Simple spike dynamics of Purkinje cells in the macaque vestibulo-cerebellum during passive whole-body self-motion.

Theories of cerebellar functions posit that the cerebellum implements internal models for online correction of motor actions and sensory estimation. As an example of such computations, an internal model resolves a sensory ambiguity where the peripheral otolith organs in the inner ear sense both head tilts and translations. Here we exploit the response dynamics of two functionally coupled Purkinje cell types in the vestibular part of the caudal vermis (lobules IX and X) to understand their role in this computation. We find that one population encodes tilt velocity, whereas the other, translation-selective, population encodes linear acceleration. We predict that an intermediate neuronal type should temporally integrate the output of tilt-selective cells into a tilt position signal.

Supervised Multisensory Calibration Signals Are Evident in VIP But Not MSTd.

Multisensory plasticity enables our senses to dynamically adapt to each other and the external environment, a fundamental operation that our brain performs continuously. We searched for neural correlates of adult multisensory plasticity in the dorsal medial superior temporal area (MSTd) and the ventral intraparietal area (VIP) in 2 male rhesus macaques using a paradigm of supervised calibration. We report little plasticity in neural responses in the relatively low-level multisensory cortical area MSTd. In contrast, neural correlates of plasticity are found in higher-level multisensory VIP, an area with strong decision-related activity. Accordingly, we observed systematic shifts of VIP tuning curves, which were reflected in the choice-related component of the population response. This is the first demonstration of neuronal calibration, together with behavioral calibration, in single sessions. These results lay the foundation for understanding multisensory neural plasticity, applicable broadly to maintaining accuracy for sensorimotor tasks.SIGNIFICANCE STATEMENT Multisensory plasticity is a fundamental and continual function of the brain that enables our senses to adapt dynamically to each other and to the external environment. Yet, very little is known about the neuronal mechanisms of multisensory plasticity. In this study, we searched for neural correlates of adult multisensory plasticity in the dorsal medial superior temporal area (MSTd) and the ventral intraparietal area (VIP) using a paradigm of supervised calibration. We found little plasticity in neural responses in the relatively low-level multisensory cortical area MSTd. By contrast, neural correlates of plasticity were found in VIP, a higher-level multisensory area with strong decision-related activity. This is the first demonstration of neuronal calibration, together with behavioral calibration, in single sessions.

Genetically eliminating Purkinje neuron GABAergic neurotransmission increases their response gain to vestibular motion.

Purkinje neurons in the caudal cerebellar vermis combine semicircular canal and otolith signals to segregate linear and gravitational acceleration, evidence for how the cerebellum creates internal models of body motion. However, it is not known which cerebellar circuit connections are necessary to perform this computation. We first showed that this computation is evolutionarily conserved and represented across multiple lobules of the rodent vermis. Then we tested whether Purkinje neuron GABAergic output is required for accurately differentiating linear and gravitational movements through a conditional genetic silencing approach. By using extracellular recordings from lobules VI through X in awake mice, we show that silencing Purkinje neuron output significantly alters their baseline simple spike variability. Moreover, the cerebellum of genetically manipulated mice continues to distinguish linear from gravitational acceleration, suggesting that the underlying computations remain intact. However, response gain is significantly increased in the mutant mice over littermate controls. Altogether, these data argue that Purkinje neuron feedback regulates gain control within the cerebellar circuit.

A model-based reassessment of the three-dimensional tuning of head direction cells in rats.

In a recent study, Shinder and Taube (Shinder ME, Taube JS. J Neurophysiol 121: 4-37, 2019) concluded that head direction cells in the anterior thalamus of rats are tuned to one-dimensional (1D, yaw-only) motion, in contrast to recent findings in bats, mice, and rats. Here we reinterpret the author's experimental results using model comparison and demonstrate that, contrary to their conclusions, experimental data actually supports the dual-axis rule (lson JJ, Jeffery KJ. JNeurophysiol 119: 192-208, 2018) and tilted azimuth model (Laurens J, Angelaki DE. Neuron 97: 275-289, 2018), where head direction cells use gravity to integrate 3D rotation signals about all cardinal axes of the head. We further show that the Shinder and Taube study is inconclusive regarding the presence of vertical orientation tuning; i.e., whether head direction cells encode 3D orientation in the horizontal and vertical planes conjunctively. Using model simulations, we demonstrate that, even if 3D tuning existed, the experimental protocol and data analyses used by Shinder and Taube would not have revealed it. We conclude that the actual experimental data of Shinder and Taube are compatible with the 3D properties of head direction cells discovered by other groups, yet incorrect conclusions were reached because of incomplete and qualitative analyses.NEW & NOTEWORTHY We conducted a model-based analysis previously published data where rat head direction cells were recorded during three-dimensional motion (Shinder ME, Taube JS. J Neurophysiol 121: 4-37, 2019). We found that these data corroborate previous models ("dual-axis rule," Page HJI, Wilson JJ, Jeffery KJ. J Neurophysiol 119: 192-208, 2018; and "tilted azimuth model," Laurens J, Angelaki DE. Neuron 97: 275-289, 2018) where head direction cells integrate rotations along all three head axes to encode head orientation in a gravity-anchored reference frame.

