1Biocomputation Research Group, University of Herfordshire, Hatfield, United Kingdom
*Email: e.bernasconi@herts.ac.uk Introduction
Transcranial magnetic stimulation (TMS) has been used for over 30 years to modulate cortical excitability and it is currently being applied to other brain regions, such as the cerebellum[1,2]. TMS is a promising technique that could be beneficial for people suffering with dystonia, essential tremor, and Parkinson’s disease[1,2]. However, research in this field provides contrasting evidence of the effects of TMS on the cerebellum[1,3]. Our goal is to study the underlying mechanisms of TMS on the cerebellum via a computational approach.
Methods We stimulated a previously developed model of the cerebellar cortex consisting of granule, Golgi and Purkinje cells[4]. To ensure uniform stimulus application, we replaced the granule cells with a multi-compartmental model by Diwakar et al[5]. We applied the stimulus as a voltage using the extracellular mechanism in NEURON [6], which requires multi-compartmental models. We stimulated all compartments of all neurons with a sinusoidal waveform, where field decay is only dependent on the distance between the source of the applied electric field (located at the origin) and the stimulated compartment[7]. We tested 6 stimulus frequencies commonly used in TMS protocols on the cerebellum: 1, 5, 10, 20 and 50 Hz. Results For stimulus frequencies up to 20 Hz, the firing rate of the Purkinje cell oscillates in response to the sinusoidal stimulus, as expected (Figure 1A-C). During the positive phase of the stimulus, the cell’s soma hyperpolarizes, while during the negative phase, it depolarizes. Increasing the stimulus frequency up to 20 Hz amplifies the modulation. The variance of the cell’s instantaneous firing rate is 0.4, 5.9, 18.9, 39.0 and 29.6 Hz2for stimulus frequencies of 1, 5, 10, 20 and 50 Hz. At 50 Hz, the cell’s instantaneous firing rate no longer follows the stimulus waveform, and instead exhibits a pronounced excitation with weaker inhibition (Figure 1D). This excitation is much stronger than that obtained at lower stimulus frequencies. Discussion The behaviour of our Purkinje cell model aligns with the findings of Rattay et al [8], suggesting that our model can serve as a useful tool to study how TMS influences cerebellar activity.
We show that stimulus frequency can significantly impact the cell’s behaviour, highlighting the importance of carefully selecting this parameter in clinical settings. High-frequency stimulation exerts a strong excitatory influence, which may have important implications for therapeutic use.Future work will extend the simulation model to the granule and Golgi cells. We plan to stimulate the network with a more realistic electric field generated using realistic anatomical head models. We will derive the electric field distribution employing SimNIBS[9].
Figure 1. Figure 1: Instantaneous firing rate of the Purkinje cell (in blue) and waveform used to stimulate the cell (in orange). The amplitude of the pulse waveform is not to scale. The stimulus applied has a frequency of 5, 10, 20 and 50 Hz in figures A, B, C and D. Acknowledgements - References [1]https://doi.org/10.1016/j.brs.2017.11.015 [2]https://doi.org/10.1016/j.neubiorev.2017.10.006 [3]https://doi.org/10.3389/fnagi.2020.578339 [4]https://doi.org/10.1007/s10827-024-00871-5 [5]https://doi.org/10.1017/10.1152/jn.90382.2008 [6]https://doi.org/10.1017/CBO9780511541612 [7]https://doi.org/10.1017/10.1007/978-3-031-08443-0_8 [8]https://doi.org/10.1109/TBME.1986.325670 [9]https://doi.org/10.1007/978-3-030-21293-3_1
