Conductance-based models of reciprocally inhibiting burst neurons suggest that intrinsic membrane properties and postinhibitory rebound (PIR) determine the amplitude and frequency of saccadic oscillations. Reduction of the low-threshold calcium currents (IT) in the model decreased the amplitude but increased the frequency of the simulated oscillations. Combined reduction of hyperpolarization-activated cation current (Ih) and IT in the model abolished the simulated oscillations. We measured the effects of a selective blocker of IT (ethosuximide) in healthy subjects on the amplitude and frequency of saccadic oscillations evoked by eye closure and of a nonselective blocker of Ih and IT (propronolol) in a patient with microsaccadic oscillation and limb tremor syndrome (mSOLT). Ethosuximide significantly reduced the amplitude but increased the frequency of the saccadic oscillations during eye closure in healthy subjects. Propranolol abolished saccadic oscillations in the mSOLT patient. These results support the hypothetical role of postinhibitory rebound, Ih, and IT, in generation of saccadic oscillations and determining their kinematic properties.

Background

The rotational vestibulo-ocular reflex (rVOR) generates compensatory eye movements in response to rotational head accelerations. The velocity-storage mechanism (VSM), which is controlled by the vestibulo-cerebellar nodulus and uvula, determines the rVOR time constant. In healthy subjects, it has been suggested that self-motion perception in response to earth-vertical axis rotations depends on the VSM in a similar way as reflexive eye movements. We aimed at further investigating this hypothesis and speculated that if the rVOR and rotational self-motion perception share a common VSM, alteration in the latter, such as those occurring after a loss of the regulatory control by vestibulo-cerebellar structures, would result in similar reflexive and perceptual response changes. We therefore set out to explore both responses in patients with vestibulo-cerebellar degeneration.

Methodology/Principal Findings

Reflexive eye movements and perceived rotational velocity were simultaneously recorded in 14 patients with chronic vestibulo-cerebellar degeneration (28–81yrs) and 12 age-matched healthy subjects (30–72yrs) after the sudden deceleration (90°/s2) from constant-velocity (90°/s) rotations about the earth-vertical yaw and pitch axes. rVOR and perceived rotational velocity data were analyzed using a two-exponential model with a direct pathway, representing semicircular canal activity, and an indirect pathway, implementing the VSM. We found that VSM time constants of rVOR and perceived rotational velocity co-varied in cerebellar patients and in healthy controls (Pearson correlation coefficient for yaw 0.95; for pitch 0.93, p<0.01). When constraining model parameters to use the same VSM time constant for rVOR and perceived rotational velocity, moreover, no significant deterioration of the quality of fit was found for both populations (variance-accounted-for >0.8).

Conclusions/Significance

Our results confirm that self-motion perception in response to rotational velocity-steps may be controlled by the same velocity storage network that controls reflexive eye movements and that no additional, e.g. cortical, mechanisms are required to explain perceptual dynamics.

We developed the head impulse testing device (HITD) based on an inertial sensing system allowing to investigate the functional performance of the rotational vestibulo-ocular reflex (VOR) by testing its gaze stabilization ability, independently from the subject’s visual acuity, in response to head impulses at different head angular accelerations ranging from 2000 to 7000 deg/s2. HITD was initially tested on 22 normal subjects, and a method to compare the results from a single subject (patient) with those from controls was set up. As a pilot study, we tested the HITD in 39 dizzy patients suffering, non-acutely, from different kinds of vestibular disorders. The results obtained with the HITD were comparable with those from the clinical head impulse test (HIT), but an higher number of abnormalities was detectable by HITD in the central vestibular disorders group. The HITD appears to be a promising tool for detecting abnormal VOR performance while providing information on the functional performance of the rotational VOR, and can provide a valuable assistance to the clinical evaluation of patients with vestibular disorders.

