Oculopalatal tremor explained by a model of inferior olivary hypertrophy and cerebellar plasticity

Abstract

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.

Acquired pendular nystagmus in multiple sclerosis and oculopalatal tremor

“…We found that the waveform and the frequency of the nystagmus in OPT was more variable and less sinusoidal than in patients with MS. While these observations have already been reported in patients with either APN due to OPT 11,22 or MS, 15,19 by comparing the 2 patient groups in the same study we show that this feature may be important for establishing a differential diagnosis between MS and OPT.…”

“…19 The more influential model of OPT suggests a dual mechanism involving inferior olivary hypertrophy and cerebellar plasticity. 22,26 First, disruption of inhibitory cerebellar modulation of the ION leads to the development of somato-somatic gap junctions between neurons, generating periodic oscillations that are transmitted to the cerebellar cortex. The second mechanism would be a superimposed cerebellar "smoothing" of the output signal leading to smoother and less periodic eye movements.…”

“…Based on the dual-model hypothesis of OPT (see above), it was recently proposed that treatments should combine drugs acting on cerebellar modulation (clonazepam, alprazolam, primidone, topiramate, memantine) and drugs reducing the electrotonic coupling between the hypertrophied inferior olive neurons by blocking connections (quinine, carbenoxolone, mefloquine). 22,26 To date, none of these combinations of drugs have been tested in patients with APN arising from OPT.…”

Oculopalatal tremor in multiple sclerosis with spontaneous resolution

“…Recent experimental data show that inferior olivary synchronization and modulation by the cerebellum play a role in OPT. 1 A literature search showed few reports of OPT from MS. An article that reviewed 171 publications on palatal myoclonus found 9 cases of MS among 287 cases. [2][3][4][5][6] However, on review many of these cases do not meet the current clinical criteria for diagnosis of MS. Neuroimaging or pathology was not available in any.…”

Eye Movement Research in the Twenty-First Century—a Window to the Brain, Mind, and More

“…NMDA receptor antagonists such as memantine and alpha-2-delta calcium channel blocker such as gabapentin have been useful to treat the pendular nystagmus due to olivo-cerebellar dysfunction in the syndrome of ocular palatal tremor and that due of demyelinating disorders [80]. Contemporary studies have identified the role of ion channels in the pathogenesis of nystagmus and saccadic oscillations [80][81][82]. Therefore, it is critical to consider selective ion channel blockers as therapeutic options for the treatment of cerebellar nystagmus [81,83].…”