Feature-selective encoding of substrate vibrations in the forelimb somatosensory cortex.

The spectral content of skin vibrations, produced by either displacing the finger across a surface texture1 or passively sensing external movements through the solid substrate2,3, provides fundamental information about our environment. Low-frequency flutter (below 50 Hz) applied locally to the primate fingertip evokes cyclically entrained spiking in neurons of the primary somatosensory cortex (S1), and thus spike rates in these neurons increase linearly with frequency4,5. However, the same local vibrations at high frequencies (over 100 Hz) cannot be discriminated on the basis of differences in discharge rates of S1 neurons4,6, because spiking is only partially entrained at these frequencies6. Here we investigated whether high-frequency substrate vibrations applied broadly to the mouse forelimb rely on a different cortical coding scheme. We found that forelimb S1 neurons encode vibration frequency similarly to sound pitch representation in the auditory cortex7,8: their spike rates are selectively tuned to a preferred value of a low-level stimulus feature without any temporal entrainment. This feature, identified as the product of frequency and a power function of amplitude, was also found to be perceptually relevant as it predicted behaviour in a frequency discrimination task. Using histology, peripheral deafferentation and optogenetic receptor tagging, we show that these selective responses are inherited from deep Pacinian corpuscles located adjacent to bones, most densely around the ulna and radius and only sparsely along phalanges. This mechanoreceptor arrangement and the tuned cortical rate code suggest that the mouse forelimb constitutes a sensory channel best adapted for passive 'listening' to substrate vibrations, rather than for active texture exploration.

Oscillatory neural responses evoked by natural vestibular stimuli in humans.

While there have been numerous studies of the vestibular system in mammals, less is known about the brain mechanisms of vestibular processing in humans. In particular, of the studies that have been carried out in humans over the last 30 years, none has investigated how vestibular stimulation (VS) affects cortical oscillations. Here we recorded high-density electroencephalography (EEG) in healthy human subjects and a group of bilateral vestibular loss patients (BVPs) undergoing transient and constant-velocity passive whole body yaw rotations, focusing our analyses on the modulation of cortical oscillations in response to natural VS. The present approach overcame significant technical challenges associated with combining natural VS with human electrophysiology and reveals that both transient and constant-velocity VS are associated with a prominent suppression of alpha power (8-13 Hz). Alpha band suppression was localized over bilateral temporo-parietal scalp regions, and these alpha modulations were significantly smaller in BVPs. We propose that suppression of oscillations in the alpha band over temporo-parietal scalp regions reflects cortical vestibular processing, potentially comparable with alpha and mu oscillations in the visual and sensorimotor systems, respectively, opening the door to the investigation of human cortical processing under various experimental conditions during natural VS.

Inference of perceptual priors from path dynamics of passive self-motion.

The monitoring of one's own spatial orientation depends on the ability to estimate successive self-motion cues accurately. This process has become to be known as path integration. A feature of sequential cue estimation, in general, is that the history of previously experienced stimuli, or priors, biases perception. Here, we investigate how during angular path integration, the prior imparted by the displacement path dynamics affects the translation of vestibular sensations into perceptual estimates. Subjects received successive whole-body yaw rotations and were instructed to report their position within a virtual scene after each rotation. The overall movement trajectory either followed a parabolic path or was devoid of explicit dynamics. In the latter case, estimates were biased toward the average stimulus prior and were well captured by an optimal Bayesian estimator model fit to the data. However, the use of parabolic paths reduced perceptual uncertainty, and a decrease of the average size of bias and thus the weight of the average stimulus prior were observed over time. The produced estimates were, in fact, better accounted for by a model where a prediction of rotation magnitude is inferred from the underlying path dynamics on each trial. Therefore, when passively displaced, we seem to be able to build, over time, from sequential vestibular measurements an internal model of the vehicle's movement dynamics. Our findings suggest that in ecological conditions, vestibular afference can be internally predicted, even when self-motion is not actively generated by the observer, thereby augmenting both the accuracy and precision of displacement perception.

Learning to integrate contradictory multisensory self-motion cue pairings.

