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Yarden, TS, Nelken I.  2017.  Stimulus-specific adaptation in a recurrent network model of primary auditory cortex.. PLoS Comput Biol.. 13(3):e1005437. doi: 10.1371/journal.pcbi.1005437. Abstract
Stimulus-specific adaptation (SSA) occurs when neurons decrease their responses to frequently-presented (standard) stimuli but not, or not as much, to other, rare (deviant) stimuli. SSA is present in all mammalian species in which it has been tested as well as in birds. SSA confers short-term memory to neuronal responses, and may lie upstream of the generation of mismatch negativity (MMN), an important human event-related potential. Previously published models of SSA mostly rely on synaptic depression of the feedforward, thalamocortical input. Here we study SSA in a recurrent neural network model of primary auditory cortex. When the recurrent, intracortical synapses display synaptic depression, the network generates population spikes (PSs). SSA occurs in this network when deviants elicit a PS but standards do not, and we demarcate the regions in parameter space that allow SSA. While SSA based on PSs does not require feedforward depression, we identify feedforward depression as a mechanism for expanding the range of parameters that support SSA. We provide predictions for experiments that could help differentiate between SSA due to synaptic depression of feedforward connections and SSA due to synaptic depression of recurrent connections. Similar to experimental data, the magnitude of SSA in the model depends on the frequency difference between deviant and standard, probability of the deviant, inter-stimulus interval and input amplitude. In contrast to models based on feedforward depression, our model shows true deviance sensitivity as found in experiments.
Wigderson, E, Nelken I, Yarom Y.  2016.  Early multisensory integration of self and source motion in the auditory system.. Proc Natl Acad Sci U S A. 113(29): 8308–8313. Abstract
Discriminating external from self-produced sensory inputs is a major challenge for brains. In the auditory system, sound localization must account for movements of the head and ears, a computation likely to involve multimodal integration. Principal neurons (PNs) of the dorsal cochlear nucleus (DCN) are known to be spatially selective and to receive multimodal sensory information. We studied the responses of PNs to body rotation with or without sound stimulation, as well as to sound source rotation with stationary body. We demonstrated that PNs are sensitive to head direction, and, in the presence of sound, they differentiate between body and sound source movement. Thus, the output of the DCN provides the brain with enough information to disambiguate the movement of a sound source from an acoustically identical relative movement produced by motion of the animal.
Rubin, J, Ulanovsky N, Nelken I, Tishby N.  2016.  The Representation of Prediction Error in Auditory Cortex.. PLoS Comput Biol. 12(8): e1005058. Abstract
To survive, organisms must extract information from the past that is relevant for their future. How this process is expressed at the neural level remains unclear. We address this problem by developing a novel approach from first principles. We show here how to generate low-complexity representations of the past that produce optimal predictions of future events. We then illustrate this framework by studying the coding of 'oddball' sequences in auditory cortex. We find that for many neurons in primary auditory cortex, trial-by-trial fluctuations of neuronal responses correlate with the theoretical prediction error calculated from the short-term past of the stimulation sequence, under constraints on the complexity of the representation of this past sequence. In some neurons, the effect of prediction error accounted for more than 50% of response variability. Reliable predictions often depended on a representation of the sequence of the last ten or more stimuli, although the representation kept only few details of that sequence.
Grimm, S, Escera C, Nelken I.  2016.  Early indices of deviance detection in humans and animal models.. Biological Psychology. Volume 116 Abstract
Detecting unexpected stimuli in the environment is a critical function of the auditory system. Responses to unexpected "deviant" sounds are enhanced compared to responses to expected stimuli. At the human scalp, deviance detection is reflected in the mismatch negativity (MMN) and in an enhancement of the middle-latency response (MLR). Single neurons often respond more strongly to a stimulus when rare than when common, a phenomenon termed stimulus-specific adaptation (SSA). Here we compare stimulus-specific adaptation with scalp-recorded deviance-related responses. We conclude that early markers of deviance detection in the time range of the MLR could be a direct correlate of cortical SSA. Both occur at an early level of cortical activation, both are robust findings with low-probability stimuli, and both show properties of genuine deviance detection. Their causal relation with the later scalp-recorded MMN is a key question in this field.
