A critical step in self-motion perception and spatial awareness is the integration of motion cues from multiple sensory organs that individually do not provide an accurate representation of the physical world. One of the best-studied sensory ambiguities is found in visual processing, and arises because of the inherent uncertainty in detecting the motion direction of an untextured contour moving within a small aperture. A similar sensory ambiguity arises in identifying the actual motion associated with linear accelerations sensed by the otolith organs in the inner ear. These internal linear accelerometers respond identically during translational motion (for example, running forward) and gravitational accelerations experienced as we reorient the head relative to gravity (that is, head tilt). Using new stimulus combinations, we identify here cerebellar and brainstem motion-sensitive neurons that compute a solution to the inertial motion detection problem. We show that the firing rates of these populations of neurons reflect the computations necessary to construct an internal model representation of the physical equations of motion.

The ability to orient and navigate through the terrestrial environment represents a computational challenge common to all vertebrates. It arises because motion sensors in the inner ear, the otolith organs, and the semicircular canals transduce self-motion in an egocentric reference frame. As a result, vestibular afferent information reaching the brain is inappropriate for coding our own motion and orientation relative to the outside world. Here we show that cerebellar cortical neuron activity in vermal lobules 9 and 10 reflects the critical computations of transforming head-centered vestibular afferent information into earth-referenced self-motion and spatial orientation signals. Unlike vestibular and deep cerebellar nuclei neurons, where a mixture of responses was observed, Purkinje cells represent a homogeneous population that encodes inertial motion. They carry the earth-horizontal component of a spatially transformed and temporally integrated rotation signal from the semicircular canals, which is critical for computing head attitude, thus isolating inertial linear accelerations during navigation.

The inferior olivary nuclei clearly play a role in creating oculopalatal tremor, but the exact mechanism is unknown. Oculopalatal tremor develops some time after a lesion in the brain that interrupts inhibition of the inferior olive by the deep cerebellar nuclei. Over time the inferior olive gradually becomes hypertrophic and its neurons enlarge developing abnormal soma-somatic gap junctions. However, results from several experimental studies have confounded the issue because they seem inconsistent with a role for the inferior olive in oculopalatal tremor, or because they ascribe the tremor to other brain areas. Here we look at 3D binocular eye movements in 15 oculopalatal tremor patients and compare their behaviour to the output of our recent mathematical model of oculopalatal tremor. This model has two mechanisms that interact to create oculopalatal tremor: an oscillator in the inferior olive and a modulator in the cerebellum. Here we show that this dual mechanism model can reproduce the basic features of oculopalatal tremor and plausibly refute the confounding experimental results. Oscillations in all patients and simulations were aperiodic, with a complicated frequency spectrum showing dominant components from 1 to 3 Hz. The model’s synchronized inferior olive output was too small to induce noticeable ocular oscillations, requiring amplification by the cerebellar cortex. Simulations show that reducing the influence of the cerebellar cortex on the oculomotor pathway reduces the amplitude of ocular tremor, makes it more periodic and pulse-like, but leaves its frequency unchanged. Reducing the coupling among cells in the inferior olive decreases the oscillation’s amplitude until they stop (at ∼20% of full coupling strength), but does not change their frequency. The dual-mechanism model accounts for many of the properties of oculopalatal tremor. Simulations suggest that drug therapies designed to reduce electrotonic coupling within the inferior olive or reduce the disinhibition of the cerebellar cortex on the deep cerebellar nuclei could treat oculopalatal tremor. We conclude that oculopalatal tremor oscillations originate in the hypertrophic inferior olive and are amplified by learning in the cerebellum.

PurposeFixational saccades shift the foveal image to counteract visual fading related to neural adaptation. Drifts are slow eye movements between two adjacent fixational saccades. We quantified fixational saccades and asked whether their changes could be attributed to pathologic drifts seen in amblyopia, one of the most common causes of blindness in childhood.MethodsThirty-six pediatric subjects with varying severity of amblyopia and eleven healthy age-matched controls held their gaze on a visual target. Eye movements were measured with high-resolution video-oculography during fellow eye-viewing and amblyopic eye-viewing conditions. Fixational saccades and drifts were analyzed in the amblyopic and fellow eye and compared with controls.ResultsWe found an increase in the amplitude with decreased frequency of fixational saccades in children with amblyopia. These alterations in fixational eye movements correlated with the severity of their amblyopia. There was also an increase in eye position variance during drifts in amblyopes. There was no correlation between the eye position variance or the eye velocity during ocular drifts and the amplitude of subsequent fixational saccade. Our findings suggest that abnormalities in fixational saccades in amblyopia are independent of the ocular drift.DiscussionThis investigation of amblyopia in pediatric age group quantitatively characterizes the fixation instability. Impaired properties of fixational saccades could be the consequence of abnormal processing and reorganization of the visual system in amblyopia. Paucity in the visual feedback during amblyopic eye-viewing condition can attribute to the increased eye position variance and drift velocity.