Humans integrate multisensory information to reduce perceptual uncertainty when perceiving the world and self. Integration fails, however, if a common causality is not attributed to the sensory signals, as would occur in conditions of spatiotemporal discrepancies. In the case of passive self-motion, visual and vestibular cues are integrated according to statistical optimality, yet the extent of cue conflicts that do not compromise this optimality is currently underexplored. Here, we investigate whether human subjects can learn to integrate two arbitrary, but co-occurring, visual and vestibular cues of self-motion. Participants made size comparisons between two successive whole-body rotations using only visual, only vestibular, and both modalities together. The vestibular stimulus provided a yaw self-rotation cue, the visual a roll (Experiment 1) or pitch (Experiment 2) rotation cue. Experimentally measured thresholds in the bimodal condition were compared with theoretical predictions derived from the single-cue thresholds. Our results show that human subjects combine and optimally integrate vestibular and visual information, each signaling self-motion around a different rotation axis (yaw vs. roll and yaw vs. pitch). This finding suggests that the experience of two temporally co-occurring but spatially unrelated self-motion cues leads to inferring a common cause for these two initially unrelated sources of information about self-motion. We discuss our results in terms of specific task demands, cross-modal adaptation, and spatial compatibility. The importance of these results for the understanding of bodily illusions is also discussed.

Peripersonal encoding of forelimb proprioception in the mouse somatosensory cortex.

Conscious perception of limb movements depends on proprioceptive neural responses in the somatosensory cortex. In contrast to tactile sensations, proprioceptive cortical coding is barely studied in the mammalian brain and practically non-existent in rodent research. To understand the cortical representation of this important sensory modality we developed a passive forelimb displacement paradigm in behaving mice and also trained them to perceptually discriminate where their limb is moved in space. We delineated the rodent proprioceptive cortex with wide-field calcium imaging and optogenetic silencing experiments during behavior. Our results reveal that proprioception is represented in both sensory and motor cortical areas. In addition, behavioral measurements and responses of layer 2/3 neurons imaged with two-photon microscopy reveal that passive limb movements are both perceived and encoded in the mouse cortex as a spatial direction vector that interfaces the limb with the body's peripersonal space.

Self-motion leads to mandatory cue fusion across sensory modalities.

When perceiving properties of the world, we effortlessly combine multiple sensory cues into optimal estimates. Estimates derived from the individual cues are generally retained once the multisensory estimate is produced and discarded only if the cues stem from the same sensory modality (i.e., mandatory fusion). Does multisensory integration differ in that respect when the object of perception is one's own body, rather than an external variable? We quantified how humans combine visual and vestibular information for perceiving own-body rotations and specifically tested whether such idiothetic cues are subjected to mandatory fusion. Participants made extensive size comparisons between successive whole body rotations using only visual, only vestibular, and both senses together. Probabilistic descriptions of the subjects' perceptual estimates were compared with a Bayes-optimal integration model. Similarity between model predictions and experimental data echoed a statistically optimal mechanism of multisensory integration. Most importantly, size discrimination data for rotations composed of both stimuli was best accounted for by a model in which only the bimodal estimator is accessible for perceptual judgments as opposed to an independent or additive use of all three estimators (visual, vestibular, and bimodal). Indeed, subjects' thresholds for detecting two multisensory rotations as different from one another were, in pertinent cases, larger than those measured using either single-cue estimate alone. Rotations different in terms of the individual visual and vestibular inputs but quasi-identical in terms of the integrated bimodal estimate became perceptual metamers. This reveals an exceptional case of mandatory fusion of cues stemming from two different sensory modalities.

The absence of eye muscle fatigue indicates that the nervous system compensates for non-motor disturbances of oculomotor function.

The physical properties of our bodies are subject to change (due to fatigue, heavy equipment, injury or aging) as we move around in the surrounding environment. The traditional definition of motor adaptation dictates that a mechanism in our brain needs to compensate for such alterations by appropriately modifying neural motor commands, if the vitally important accuracy of executed movements is to be preserved. In this article we describe how a repetitive eye movement task brings about changes in eye saccade kinematics that compromise accurate motor performance in the absence of a proper compensatory response. Surgical lesions in animals and human patient studies have previously demonstrated that an intact cerebellum is necessary for the compensation to arise and prevent the occurrence of hypometric movements. Here we identified the dynamic properties of the eye plant by recording from abducens motoneurons responsible for the required movement and measured the muscle response to microstimulation of the abducens nucleus in rhesus monkeys. The ensuing results demonstrate that the muscular periphery remains intact during the fatiguing eye movement task, while internal sources of noise (drowsiness, attentional modulation, neuronal fatigue etc.) must be responsible for a diminished oculomotor performance. This finding leads to the important realization that while supervising the accuracy of our movements, the nervous system takes additionally into account and adapts to any disruptive processes within the brain itself, clearly unrelated to the dynamical behavior of muscles or the environment. The existence of this supplementary mechanism forces a reassessment of traditional views of cerebellum-dependent motor adaptation.

