CNS*2025 Florence

P270 Subthreshold extracellular electric fields alter how neurons respond to naturally occurring synaptic inputs in temporal interference stimulation

Ieva Kerseviciute1, Michele Migliore2, Rosanna Migliore2,Ausra Saudargiene*3, Adam Williamson4

1The Life Sciences Center, Vilnius University, Vilnius, Lithuania
2Institute of Biophysics, National Research Council, Palermo, Italy
3Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas, Lithuania
4St. Anne’s University Hospital, Brno, Czech Republic

*Email: ausra.saudargiene@lsmu.lt

Introduction



Temporal interference (TI) stimulation enables noninvasive and spatially selective neuromodulation of deep brain structures [1,2]. This approach exploits the nonlinear response of neurons to electric fields by delivering multiple kHz-range oscillations, which interfere and generate an effective low-frequency envelope only at the target site [1,2]. This mechanism allows for selective activation of deep neuronal populations without affecting the overlying tissue. Recent studies have successfully applied this stimulation to the human hippocampus, showing significant effects on memory function [3, 4]. Despite its potential for clinical applications, the neural mechanisms underlying TI-induced effects remain poorly understood.

Methods

We used a biophysically accurate computational neuron model to investigate how subthreshold electric fields influence neural activity in the CA1 hippocampal pyramidal neurons. These neurons receive inputs from Schaffer collaterals, known to play an integral role in memory formation. To replicate this connectivity, we implemented AMPA and NMDA synapses at the proximal apical dendrites, with synaptic activity driven by hippocampal CA3 activity recordedin-vivo. The model neuron was placed in a uniform electric field, simulating the effects of an externally applied field between two conducting plates.

Results

Consistent with previously published modelling results [4], we observed that the electric field strength required to elicit action potentials grew with increasing carrier frequency. Moreover, the subthreshold electric field strength also depended on the orientation of the model neuron in the electric field, requiring higher amplitude when the neuron was perpendicular rather than parallel to the direction of the electric field. Following an long-term potentiation (LTP) induction protocol, the subthreshold stimulation affected the synaptic weight distribution by altering the spike timing, firing frequency, and inter-spike interval patterns. A similar effect was observed with naturally occurring synaptic inputs.

Discussion

In summary, our model shows that subthreshold electric fields alter how neurons respond to naturally occurring synaptic inputs by affecting underlying long-term synaptic plasticity processes. The impact of TI on synaptic plasticity may underlie its effects on memory enhancement, observed in human experiments. The stimulation efficacy is partly determined by the neuron orientation in the electric field, as not all neurons are affected equally. Since our study focuses on single-neuron processes, further research is needed to explore network-level effects.





Acknowledgements
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We acknowledge a contribution from the Italian National Recovery and Resilience Plan (NRRP), M4C2, funded by the European Union – NextGenerationEU (Project IR0000011, CUP B51E22000150006, "EBRAINS-Italy", and support from EU HORIZON-INFRA-2022-SERV-B-01, project 101147319 — EBRAINS 2.0.





References


[1]https://doi.org/10.1016/j.cell.2017.05.024
[2]https://doi.org/10.1126/science.aau4915
[3]https://doi.org/10.1038/s41593-023-01456-8

[4]https://doi.org/10.1101/2024.12.05.24303799