Tremor disorders pose fundamental questions about disease mechanisms, and challenges to successful neurotherapeutics: What causes motor circuits to oscillate in disorders in which the central nervous system otherwise seems normal? How does inheritance 'determine' the clinical phenotype in familial tremor disorders? Here, we address these questions. Analogies between the neural circuits controlling rapid eye movements (saccades) and those controlling limb movements allow us to translate the interpretations from the saccadic systems to the limb movement system. Moreover, the relatively well understood neurophysiology of the ocular motor system offers a unique opportunity to test specific hypotheses about normal and abnormal motor control of both eye and limb movements. We describe a new familial disorder--'micro-saccadic oscillations and limb tremor (microSOLT)'--in a mother and daughter who had tiny saccadic oscillations of the eyes and tremor of the hands. This unique oscillatory movement disorder resembles other common tremor disorders (such as essential tremor) that occur in patients who have an otherwise normally functioning central nervous system. We hypothesize that microSOLT is caused by an inherited abnormality that results in abnormal membrane properties causing reduced external inhibition in the premotor neurons that generate the high-frequency discharge (burst) for saccades and for ballistic limb movements. To test this hypothesis, we recorded hand tremor and eye movements in two patients with microSOLT and particularly during natural circumstances when inhibition of the premotor saccadic burst neurons is removed (e.g. eye closure). We then simulated a conductance-based model for the premotor commands which included excitatory and reciprocally inhibitory burst neurons. The structure of this physiologically realistic model was based upon known cell types and anatomical connections in the brainstem (for saccades) and the thalamus (for limb movements). The physiological phenomenon of post-inhibitory rebound in premotor burst neurons makes the circuit inherently unstable and prone to oscillate unless prevented by external inhibition. Indeed, with simulated reduction of external inhibition (in this case glycinergic), saccadic oscillations and limb tremor were reproduced. Our results suggest that a single-inherited deficit can alter membrane properties, which impairs inhibition in an inherently unstable neural circuit causing the eye and limb oscillations in microSOLT. This concept has broad implications for understanding the mechanism and designing rationale pharmacotherapy for abnormal oscillations and may be applicable to other common disorders in which there are no structural abnormalities in the brain such as essential tremor.

The ability to navigate in the world and execute appropriate behavioral and motor responses depends critically on our capacity to construct an accurate internal representation of our current motion and orientation in space. Vestibular sensory signals are among those that may make an essential contribution to the construction of such 'internal models'. Movement in a gravitational environment represents a situation where the construction of internal models becomes particularly important because the otolith organs, like any linear accelerometer, sense inertial and gravitational accelerations equivalently. Otolith afferents thus provide inherently ambiguous motion information, as they respond identically to translation and head reorientation relative to gravity. Resolution of this ambiguity requires the nonlinear integration of linear acceleration and angular velocity cues, as predicted by the physical equations of motion. Here, we summarize evidence that during translations and tilts from upright the firing rates of brainstem and cerebellar neurons encode a combination of dynamically processed semicircular canal and otolith signals appropriate to construct an internal model representation of the computations required for inertial motion detection.

The most medial of the deep cerebellar nuclei, the fastigial nucleus (FN), receives sensory vestibular information and direct inhibition from the cerebellar vermis. We investigated the signal processing in the primate FN by recording single-unit activities during translational motion, rotational motion, and eye movements. Firing rate modulation during horizontal plane translation in the absence of eye movements was observed in all non-eye-movement-sensitive cells and 26% of the pursuit eye-movement-sensitive neurons in the caudal FN. Many non-eye-movement-sensitive cells recorded in the rostral FN of three fascicularis monkeys exhibited convergence of signals from both the otolith organs and the semicircular canals. At low frequencies of translation, the majority of these rostral FN cells changed their firing rates in phase with head velocity rather than linear acceleration. As frequency increased, FN vestibular neurons exhibited a wide range of response dynamics with most cells being characterized by increasing phase leads as a function of frequency. Unlike cells in the vestibular nuclei, none of the rostral FN cells responded to rotational motion alone, without simultaneously exhibiting sensitivity to translational motion. Modulation during earth-horizontal axis rotation was observed in more than half (77%) of the neurons, although with smaller gains than during translation. In contrast, only 47% of the cells changed their firing rates during earth-vertical axis rotations in the absence of a dynamic linear acceleration stimulus. These response properties suggest that the rostral FN represents a main processing center of otolith-driven information for inertial motion detection and spatial orientation.

Knowledge of body motion through space is necessary for spatial orientation, self-motion perception, and postural control. Yet, sensory afferent signals may not directly provide such information to the brain. Because motion detected by the vestibular end organs is encoded in a head-fixed frame of reference, a coordinate transformation is thus required to encode body motion. In this study, we investigated whether cerebellar motion-sensitive neurons encode the translation of the body through space. We systematically changed both the direction of motion relative to the body and the static orientation of the head relative to the trunk. The activities of motion-sensitive neurons in the most medial of the deep cerebellar nuclei, the rostral fastigial nucleus, were compared with those in the brainstem vestibular nuclei. We found a distributed representation of reference frames for motion in the rostral fastigial nucleus, in contrast to cells in the vestibular nuclei, which primarily encoded motion in a head-fixed reference frame. This differential representation of motionrelated information implies potential differences in the functional roles of these areas.