Khouri, L, Nelken I.  2015.  Detecting the unexpected. Current Opinion in Neurobiology. Volume 35 Abstract
Sensory input is inherently dynamic and redundant. Humans and animals alike show a remarkable ability to extract regularities from the sensory scene and dynamically update their responses to the environment. This type of short-term plasticity occurs on time scales ranging from seconds to minutes (and possibly longer). Mismatch Negativity (a component of the human event-related potentials, MMN) and Stimulus Specific Adaptation (a single-neuron analogue, SSA) are two examples of this form of short-term plasticity. Conceptually, both are thought to express a form of surprise and to represent predictive processing. MMN and SSA therefore provide us with handles for investigating this important time scale of short-term plasticity.
Slomowitz, E, Styr B, Vertkin I, Milshtein-Parush H, Nelken I, Slutsky M, Slutsky I.  2015.  Interplay between population firing stability and single neuron dynamics in hippocampal networks.. eLIFE. Abstract
Neuronal circuits' ability to maintain the delicate balance between stability and flexibility in changing environments is critical for normal neuronal functioning. However, to what extent individual neurons and neuronal populations maintain internal firing properties remains largely unknown. In this study, we show that distributions of spontaneous population firing rates and synchrony are subject to accurate homeostatic control following increase of synaptic inhibition in cultured hippocampal networks. Reduction in firing rate triggered synaptic and intrinsic adaptive responses operating as global homeostatic mechanisms to maintain firing macro-stability, without achieving local homeostasis at the single-neuron level. Adaptive mechanisms, while stabilizing population firing properties, reduced short-term facilitation essential for synaptic discrimination of input patterns. Thus, invariant ongoing population dynamics emerge from intrinsically unstable activity patterns of individual neurons and synapses. The observed differences in the precision of homeostatic control at different spatial scales challenge cell-autonomous theory of network homeostasis and suggest the existence of network-wide regulation rules.
Barniv, D, Nelken I.  2015.  Auditory Streaming as an Online Classification Process with Evidence Accumulation.. PLoS One. 10(12): e0144788. Abstract
When human subjects hear a sequence of two alternating pure tones, they often perceive it in one of two ways: as one integrated sequence (a single "stream" consisting of the two tones), or as two segregated sequences, one sequence of low tones perceived separately from another sequence of high tones (two "streams"). Perception of this stimulus is thus bistable. Moreover, subjects report on-going switching between the two percepts: unless the frequency separation is large, initial perception tends to be of integration, followed by toggling between integration and segregation phases. The process of stream formation is loosely named "auditory streaming". Auditory streaming is believed to be a manifestation of human ability to analyze an auditory scene, i.e. to attribute portions of the incoming sound sequence to distinct sound generating entities. Previous studies suggested that the durations of the successive integration and segregation phases are statistically independent. This independence plays an important role in current models of bistability. Contrary to this, we show here, by analyzing a large set of data, that subsequent phase durations are positively correlated. To account together for bistability and positive correlation between subsequent durations, we suggest that streaming is a consequence of an evidence accumulation process. Evidence for segregation is accumulated during the integration phase and vice versa; a switch to the opposite percept occurs stochastically based on this evidence. During a long phase, a large amount of evidence for the opposite percept is accumulated, resulting in a long subsequent phase. In contrast, a short phase is followed by another short phase. We implement these concepts using a probabilistic model that shows both bistability and correlations similar to those observed experimentally.
Busche, M A, Kekuš M, Adelsberger H, Noda T, Förstl H, Nelken I, Konnerth A.  2015.  Rescue of long-range circuit dysfunction in Alzheimer's disease models.. Nature Neuroscience. Abstract
Alzheimer's disease (AD) is associated with defects of synaptic connectivity. Such defects may not be restricted to local neuronal interactions but may extend to long-range brain activities, such as slow-wave oscillations that are particularly prominent during non-rapid eye movement (non-REM) sleep and are important for integration of information across distant brain regions involved in memory consolidation. There is increasing evidence that sleep is often impaired in AD, but it is unclear whether this impairment is directly related to amyloid-β (Aβ) pathology. Here we demonstrate that slow-wave activity is severely altered in the neocortex, thalamus and hippocampus in mouse models of AD amyloidosis. Most notably, our results reveal an Aβ-dependent impairment of slow-wave propagation, which causes a breakdown of the characteristic long-range coherence of slow-wave activity. The finding that the impairment can be rescued by enhancing GABAAergic inhibition identifies a synaptic mechanism underlying Aβ-dependent large-scale circuit dysfunction.