The role of the cerebellum in saccadic adaptation as a window into neural mechanisms of motor learning.

How does the nervous system guide the muscular periphery during the acquisition of a new motor skill? This is a fundamental question for researchers trying to understand the neural basis of motor learning. Recent advances in studying a valuable example of short-term motor learning, namely the adaptation of saccadic eye movements, have revealed neuronal processes in the cerebellum that underlie the unfolding of the learned behavior. In this review, we describe the latest findings from electrophysiology studies of saccadic adaptation and how they can generalize to more elaborate examples of cerebellum-dependent adaptation of movements. We focus our discussion on the plastic changes that are observed in the firing properties of Purkinje cells during the acquisition of the wanted motor response and describe how the altered activity of these neurons modifies the dynamics of the cerebellar microcircuitry. We finally demonstrate how such task-related modifications in the cerebellum are appropriate to fine-tune extracerebellar pre-motor structures and induce the learned behavior.

A common computational principle for vibrotactile pitch perception in mouse and human.

We live surrounded by vibrations generated by moving objects. These oscillatory stimuli propagate through solid substrates, are sensed by mechanoreceptors in our body and give rise to perceptual attributes such as vibrotactile pitch (i.e. the perception of how high or low a vibration's frequency is). Here, we establish a mechanistic relationship between vibrotactile pitch perception and the physical properties of vibrations using behavioral tasks, in which vibratory stimuli were delivered to the human fingertip or the mouse forelimb. The resulting perceptual reports were analyzed with a model demonstrating that physically different combinations of vibration frequencies and amplitudes can produce equal pitch perception. We found that the perceptually indistinguishable but physically different stimuli follow a common computational principle in mouse and human. It dictates that vibrotactile pitch perception is shifted with increases in amplitude toward the frequency of highest vibrotactile sensitivity. These findings suggest the existence of a fundamental relationship between the seemingly unrelated concepts of spectral sensitivity and pitch perception.

Orientation Preference Maps in Microcebus murinus Reveal Size-Invariant Design Principles in Primate Visual Cortex.

Orientation preference maps (OPMs) are a prominent feature of primary visual cortex (V1) organization in many primates and carnivores. In rodents, neurons are not organized in OPMs but are instead interspersed in a "salt and pepper" fashion, although clusters of orientation-selective neurons have been reported. Does this fundamental difference reflect the existence of a lower size limit for orientation columns (OCs) below which they cannot be scaled down with decreasing V1 size? To address this question, we examined V1 of one of the smallest living primates, the 60-g prosimian mouse lemur (Microcebus murinus). Using chronic intrinsic signal imaging, we found that mouse lemur V1 contains robust OCs, which are arranged in a pinwheel-like fashion. OC size in mouse lemurs was found to be only marginally smaller compared to the macaque, suggesting that these circuit elements are nearly incompressible. The spatial arrangement of pinwheels is well described by a common mathematical design of primate V1 circuit organization. In order to accommodate OPMs, we found that the mouse lemur V1 covers one-fifth of the cortical surface, which is one of the largest V1-to-cortex ratios found in primates. These results indicate that the primate-type visual cortical circuit organization is constrained by a size limitation and raises the possibility that its emergence might have evolved by disruptive innovation rather than gradual change.

Characteristics of responses of Golgi cells and mossy fibers to eye saccades and saccadic adaptation recorded from the posterior vermis of the cerebellum.

The anatomical organization of the granular layer of the cerebellum suggests an important function for Golgi cells (GC) in the pathway conveying mossy fiber (MF) afferents to Purkinje cells. Based on such anatomic observations, early proposals have attributed a role in "gain control" for GCs, a function disputed by recent investigations, which assert that GCs instead contribute to oscillatory mechanisms. However, conclusive physiological evidence based on studies of cerebellum-dependent behavior supporting/dismissing the gain control proposition has been lacking as of yet. We addressed the possible function of this interneuron by recording the activity of a large number of both MFs and GCs during saccadic eye movements from the same cortical area of the monkey cerebellum, namely the oculomotor vermis (OMV). Our cellular identification conformed to previously established criteria, mainly to juxtacellular labeling studies correlating physiological parameters with cell morphology. Response patterns of both MFs and GCs were highly heterogeneous. MF discharges correlated linearly with eye saccade metrics and timing, showing directional preference and precise direction tuning. In contrast, GC discharges did not correlate strongly with the metrics or direction of movement. Their discharge properties were also unaffected by motor learning during saccadic adaptation. The OMV therefore receives a barrage of information about eye movements from different oculomotor areas over the MF pathway, which is not reflected in GCs. The unspecificity of GCs has important implications for the intricacies of neuronal processing in the granular layer, clearly discrediting their involvement in gain control and instead suggesting a more secluded role for these interneurons.

