the unexpected stimuli that break those predictions. Such a system can be easily impaired by the distortion of auditory information processing that accompanies hearing loss. Changes in cholinergic neuromodulation have been found to alter auditory deviance detection both in humans and animal models. Interestingly, some theories propose a role for acetylcholine in the development of Alzheimer's disease, the most common type of dementia. Acetylcholine is involved in multiple neurobiological processes such as attention, learning, memory, arousal, sleep and/or cognitive reinforcement, and has direct influence on the auditory system at the levels of the inferior colliculus and auditory cortex. Here we comment on the possible links between acetylcholine, hearing loss, and Alzheimer's disease, and association that is worth further investigation.

Corticothalamic Pathways in Auditory Processing: Recent Advances and Insights From Other Sensory Systems.

The corticothalamic (CT) pathways emanate from either Layer 5 (L5) or 6 (L6) of the neocortex and largely outnumber the ascending, thalamocortical pathways. The CT pathways provide the anatomical foundations for an intricate, bidirectional communication between thalamus and cortex. They act as dynamic circuits of information transfer with the ability to modulate or even drive the response properties of target neurons at each synaptic node of the circuit. L6 CT feedback pathways enable the cortex to shape the nature of its driving inputs, by directly modulating the sensory message arriving at the thalamus. L5 CT pathways can drive the postsynaptic neurons and initiate a transthalamic corticocortical circuit by which cortical areas communicate with each other. For this reason, L5 CT pathways place the thalamus at the heart of information transfer through the cortical hierarchy. Recent evidence goes even further to suggest that the thalamus via CT pathways regulates functional connectivity within and across cortical regions, and might be engaged in cognition, behavior, and perceptual inference. As descending pathways that enable reciprocal and context-dependent communication between thalamus and cortex, we venture that CT projections are particularly interesting in the context of hierarchical perceptual inference formulations such as those contemplated in predictive processing schemes, which so far heavily rely on cortical implementations. We discuss recent proposals suggesting that the thalamus, and particularly higher order thalamus via transthalamic pathways, could coordinate and contextualize hierarchical inference in cortical hierarchies. We will explore these ideas with a focus on the auditory system.

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.

In vivo whole-cell recordings of stimulus-specific adaptation in the inferior colliculus.

The inferior colliculus is an auditory structure where inputs from multiple lower centers converge, allowing the emergence of complex coding properties of auditory information such as stimulus-specific adaptation. Stimulus-specific adaptation is the adaptation of neuronal responses to a specific repeated stimulus, which does not entirely generalize to other new stimuli. This phenomenon provides a mechanism to emphasize saliency and potentially informative sensory inputs. Stimulus-specific adaptation has been traditionally studied analyzing the somatic spiking output. However, studies that correlate within the same inferior colliculus neurons their intrinsic properties, subthreshold responses and the level of acoustic stimulus-specific adaptation are still pending. For this, we recorded in vivo whole-cell patch-clamp neurons in the mouse inferior colliculus while stimulating with current injections or the classic auditory oddball paradigm. Our data based on cases of ten neuron, suggest that although passive properties were similar, intrinsic properties differed between adapting and non-adapting neurons. Non-adapting neurons showed a sustained-regular firing pattern that corresponded to central nucleus neurons and adapting neurons at the inferior colliculus cortices showed variable firing patterns. Our current results suggest that synaptic stimulus-specific adaptation was variable and could not be used to predict the presence of spiking stimulus-specific adaptation. We also observed a small trend towards hyperpolarized membrane potentials in adapting neurons and increased synaptic inhibition with consecutive stimulus repetitions in all neurons. This finding indicates a more simple type of adaptation, potentially related to potassium conductances. Hence, these data represent a modest first step in the intracellular study of stimulus-specific adaptation in inferior colliculus neurons in vivo that will need to be expanded with pharmacological manipulations to disentangle specific ionic channels participation.

Deviance detection in physiologically identified cell types in the rat auditory cortex.