Rapid shifts of the point of visual fixation between equidistant targets require equal-sized saccades of each eye. The brainstem medial longitudinal fasciculus (MLF) plays a cardinal role in ensuring that horizontal saccades between equidistant targets are tightly yoked. Lesions of the MLF—internuclear ophthalmoparesis (INO)—cause horizontal saccades to become disjunctive: adducting saccades are slow, small, or absent. However, in INO, convergence movements may remain intact. We studied horizontal gaze shifts between equidistant targets and between far and near targets aligned on the visual axis of one eye (Müller test paradigm) in five cases of INO and five control subjects. We estimated the saccadic component of each movement by measuring peak velocity and peak acceleration. We tested whether the ratio of the saccadic component of the adducting/abducting eyes stayed constant or changed for the two types of saccades. For saccades made by control subjects between equidistant targets, the group mean ratio (±SD) of adducting/abducting peak velocity was 0.96 ± 0.07 and adducting/abducting peak acceleration was 0.94 ± 0.09. Corresponding ratios for INO cases were 0.45 ± 0.10 for peak velocity and 0.27 ± 0.11 for peak acceleration, reflecting reduced saccadic pulses for adduction. For control subjects, during the Müller paradigm, the adducting/abducting ratio was 1.25 ± 0.14 for peak velocity and 1.03 ± 0.12 for peak acceleration. Corresponding ratios for INO cases were 0.82 ± 0.18 for peak velocity and 0.48 ± 0.13 for peak acceleration. When adducting/abducting ratios during Müller versus equidistant targets paradigms were compared, INO cases showed larger relative increases for both peak velocity and peak acceleration compared with control subjects. Comparison of similar-sized movements during the two test paradigms indicated that whereas INO patients could decrease peak velocity of their abducting eye during the Müller paradigm, they were unable to modulate adducting velocity in response to viewing conditions. However, the initial component of each eye’s movement was similar in both cases, possibly reflecting activation of saccadic burst neurons. These findings support the hypothesis that horizontal saccades are governed by disjunctive signals, preceded by an initial, high-acceleration conjugate transient and followed by a slower vergence component.

Saccadic oscillations threaten clear vision by causing image motion on the retina. They are either purely horizontal (ocular flutter) or multidimensional (opsoclonus). We propose that ion channel dysfunction in the burst cell membrane is the underlying abnormality. We have tested this hypothesis by simulating a neuromimetic computational model of the burst neurons. This biologically realistic model mimics the physiologic properties and anatomic connections in the brainstem saccade generator. A rebound firing after sustained inhibition, called post-inhibitory rebound (PIR), and reciprocal inhibition between premotor saccadic burst neurons are the key features of this conceptual scheme. PIR and reciprocal inhibition make the circuits that generate the saccadic burst inherently unstable and can lead to oscillations unless stabilized by external inhibition. Our simulations suggest that alterations in membrane properties that lead to an increase in PIR, a reduction in external glycinergic inhibition, or both can cause saccadic oscillations.

Background

Essential tremor (ET) is the most common movement disorder and its pathophysiology is unknown. We hypothesize that increased membrane excitability in motor circuits has a key role in the pathogenesis of ET. Specifically, we propose that neural circuits controlling ballistic movements are inherently unstable due to their underlying reciprocal innervation. Such instability is enhanced by increased neural membrane excitability and the circuit begins to oscillate. These oscillations manifest as tremor.

Methods

Postural limb tremor was recorded in 22 ET patients and then the phenotype was simulated with a conductance-based neuromimetic model of ballistic movements. The model neuron was Hodgkin-Huxley type with added hyperpolarization activated cation current (Ih), low threshold calcium current (IT), and GABA and glycine mediated chloride currents. The neurons also featured the neurophysiological property of rebound excitation after release from sustained inhibition (post-inhibitory rebound). The model featured a reciprocally innervated circuit of neurons that project to agonist and antagonist muscle pairs.

Results

Neural excitability was modulated by changing Ih and/or IT. Increasing Ih and/or IT further depolarized the membrane and thus increased excitability. The characteristics of the tremor from all ET patients were simulated when Ih was increased to ~10× the range of physiological values. In contrast, increasing other membrane conductances, while keeping Ih at a physiological value, did not simulate the tremor. Increases in Ih and IT determined the frequency and amplitude of the simulated oscillations.

Conclusion

These simulations support the hypothesis that increased membrane excitability in potentially unstable, reciprocally innervated circuits can produce oscillations that resemble ET. Neural excitability could be increased in a number of ways. In this study membrane excitability was increased by up-regulating Ih and IT. This approach suggests new experimental and clinical ways to understand and treat common tremor disorders.