Role of cerebellar GABAergic dysfunctions in the origins of essential tremor

Abstract

Essential tremor (ET) is among the most prevalent movement disorders, but its origins are elusive. The inferior olivary nucleus (ION) has been hypothesized as the prime generator of tremor because of the pacemaker properties of ION neurons, but structural and functional changes in ION are unlikely under ET. Abnormalities have instead been reported in the cerebello-thalamo-cortical network, including dysfunctions of the GABAergic projections from the cerebellar cortex to the dentate nucleus. It remains unclear, though, how tremor would relate to a dysfunction of cerebellar connectivity. To address this question, we built a computational model of the cortico-cerebello-thalamo-cortical loop. We simulated the effects of a progressive loss of GABAA α1-receptor subunits and up-regulation of α2/3-receptor subunits in the dentate nucleus, and correspondingly, we studied the evolution of the firing patterns along the loop. The model closely reproduced experimental evidence for each structure in the loop. It showed that an alteration of amplitudes and decay times of the GABAergic currents to the dentate nucleus can facilitate sustained oscillatory activity at tremor frequency throughout the network as well as a robust bursting activity in the thalamus, which is consistent with observations of thalamic tremor cells in ET patients. Tremor-related oscillations initiated in small neural populations and spread to a larger network as the synaptic dysfunction increased, while thalamic high-frequency stimulation suppressed tremor-related activity in thalamus but increased the oscillation frequency in the olivocerebellar loop. These results suggest a mechanism for tremor generation under cerebellar dysfunction, which may explain the origin of ET.

Non-invasive Amelioration of Essential Tremor via Phase-Locked Disruption of its Temporal Coherence

“…The mechanism of action of our neuromodulatory strategy, as revealed via feature-based statistical learning and neurophysiological modelling, involves direct perturbation of the cascade of coherent activities that generate the tremor oscillation in the olivocerebellar loop. This mechanism of action differs from existing Vim DBS therapy for ET which masks the tremor oscillation in the thalamocortical loop but does not mitigate its generation in the olivocerebellar loop 15 . In the future, neuromodulatory strategies that target the temporal coherence of the pathology may offer new opportunities to treat a wide range of brain disorders underpinned by aberrant synchronous oscillations.…”

“…To explore the neurophysiological mechanism of our stimulation strategy we used a computational model of the CCTC network under ET condition 15 and tested the effect of phase-locked stimulation of the cerebellum on the spiking dynamics. Fig.…”

“…6a shows a schematic representation of the model. As in our previous study 15 , the power spectrum density (PSD) between 4 -12Hz of the ventral intermediate thalamus (Vim) was used as a proxy to the tremor activity. Fig.…”

“…CCTC network model under ET condition was simulated as in Zhang et al 15 . The model is available on ModelDB (http://modeldb.yale.edu/257028).…”

“…It consisted of 425 singlecompartment, biophysics-based neurons from the olivocerebellar and thalamocortical loops, including 40 inferior olivary nucleus (ION) neurons in the brainstem, 200 Purkinje cells (PCs) and 20 granular layer clusters (GrL) in the cerebellar cortex, 5 glutamatergic deep cerebellar projection neurons (DCNs) and 5 nucleoolivary (NO) neuron in the dentate nucleus, 5 ventral intermediate thalamus (Vim) thalamocortical (TC) neurons, 100 pyramidal (PYN) neurons, and 10 fast-spiking interneurons (FSI). As in our previous study 15 , the ET condition was simulated by reducing the conductivity and increasing the decay time of the PCs' GABAergic currents to the DCN, which mimics the loss of GABAA α 1 -receptor subunits and an upregulation of α 2 /α 3 -receptor subunits in the cerebellum. Five instances of the model were considered and for each instance, simulations were repeated under normal condition, ET condition with no stimulation, and ET condition with stimulation of the cerebellum.…”