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.
Highlights
Essential tremor (ET) is among the most prevalent movement disorders, but its origins are elusive
In addition to reproducing the neuronal activity observed in vivo in Purkinje cells and deep cerebellar neurons from healthy nonhuman primates (SI Appendix, Fig. S2), the injected current parameters and synaptic gains in the CCTC loop were constrained such that the average firing rates of NO, thalamocortical neuron (TC), and pyramidal neurons (PYN) cells match the range of experimental values reported in refs. 31, 37, and 42 from in vivo recordings in healthy animals (NO, 5.5 ± 2.0 Hz; TC, 26.6 ± 4.2 Hz; PYN, 23.1 ± 5.0 Hz, mean ± SD; values estimated over 60,000-ms-long simulation)
We analyzed the burstiness of the deep cerebellar projection neuron (DCN) for the pair of parameters (R, τPC→DCN) considered in Fig. 3 B–E (ET case), and we found that when 185-Hz ventral intermediate thalamus (Vim)-deep brain stimulation (DBS) was applied, the length of the DCN interburst intervals decreased by 21.3 ± 14.8%
Summary
Essential tremor (ET) is among the most prevalent movement disorders, but its origins are elusive. Instead, that ET is associated with microstructural changes and neuronal dysfunctions in the cerebellum [13,14,15] including a loss of dendritic spines in Purkinje cells in the cerebellar cortex, a decrease in GABAA and GABAB receptors in the dentate nucleus, and a deficit of bound GABA transmitters [16,17,18,19] These changes have been correlated with the tremor severity [13] and may lead to significant alterations in the motor network [20, 21]. Our results provide an explanation of how local synaptic abnormalities would lead to widespread tremor-related neural activity in ET and suggest that compensatory processes in degenerative diseases may underlie brain dysfunction
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