In vivo properties of cerebellar interneurons in the macaque caudal vestibular vermis.

KEY POINTS: We quantify both spontaneous and stimulus-driven responses of interneurons in lobules X (nodulus) and IXc,d (ventral uvula) of the caudal vermis during vestibular stimulation. Based on baseline firing, at least three types of neuronal populations could be distinguished. First, there was a group of very regular firing neurons with high mean discharge rates. Second, there was a group of low firing neurons with a range of discharge regularity. Third, we also encountered putative interneurons with discharge regularity and mean firing rates that were indistinguishable from those of physiologically identified Purkinje cells. The vestibular responses of putative interneurons were generally similar to those of Purkinje cells, thus encoding tilt, translation or mixtures of these signals. Mossy fibres showed unprocessed, otolith afferent-like properties. The cerebellar cortex is among the brain's most well-studied circuits and includes distinct classes of excitatory and inhibitory interneurons. Several studies have attempted to characterize the in vivo properties of cerebellar interneurons, yet little is currently known about their stimulus-driven properties. Here we quantify both spontaneous and stimulus-driven responses of interneurons in lobules X (nodulus) and IXc,d (ventral uvula) of the macaque caudal vermis during vestibular stimulation. Interneurons were identified as cells located >100 µm from the Purkinje cell layer that did not exhibit complex spikes. Based on baseline firing, three types of interneurons could be distinguished. First, there was a group of very regular firing interneurons with high mean discharge rates, which consistently encoded tilt, rather than translational head movements. Second, there was a group of low firing interneurons with a range of discharge regularity. This group had more diverse vestibular properties, where most were translation-selective and a few tilt- or gravitoinertial acceleration-selective. Third, we also encountered interneurons that were similar to Purkinje cells in terms of discharge regularity and mean firing rate. This group also encoded mixtures of tilt and translation signals. A few mossy fibres showed unprocessed, otolith afferent-like properties, encoding the gravitoinertial acceleration. We conclude that tilt- and translation-selective signals, which reflect neural computations transforming vestibular afferent information, are not only encountered in Purkinje cell responses. Instead, upstream interneurons within the cerebellar cortex are also characterized by similar properties, thus implying a widespread network computation.

A spinal cord neuroprosthesis for locomotor deficits due to Parkinson's disease.

People with late-stage Parkinson's disease (PD) often suffer from debilitating locomotor deficits that are resistant to currently available therapies. To alleviate these deficits, we developed a neuroprosthesis operating in closed loop that targets the dorsal root entry zones innervating lumbosacral segments to reproduce the natural spatiotemporal activation of the lumbosacral spinal cord during walking. We first developed this neuroprosthesis in a non-human primate model that replicates locomotor deficits due to PD. This neuroprosthesis not only alleviated locomotor deficits but also restored skilled walking in this model. We then implanted the neuroprosthesis in a 62-year-old male with a 30-year history of PD who presented with severe gait impairments and frequent falls that were medically refractory to currently available therapies. We found that the neuroprosthesis interacted synergistically with deep brain stimulation of the subthalamic nucleus and dopaminergic replacement therapies to alleviate asymmetry and promote longer steps, improve balance and reduce freezing of gait. This neuroprosthesis opens new perspectives to reduce the severity of locomotor deficits in people with PD.

Spinning versus wobbling: how the brain solves a geometry problem.

Oscillating an animal out-of-phase simultaneously about the roll and pitch axes ("wobble") changes continuously the orientation of the head relative to gravity. For example, it may gradually change from nose-up, to ear-down, nose-down, ear-down, and back to nose-up. Rotations about the longitudinal axis ("spin") can change the orientation of the head relative to gravity in the same way, provided the axis is tilted from vertical. During both maneuvers, the otolith organs in the inner ear detect the change in head orientation relative to gravity, whereas the semicircular canals will only detect oscillations in velocity (wobble), but not any rotation at constant velocity (spin). Geometrically, the whole motion can be computed based on information about head orientation relative to gravity and the wobble velocity. We subjected monkeys (Macaca mulatta) to combinations of spin and wobble and found that the animals were always able to correctly estimate their spin velocity. Simulations of these results with an optimal Bayesian model of vestibular information processing suggest that the brain integrates gravity and velocity information based on a geometrically coherent three-dimensional representation of head-in-space motion.

