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Abstract Objective.Cerebellar transcranial magnetic stimulation (TMS) has been proposed to suppress limb tremors in essential tremor (ET), but mixed results have been reported so far, both when pulses are applied repetitively TMS (rTMS) and in bursts. We aim to investigate the cellular effects of TMS on the cerebellum under ET through numerical simulations.Approach.A computational model of the olivo-cerebello-thalamocortical pathways exhibiting the main neural biomarkers of ET (i.e. circuit-wide tremor-locked neural oscillations) was expanded to incorporate the effects of TMS-induced electric field (E-field) on Purkinje cells. TMS pulse amplitude, frequency, and temporal pattern were varied, and the resultant effects on ET biomarkers were assessed. Four levels of cellular response to TMS were considered, ranging from low to high cell recruitment underneath the coil, and three stimulation patterns were tested, i.e. rTMS, irregular TMS (ir-TMS, pulses were arranged according to Sobol sequences with average frequency matching rTMS), and phase-locked TMS (PL-TMS).Main results.rTMS can suppress ET oscillations, but its efficacy depends on tremor frequency and recruitment level, with these factors shaping a narrow range of effective settings. The ratio between tremor and rTMS frequencies also affects the neural response and further narrows the span of viable settings, while ir-TMS is ineffective. PL-TMS is highly effective and robust against changes to cell recruitment level and tremor frequency. Across all scenarios, PL-TMS provides a rapid (i.e. within seconds) suppression of tremor oscillations and, when both PL-TMS and rTMS are effective, the time to tremor suppression decreases by 50% or more in PL-TMS versus rTMS. At the cellular level, PL-TMS operates by disrupting the synchronization along the olivo-cerebellar loop, and the preferred phases map onto the mid-region of the silent period between complex spikes of the Purkinje cells.Significance.Cerebellar PL-TMS can provide robust suppression of ET oscillations while operating within safety boundaries.
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Role of cerebellar GABAergic dysfunctions in the origins of essential tremor
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 GABA A α 1 -receptor subunits and up-regulation of α 2/3 -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.
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- Award ID(s):
- 1845348
- PAR ID:
- 10135432
- Date Published:
- Journal Name:
- Proceedings of the National Academy of Sciences
- Volume:
- 116
- Issue:
- 27
- ISSN:
- 0027-8424
- Page Range / eLocation ID:
- 13592 to 13601
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1073/pnas.1817689116