Auditory deviance detection is a function of the auditory system that allows reduction of the processing demand for repetitive stimuli while stressing unpredictable ones, which are potentially more informative. Deviance detection has been extensively studied in humans using the oddball paradigm, which evokes an event-related potential known as mismatch negativity (MMN). The same stimulation paradigms are used in animal studies that aim to elucidate the neuronal mechanisms underlying deviance detection. In order to understand the circuitry responsible for deviance detection in the auditory cortex (AC), it is necessary to determine the properties of excitatory and inhibitory neurons separately. Measuring the spike widths of neurons recorded extracellularly from the anaesthetized rat AC, we classified them as fast spiking or regular spiking units. These two neuron types are generally considered as putative inhibitory or excitatory, respectively. In response to an oddball paradigm, we found that both types of units showed similar amounts of deviance detection overall. When considering each AC field separately, we found that only in A1 fast spiking neurons showed higher deviance detection levels than regular spiking neurons, while in the rest of the fields there was no such distinction. Interpreting these responses in the context of the predictive coding framework, we found that the responses of both types of units reflect mainly prediction error signaling (i.e., genuine deviance detection) rather than repetition suppression.

The Role of Glutamate Neurotransmission in Mismatch Negativity (MMN), A Measure of Auditory Synaptic Plasticity and Change-detection.

Mismatch negativity (MMN) is an electrophysiological signature that occurs in response to unexpected stimuli. It is often referred to as a measure of memory-based change detection, because the elicitation of a prediction error response relies on the formation of a prediction, which in turn, is dependent upon intact memory of previous auditory stimulation. As such, the MMN is altered in conditions in which memory is affected, such as Alzheimer's disease, schizophrenia and healthy aging. The most prominent pharmacological finding for MMN strengthens the link between MMN and synaptic plasticity, as glutamate N-methyl-d-aspartate receptor (NMDA-R) antagonists reduce the MMN response. However, recent data has begun to demonstrate that the link between NMDA-R function and MMN is not as clear as once thought, with low dose and low affinity NMDA-R antagonists observed to facilitate MMN.

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.

The effect of NMDA-R antagonist, MK-801, on neuronal mismatch along the rat auditory thalamocortical pathway.

Efficient sensory processing requires that the brain maximize its response to unexpected stimuli, while suppressing responsivity to expected events. Mismatch negativity (MMN) is an auditory event-related potential that occurs when a regular pattern is interrupted by an event that violates the expected properties of the pattern. According to the predictive coding framework there are two mechanisms underlying the MMN: repetition suppression and prediction error. MMN has been found to be reduced in individuals with schizophrenia, an effect believed to be underpinned by glutamate N-methyl-D-aspartate receptor (NMDA-R) dysfunction. In the current study, we aimed to test how the NMDA-R antagonist, MK-801 in the anaesthetized rat, affected repetition suppression and prediction error processes along the auditory thalamocortical pathway. We found that low-dose systemic administration of MK-801 differentially affect thalamocortical responses, namely, increasing thalamic repetition suppression and cortical prediction error. Results demonstrate an enhancement of neuronal mismatch, also confirmed by large scale-responses. Furthermore, MK-801 produces faster and stronger dynamics of adaptation along the thalamocortical hierarchy. Clearly more research is required to understand how NMDA-R antagonism and dosage affects processes contributing to MMN. Nonetheless, because a low dose of an NMDA-R antagonist increased neuronal mismatch, the outcome has implications for schizophrenia treatment.

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.

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.

Stimulus-specific adaptation in the anesthetized mouse revealed by brainstem auditory evoked potentials.

Neural responses to sensory inputs in a complex and natural environment must be weighted according to their relevance. To do so, the brain needs to be able to deal with sudden stimulus fluctuations in an ever-changing acoustic environment. Stimulus-specific adaptation (SSA) is a phenomenon of some neurons along the auditory pathway that show a reduced response to repetitive sounds while responsive to those that occur rarely. SSA has been shown from the inferior colliculus to auditory cortex, but has not been detected in the cochlear nucleus. To discover where SSA is first generated along the auditory pathway, auditory brainstem responses (ABRs) to pure tones were evaluated in anesthetized mice using an oddball paradigm. Using a typical narrow band-pass filter, changes in the ABRs suggest unspecific short-term adaptation may occur as early as the auditory nerve fibers. Furthermore, after applying a wide band-pass filter -allowing the visualization of a late slow wave in the ABR- we found a reduction of the amplitude of the response to repetitive sounds, compared to rare ones, in the slow wave component P0 that follow the fast wave V. Previous studies have shown the P0 shows temporal correlation with the sustained responses of inferior colliculus, thus we suggest that this nucleus is the first to show stimulus specific adaptation in the auditory pathway.