Moshitch, D, Nelken I.  2014.  The Representation of Interaural Time Differences in High-Frequency Auditory Cortex.. Cerebral cortex. Abstract
Early representations of auditory features often involve neuronal populations whose tuning is substantially wider than behavioral discrimination thresholds. Although behavioral discrimination performance can be sometimes achieved by single neurons when using the appropriate part of their (wide) tuning curves, neurons that encode the resulting high-acuity representations have rarely been described. Here we demonstrate the existence of neurons with extremely narrow tuning for interaural time differences (ITDs), a major physical cue for the azimuth of sound sources. The tuning width of ITD-tuned brainstem neurons is mostly determined by the properties of their acoustic input, and may be 10-100 times wider than behavioral thresholds. In contrast, we show that tuning widths of some neurons in the primary auditory cortex in the cat high-frequency auditory cortex (measured using transposed stimulus) can be very sharp and approach behavioral thresholds. Furthermore, while best ITDs of brainstem neurons often lie outside the range of naturally encountered ITDs (the ethological range), the range of best ITDs of the narrowly tuned cortical neurons corresponds well to the ethological range. Thus, our results suggest that the auditory cortex contains a high-resolution representation of ITDs that explicitly decodes the widely tuned brainstem representations.
Nelken, I, Bizley J, Shamma SA, Wang X.  2014.  Auditory cortical processing in real-world listening: the auditory system going real.. J Neurosci. 34(46):15135-8. Abstract
The auditory sense of humans transforms intrinsically senseless pressure waveforms into spectacularly rich perceptual phenomena: the music of Bach or the Beatles, the poetry of Li Bai or Omar Khayyam, or more prosaically the sense of the world filled with objects emitting sounds that is so important for those of us lucky enough to have hearing. Whereas the early representations of sounds in the auditory system are based on their physical structure, higher auditory centers are thought to represent sounds in terms of their perceptual attributes. In this symposium, we will illustrate the current research into this process, using four case studies. We will illustrate how the spectral and temporal properties of sounds are used to bind together, segregate, categorize, and interpret sound patterns on their way to acquire meaning, with important lessons to other sensory systems as well.
Nelken, I.  2014.  Stimulus-specific adaptation and deviance detection in the auditory system: experiments and models.. Biological cybernetics. Abstract
Stimulus-specific adaptation (SSA) is the reduction in the response to a common stimulus that does not generalize, or only partially generalizes, to other, rare stimuli. SSA has been proposed to be a correlate of 'deviance detection', an important computational task of sensory systems. SSA is ubiquitous in the auditory system: It is found both in cortex and in subcortical stations, and it has been demonstrated in many mammalian species as well as in birds. A number of models have been suggested in the literature to account for SSA in the auditory domain. In this review, the experimental literature is critically examined in relationship to these models. While current models can all account for auditory SSA to some degree, none is fully compatible with the available findings.
Moshitch, D, Nelken I.  2014.  Using Tweedie distributions for fitting spike count data.. Journal of neuroscience methods. 225C:13-28. Abstract
The nature of spike count distributions is of great practical concern for the analysis of neural data. These distributions often have a tendency for 'failures' and a long tail of large counts, and may show a strong dependence of variance on the mean. Furthermore, spike count distributions often show multiplicative rather than additive effects of covariates. We analyzed the responses of neurons in primary auditory cortex to transposed stimuli as a function of interaural time differences (ITD). In more than half of the cases, the variance of neuronal responses showed a supralinear dependence on the mean spike count.