Motion sickness on tilting trains.

Trains that tilt on curves can go faster, but passengers complain of motion sickness. We studied the control signals and tilts to determine why this occurs and how to maintain speed while eliminating motion sickness. Accelerometers and gyros monitored train and passenger yaw and roll, and a survey evaluated motion sickness. The experimental train had 3 control configurations: an untilted mode, a reactive mode that detected curves from sensors on the front wheel set, and a predictive mode that determined curves from the train's position on the tracks. No motion sickness was induced in the untilted mode, but the train ran 21% slower than when it tilted 8° in either the reactive or predictive modes (113 vs. 137 km/h). Roll velocities rose and fell faster in the predictive than the reactive mode when entering and leaving turns (0.4 vs. 0.8 s for a 4°/s roll tilt, P<0.001). Concurrently, motion sickness was greater (P<0.001) in the reactive mode. We conclude that the slower rise in roll velocity during yaw rotations on entering and leaving curves had induced the motion sickness. Adequate synchronization of roll tilt with yaw velocity on curves will reduce motion sickness and improve passenger comfort on tilting trains.

The otolith vermis: A systems neuroscience theory of the Nodulus and Uvula.

The Nodulus and Uvula (NU) (lobules X and IX of the cerebellar vermis) form a prominent center of vestibular information processing. Over decades, fundamental and clinical research on the NU has uncovered many aspects of its function. Those include the resolution of a sensory ambiguity inherent to inertial sensors in the inner ear, the otolith organs; the use of gravity signals to sense head rotations; and the differential processing of self-generated and externally imposed head motion. Here, I review these works in the context of a theoretical framework of information processing called the internal model hypothesis. I propose that the NU implements a forward internal model to predict the activation of the otoliths, and outputs sensory predictions errors to correct internal estimates of self-motion or to drive learning. I show that a Kalman filter based on this framework accounts for various functions of the NU, neurophysiological findings, as well as the clinical consequences of NU lesions. This highlights the role of the NU in processing information from the otoliths and supports its denomination as the "otolith" vermis.

Influence of sensory modality and control dynamics on human path integration.

Path integration is a sensorimotor computation that can be used to infer latent dynamical states by integrating self-motion cues. We studied the influence of sensory observation (visual/vestibular) and latent control dynamics (velocity/acceleration) on human path integration using a novel motion-cueing algorithm. Sensory modality and control dynamics were both varied randomly across trials, as participants controlled a joystick to steer to a memorized target location in virtual reality. Visual and vestibular steering cues allowed comparable accuracies only when participants controlled their acceleration, suggesting that vestibular signals, on their own, fail to support accurate path integration in the absence of sustained acceleration. Nevertheless, performance in all conditions reflected a failure to fully adapt to changes in the underlying control dynamics, a result that was well explained by a bias in the dynamics estimation. This work demonstrates how an incorrect internal model of control dynamics affects navigation in volatile environments in spite of continuous sensory feedback.

The functional significance of velocity storage and its dependence on gravity.

Research in the vestibular field has revealed the existence of a central process, called 'velocity storage', that is activated by both visual and vestibular rotation cues and is modified by gravity, but whose functional relevance during natural motion has often been questioned. In this review, we explore spatial orientation in the context of a Bayesian model of vestibular information processing. In this framework, deficiencies/ambiguities in the peripheral vestibular sensors are compensated for by central processing to more accurately estimate rotation velocity, orientation relative to gravity, and inertial motion. First, an inverse model of semicircular canal dynamics is used to reconstruct rotation velocity by integrating canal signals over time. However, its low-frequency bandwidth is limited to avoid accumulation of noise in the integrator. A second internal model uses this reconstructed rotation velocity to compute an internal estimate of tilt and inertial acceleration. The bandwidth of this second internal model is also restricted at low frequencies to avoid noise accumulation and drift of the tilt/translation estimator over time. As a result, low-frequency translation can be erroneously misinterpreted as tilt. The time constants of these two integrators (internal models) can be conceptualized as two Bayesian priors of zero rotation velocity and zero linear acceleration, respectively. The model replicates empirical observations like 'velocity storage' and 'frequency segregation' and explains spatial orientation (e.g., 'somatogravic') illusions. Importantly, the functional significance of this network, including velocity storage, is found during short-lasting, natural head movements, rather than at low frequencies with which it has been traditionally studied.