Pupil Size Coupling to Cortical States Protects the Stability of Deep Sleep via Parasympathetic Modulation.

During wakefulness, pupil diameter can reflect changes in attention, vigilance, and cortical states. How pupil size relates to cortical activity during sleep, however, remains unknown. Pupillometry during natural sleep is inherently challenging since the eyelids are usually closed. Here, we present a novel head-fixed sleep paradigm in combination with infrared back-illumination pupillometry (iBip) allowing robust tracking of pupil diameter in sleeping mice. We found that pupil size can be used as a reliable indicator of sleep states and that cortical activity becomes tightly coupled to pupil size fluctuations during non-rapid eye movement (NREM) sleep. Pharmacological blocking experiments indicate that the observed pupil size changes during sleep are mediated via the parasympathetic system. We furthermore found that constrictions of the pupil during NREM episodes might play a protective role for stability of sleep depth. These findings reveal a fundamental relationship between cortical activity and pupil size, which has so far been hidden behind closed eyelids.

Optimal visuo-vestibular integration for self-motion perception in patients with unilateral vestibular loss.

Unilateral vestibular loss (UVL) is accompanied by deficits in processing of visual and vestibular self-motion cues. The present study examined whether multisensory integration of these two types of information is, nevertheless, intact in such patients. Patients were seated on a rotating platform with a screen simulating 3D rotation in front of them and asked to judge the relative magnitude of two successive rotations in the yaw plane in three conditions: vestibular stimulation, visual stimulation and bimodal stimulation (congruent stimuli from both modalities together). Similar to findings in healthy controls, UVL patients exhibited optimal multisensory integration during both ipsi- and contralesional rotations. The benefit of multisensory integration was more pronounced on the ipsilesional side. These results show that visuo-vestibular integration for passive self-motion is automatic and suggests that it functions without additional cognitive mechanisms, unlike more complex multisensory tasks such as postural control and spatial navigation, previously shown to be impaired in UVL patients.

Rapid Integration of Artificial Sensory Feedback during Operant Conditioning of Motor Cortex Neurons.

Neuronal motor commands, whether generating real or neuroprosthetic movements, are shaped by ongoing sensory feedback from the displacement being produced. Here we asked if cortical stimulation could provide artificial feedback during operant conditioning of cortical neurons. Simultaneous two-photon imaging and real-time optogenetic stimulation were used to train mice to activate a single neuron in motor cortex (M1), while continuous feedback of its activity level was provided by proportionally stimulating somatosensory cortex. This artificial signal was necessary to rapidly learn to increase the conditioned activity, detect correct performance, and maintain the learned behavior. Population imaging in M1 revealed that learning-related activity changes are observed in the conditioned cell only, which highlights the functional potential of individual neurons in the neocortex. Our findings demonstrate the capacity of animals to use an artificially induced cortical channel in a behaviorally relevant way and reveal the remarkable speed and specificity at which this can occur.

Visual-vestibular interaction hypothesis for the control of orienting gaze shifts by brain stem omnipause neurons.

Models of combined eye-head gaze shifts all aim to realistically simulate behaviorally observed movement dynamics. One of the most problematic features of such models is their inability to determine when a saccadic gaze shift should be initiated and when it should be ended. This is commonly referred to as the switching mechanism mediated by omni-directional pause neurons (OPNs) in the brain stem. Proposed switching strategies implemented in existing gaze control models all rely on a sensory error between instantaneous gaze position and the spatial target. Accordingly, gaze saccades are initiated after presentation of an eccentric visual target and subsequently terminated when an internal estimate of gaze position becomes nearly equal to that of the target. Based on behavioral observations, we demonstrate that such a switching mechanism is insufficient and is unable to explain certain types of movements. We propose an improved hypothesis for how the OPNs control gaze shifts based on a visual-vestibular interaction of signals known to be carried on anatomical projections to the OPN area. The approach is justified by the analysis of recorded gaze shifts interrupted by a head brake in animal subjects and is demonstrated by implementing the switching mechanism in an anatomically based gaze control model. Simulated performance reveals that a weighted sum of three signals: gaze motor error, head velocity, and eye velocity, hypothesized as inputs to OPNs, successfully reproduces diverse behaviorally observed eye-head movements that no other existing model can account for.