Grodzinsky, Y, Nelken I.  2014.  The neural code that makes us human.. Science. 343(6174):978-9.
Hershenhoren, I, Taaseh N, Antunes FM, Nelken I.  2014.  Intracellular correlates of stimulus-specific adaptation.. J Neurosci.. 34(9):3303-19. Abstract
Stimulus-specific adaptation (SSA) is the reduction in response to a common stimulus that does not generalize, or only partially generalizes, to rare stimuli. SSA is strong and widespread in primary auditory cortex (A1) of rats, but is weak or absent in the main input station to A1, the ventral division of the medial geniculate body. To study SSA in A1, we recorded neural activity in A1 intracellularly using sharp electrodes. We studied the responses to tone pips of the same frequency in different contexts: as Standard and Deviants in Oddball sequences; in equiprobable sequences; in sequences consisting of rare tone presentations; and in sequences composed of many different frequencies, each of which was rare. SSA was found both in subthreshold membrane potential fluctuations and in spiking responses of A1 neurons. SSA for changes in frequency was large at a frequency difference of 44% between Standard and Deviant, and clearly present with tones separated by as little as 4%, near the behavioral frequency difference limen in rats. When using equivalent measures, SSA in spiking responses was generally larger than the SSA at the level of the membrane potential. This effect can be traced to the nonlinearity of the transformation between membrane potential to spikes. Using the responses to the same tone in different contexts made it possible to demonstrate that cortical SSA could not be fully explained by adaptation in narrow frequency channels, even at the level of the membrane potential. We conclude that local processing significantly contributes to the generation of cortical SSA.
Mizrahi, A, Shalev A, Nelken I.  2014.  Single neuron and population coding of natural sounds in auditory cortex.. Current opinion in neurobiology. 24C:103-110. Abstract
The auditory system drives behavior using information extracted from sounds. Early in the auditory hierarchy, circuits are highly specialized for detecting basic sound features. However, already at the level of the auditory cortex the functional organization of the circuits and the underlying coding principles become different. Here, we review some recent progress in our understanding of single neuron and population coding in primary auditory cortex, focusing on natural sounds. We discuss possible mechanisms explaining why single neuron responses to simple sounds cannot predict responses to natural stimuli. We describe recent work suggesting that structural features like local subnetworks rather than smoothly mapped tonotopy are essential components of population coding. Finally, we suggest a synthesis of how single neurons and subnetworks may be involved in coding natural sounds.
Xu, X, Yu X, He J, Nelken I.  2014.  Across-ear stimulus-specific adaptation in the auditory cortex.. Frontiers in neural circuits. 8:89. Abstract
The ability to detect unexpected or deviant events in natural scenes is critical for survival. In the auditory system, neurons from the midbrain to cortex adapt quickly to repeated stimuli but this adaptation does not fully generalize to other rare stimuli, a phenomenon called stimulus-specific adaptation (SSA). Most studies of SSA were conducted with pure tones of different frequencies, and it is by now well-established that SSA to tone frequency is strong and robust in auditory cortex. Here we tested SSA in the auditory cortex to the ear of stimulation using broadband noise. We show that cortical neurons adapt specifically to the ear of stimulation, and that the contrast between the responses to stimulation of the same ear when rare and when common depends on the binaural interaction class of the neurons.
de Hoz, L, Nelken I.  2014.  Frequency tuning in the behaving mouse: different bandwidths for discrimination and generalization.. PloS one. 9(3):e91676. Abstract
When faced with sensory stimuli, an organism may be required to detect very small differences in a physical parameter (discrimination), while in other situations it may have to generalize over many possible values of the same physical parameter. This decision may be based both on learned information and on sensory aspects of perception. In the present study we describe frequency processing in the behaving mouse using both discrimination and generalization as two key aspects of behaviour. We used a novel naturalistic behavioural apparatus designed for mice, the Audiobox, and paradigm contingencies that were identical for both auditory discrimination and generalization, the latter measured using latent inhibition. Mice learned to discriminate between frequencies that were an octave apart in a single trial. They showed significant discrimination between tone frequencies that were as close as 4-7%, and had d' of about 1 for ΔF of around 10%. In contrast, pre-exposure frequencies that were half an octave or less below the conditioned tone elicited latent inhibition, showing a generalization bandwidth of at least half an octave. Thus, in the same apparatus and using the same general memory paradigm, mice showed generalization gradients that were considerably wider than their discrimination threshold, indicating that environmental requirements and previous experience can determine whether the same two frequencies will be considered same or different. Remarkably, generalization gradients paralleled the typical bandwidths established in the auditory periphery and midbrain, suggesting that frequencies may be considered similar when falling within the same critical band.