Proper layering is important for precisely timed activation of hippocampal mossy cells.

The mammalian cortex exhibits a laminated structure that may underlie optimal synaptic connectivity and support temporally precise activation of neurons. In 'reeler' mice, the lack of the extracellular matrix protein Reelin leads to abnormal positioning of cortical neurons and disrupted layering. To address how these structural changes impact neuronal function, we combined electrophysiological and neuroanatomical techniques to investigate the synaptic activation of hippocampal mossy cells (MCs), the cell type that integrates the output of dentate gyrus granule cells (GCs). While somatodendritic domains of wild-type (WT) MCs were confined to the hilus, the somata and dendrites of reeler MCs were often found in the molecular layer, where the perforant path (PP) terminates. Most reeler MCs received aberrant monosynaptic excitatory input from the PP, whereas the disynaptic input to MCs via GCs was decreased and inhibition was increased. In contrast to the uniform disynaptic discharge of WT MCs, many reeler cells discharged with short, monosynaptic latencies, while others fired with long latencies over a broad temporal window in response to PP activation. Thus, disturbed lamination results in aberrant synaptic connectivity and altered timing of action potential generation. These results highlight the importance of a layered cortical structure for information processing.

Spatial modulation of hippocampal activity in freely moving macaques.

The hippocampal formation is linked to spatial navigation, but there is little corroboration from freely moving primates with concurrent monitoring of head and gaze stances. We recorded neural activity across hippocampal regions in rhesus macaques during free foraging in an open environment while tracking their head and eye. Theta activity was intermittently present at movement onset and modulated by saccades. Many neurons were phase-locked to theta, with few showing phase precession. Most neurons encoded a mixture of spatial variables beyond place and grid tuning. Spatial representations were dominated by facing location and allocentric direction, mostly in head, rather than gaze, coordinates. Importantly, eye movements strongly modulated neural activity in all regions. These findings reveal that the macaque hippocampal formation represents three-dimensional (3D) space using a multiplexed code, with head orientation and eye movement properties being dominant during free exploration.

Processing of angular motion and gravity information through an internal model.

The vestibular organs in the base of the skull provide important information about head orientation and motion in space. Previous studies have suggested that both angular velocity information from the semicircular canals and information about head orientation and translation from the otolith organs are centrally processed in an internal model of head motion, using the principles of optimal estimation. This concept has been successfully applied to model behavioral responses to classical vestibular motion paradigms. This study measured the dynamic of the vestibuloocular reflex during postrotatory tilt, tilt during the optokinetic afternystagmus, and off-vertical axis rotation. The influence of otolith signal on the VOR was systematically varied by using a series of tilt angles. We found that the time constants of responses varied almost identically as a function of gravity in these paradigms. We show that Bayesian modeling could predict the experimental results in an accurate and consistent manner. In contrast to other approaches, the Bayesian model also provides a plausible explanation of why these vestibulooculo motor responses occur as a consequence of an internal process of optimal motion estimation.

Time Course of Sensory Substitution for Gravity Sensing in Visual Vertical Orientation Perception following Complete Vestibular Loss.

Loss of vestibular function causes severe acute symptoms of dizziness and disorientation, yet the brain can adapt and regain near to normal locomotor and orientation function through sensory substitution. Animal studies quantifying functional recovery have yet been limited to reflexive eye movements. Here, we studied the interplay between vestibular and proprioceptive graviception in macaque monkeys trained in an earth-vertical visual orientation (subjective visual vertical; SVV) task and measured the time course of sensory substitution for gravity perception following complete bilateral vestibular loss (BVL). Graviceptive gain, defined as the ratio of perceived versus actual tilt angle, decreased to 20% immediately following labyrinthectomy, and recovered to nearly prelesion levels with a time constant of approximately three weeks of postsurgery testing. We conclude that proprioception accounts for up to 20% of gravity sensing in normal animals, and is re-weighted to substitute completely perceptual graviception after vestibular loss. We show that these results can be accounted for by an optimal sensory fusion model.

The head direction cell network: attractor dynamics, integration within the navigation system, and three-dimensional properties.

Knowledge of head direction cell function has progressed remarkably in recent years. The predominant theory that they form an attractor has been confirmed by several experiments. Candidate pathways that may convey visual input have been identified. The pre-subicular circuitry that conveys head direction signals to the medial entorhinal cortex, potentially sustaining path integration by grid cells, has been resolved. Although the neuronal substrate of the attractor remains unknown in mammals, a simple head direction network, whose structure is astoundingly similar to neuronal models theorized decades earlier, has been identified in insects. Finally, recent experiments have revealed that these cells do not encode head direction in the horizontal plane only, but also in vertical planes, thus providing a 3D orientation signal.