Nelken, I, Bizley J, Shamma SA, Wang X.  2014.  Auditory cortical processing in real-world listening: the auditory system going real.. The Journal of Neuroscience. Abstract
The auditory sense of humans transforms intrinsically senseless pressure waveforms into spectacularly rich perceptual phenomena: the music of Bach or the Beatles, the poetry of Li Bai or Omar Khayyam, or more prosaically the sense of the world filled with objects emitting sounds that is so important for those of us lucky enough to have hearing. Whereas the early representations of sounds in the auditory system are based on their physical structure, higher auditory centers are thought to represent sounds in terms of their perceptual attributes. In this symposium, we will illustrate the current research into this process, using four case studies. We will illustrate how the spectral and temporal properties of sounds are used to bind together, segregate, categorize, and interpret sound patterns on their way to acquire meaning, with important lessons to other sensory systems as well.
Nelken, I, de Cheveigne A.  2013.  An ear for statistics. Nature Neuroscience.. 16(4):381-382.
Rothschild, G, Cohen L, Mizrahi A, Nelken I.  2013.  Elevated correlations in neuronal ensembles of mouse auditory cortex following parturition.. The Journal of neuroscience : the official journal of the Society for Neuroscience. 33(31):12851-61. Abstract
The auditory cortex is malleable by experience. Previous studies of auditory plasticity have described experience-dependent changes in response profiles of single neurons or changes in global tonotopic organization. However, experience-dependent changes in the dynamics of local neural populations have remained unexplored. In this study, we examined the influence of a dramatic yet natural experience in the life of female mice, giving birth and becoming a mother on single neurons and neuronal ensembles in the primary auditory cortex (A1). Using in vivo two-photon calcium imaging and electrophysiological recordings from layer 2/3 in A1 of mothers and age-matched virgin mice, we monitored changes in the responses to a set of artificial and natural sounds. Population dynamics underwent large changes as measured by pairwise and higher-order correlations, with noise correlations increasing as much as twofold in lactating mothers. Concomitantly, changes in response properties of single neurons were modest and selective. Remarkably, despite the large changes in correlations, information about stimulus identity remained essentially the same in the two groups. Our results demonstrate changes in the correlation structure of neuronal activity as a result of a natural life event.
Globerson, E, Nelken I.  2013.  The neuro-pianist.. Frontiers in systems neuroscience. 7:35.
Nelken, I, Yaron A, Polterovich A, Hershenhoren I.  2013.  Stimulus-specific adaptation beyond pure tones.. Advances in experimental medicine and biology. 787:411-8. Abstract
Detecting rare and surprising events is a useful strategy for sensory -systems. In the human auditory system, deviance detection is indexed by an important component of the auditory event-related potentials, the mismatch negativity (MMN). Responses of single neurons in the inferior colliculus, medial geniculate body, and auditory cortex of mammals (cats, rats, and mice) show responses that share some properties with MMN: they are evoked by rare events, are preattentive (in as much as they occur in anesthetized animals), and, at least at the level of primary auditory cortex, cannot be accounted for by simple fatigue of the incoming sensory information. Here we extend these results to deviations beyond tone frequency. Recording in rat primary auditory cortex and using oddball sequences consisting of two frozen tokens of broadband noise samples, we found differences between the responses to the same token when used as the common and when used as the deviant, showing an exquisite sensitivity to the small differences between two spectro-temporally similar sounds. Similarly, differential adaptation can be demonstrated when using two word-like stimuli that have been derived from human speech but adapted to the rat auditory system. Thus, differential adaptation to common and rare sounds is present also with sounds whose complexity mirrors that of natural environments.
Grienberger, C, Adelsberger H, Stroh A, Milos R-I, Garaschuk O, Schierloh A, Nelken I, Konnerth A.  2012.  Sound-evoked network calcium transients in mouse auditory cortex in vivo.. The Journal of physiology. 590(Pt 4):899-918. Abstract
Population calcium signals generated by the action potential activity of local clusters of neurons have been recorded in the auditory cortex of mice using an optical fibre-based approach. These network calcium transients (NCaTs) occurred spontaneously as well as in response to sound stimulation. Two-photon calcium imaging experiments suggest that neurons and neuropil contribute about equally to the NCaT. Sound-evoked calcium signals had two components: an early, fast increase in calcium concentration, which corresponds to the short-latency spiking responses observed in electrophysiological experiments, and a late, slow calcium transient which lasted for at least 1 s. The slow calcium transients evoked by sound were essentially identical to spontaneous NCaTs. Their sizes were dependent on the spontaneous activity level at sound onset, suggesting that spontaneous and sensory-evoked NCaTs excluded each other. When using pure tones as stimulus, the early evoked calcium transients were more narrowly tuned than the slow NCaTs. The slow NCaTs were correlated with global ‘up states' recorded with epidural potentials, and sound presented during an epidural ‘down state' triggered a calcium transient that was associated with an epidural ‘up state'. Essentially indistinguishable calcium transients were evoked by optogenetic activation of local clusters of layer 5 pyramidal neurons in the auditory cortex, indicating that these neurons play an important role in the generation of the calcium signal. Taken together, our results identify sound-evoked slow NCaTs as an integral component of neuronal signalling in the mouse auditory cortex, reflecting the prolonged neuronal activity of local clusters of neurons that can be activated even by brief stimuli.
Yaron, A, Hershenhoren I, Nelken I.  2012.  Sensitivity to Complex Statistical Regularities in Rat Auditory Cortex. Neuron. 76(3):603-615. Abstract
SummaryNeurons in auditory cortex are sensitive to the probability of stimuli: responses to rare stimuli tend to be stronger than responses to common ones. Here, intra- and extracellular recordings from the auditory cortex of halothane-anesthetized rats revealed the existence of a finer sensitivity to the structure of sound sequences. Using oddball sequences in which the order of stimulus presentations is periodic, we found that tones in periodic sequences evoked smaller responses than the same tones in random sequences. Significant reduction in the responses to the common tones in periodic relative to random sequences occurred even when these tones consisted of 95% of the stimuli in the sequence. The reduction in responses paralleled the complexity of the sound sequences and could not be explained by short-term effects of clusters of deviants on succeeding standards. We conclude that neurons in auditory cortex are sensitive to the detailed structure of sound sequences over timescales of minutes.
Chechik, G, Nelken I.  2012.  Auditory abstraction from spectro-temporal features to coding auditory entities. Proceedings of the National Academy of Sciences of the United States of America. Abstract
The auditory system extracts behaviorally relevant information from acoustic stimuli. The average activity in auditory cortex is known to be sensitive to spectro-temporal patterns in sounds. However, it is not known whether the auditory cortex also processes more abstract features of sounds, which may be more behaviorally relevant than spectro-temporal patterns. Using recordings from three stations of the auditory pathway, the inferior colliculus (IC), the ventral division of the medial geniculate body (MGB) of the thalamus, and the primary auditory cortex (A1) of the cat in response to natural sounds, we compared the amount of information that spikes contained about two aspects of the stimuli: spectro-temporal patterns, and abstract entities present in the same stimuli such as a bird chirp, its echoes, and the ambient noise. IC spikes conveyed on average approximately the same amount of information about spectro-temporal patterns as they conveyed about abstract auditory entities, but A1 and the MGB neurons conveyed on average three times more information about abstract auditory entities than about spectro-temporal patterns. Thus, the majority of neurons in auditory thalamus and cortex coded well the presence of abstract entities in the sounds without containing much information about their spectro-temporal structure, suggesting that they are sensitive to abstract features in these sounds.