A gravity-based three-dimensional compass in the mouse brain.

Gravity sensing provides a robust verticality signal for three-dimensional navigation. Head direction cells in the mammalian limbic system implement an allocentric neuronal compass. Here we show that head-direction cells in the rodent thalamus, retrosplenial cortex and cingulum fiber bundle are tuned to conjunctive combinations of azimuth and tilt, i.e. pitch or roll. Pitch and roll orientation tuning is anchored to gravity and independent of visual landmarks. When the head tilts, azimuth tuning is affixed to the head-horizontal plane, but also uses gravity to remain anchored to the allocentric bearings in the earth-horizontal plane. Collectively, these results demonstrate that a three-dimensional, gravity-based, neural compass is likely a ubiquitous property of mammalian species, including ground-dwelling animals.

The Macaque Cerebellar Flocculus Outputs a Forward Model of Eye Movement.

The central nervous system (CNS) achieves fine motor control by generating predictions of the consequences of the motor command, often called forward models of the movement. These predictions are used centrally to detect not-self generated sensations, to modify ongoing movements, and to induce motor learning. However, finding a neuronal correlate of forward models has proven difficult. In the oculomotor system, we can identify neuronal correlates of forward models vs. neuronal correlates of motor commands by examining neuronal responses during smooth pursuit at eccentric eye positions. During pursuit, torsional eye movement information is not present in the motor command, but it is generated by the mechanic of the orbit. Importantly, the directionality and approximate magnitude of torsional eye movement follow the half angle rule. We use this rule to investigate the role of the cerebellar flocculus complex (FL, flocculus and ventral paraflocculus) in the generation of forward models of the eye. We found that mossy fibers (input elements to the FL) did not change their response to pursuit with eccentricity. Thus, they do not carry torsional eye movement information. However, vertical Purkinje cells (PCs; output elements of the FL) showed a preference for counter-clockwise (CCW) eye velocity [corresponding to extorsion (outward rotation) of the ipsilateral eye]. We hypothesize that FL computes an estimate of torsional eye movement since torsion is present in PCs but not in mossy fibers. Overall, our results add to those of other laboratories in supporting the existence in the CNS of a predictive signal constructed from motor command information.

Prediction Algorithm of the Cat Spinal Segments Lengths and Positions in Relation to the Vertebrae.

Detailed knowledge of the topographic organization and precise access to the spinal cord segments is crucial for the neurosurgical manipulations as well as in vivo neurophysiological investigations of the spinal networks involved in sensorimotor and visceral functions. Because of high individual variability, accurate identification of particular portion of the lumbosacral enlargement is normally possible only during postmortem dissection. Yet, it is often necessary to determine the precise location of spinal segments prior to in vivo investigation, targeting spinal cord manipulations, neurointerface implantations, and neuronal activity recordings. To solve this problem, we have developed an algorithm to predict spinal segments locations based on their relation to vertebral reference points. The lengths and relative positions of the spinal cord segments (T13-S3) and the vertebrae (VT13-VL7) were measured in 17 adult cats. On the basis of these measurements, we elaborated the estimation procedure: the cubic regression of the ratio of the segment's length to the lengths of the VL2 vertebra was used for the determination of segment's length; and the quadratic regression of the ratio of their positions in relation to the VL2 rostral part was used to determine the position of the segments. The coefficients of these regressions were calculated at the training sample (nine cats) and were then confirmed at the testing sample (eight cats). Although the quality of the prediction is decreased in the caudal direction, we found high correlations between the regressions and real data. The proposed algorithm can be further translated to other species including human. Anat Rec, 302:1628-1637, 2019. © 2018 American Association for Anatomy.

The Brain Compass: A Perspective on How Self-Motion Updates the Head Direction Cell Attractor.

Head direction cells form an internal compass signaling head azimuth orientation even without visual landmarks. This property is generated by a neuronal ring attractor that is updated using rotation velocity cues. The properties and origin of this velocity drive remain, however, unknown. We propose a quantitative framework whereby this drive represents a multisensory self-motion estimate computed through an internal model that uses sensory prediction errors of vestibular, visual, and somatosensory cues to improve on-line motor drive. We show how restraint-dependent strength of recurrent connections within the attractor can explain differences in head direction cell firing between free foraging and restrained passive rotation. We also summarize recent findings on how gravity influences azimuth coding, indicating that the velocity drive is not purely egocentric. Finally, we show that the internal compass may be three-dimensional and hypothesize that the additional vertical degrees of freedom use global allocentric gravity cues.