Introduction: Temporal interference stimulation (TIS) was developed as an alternative method of transcranial brain stimulation to noninvasively modulate neural circuits deep in the human brain. Existing clinical transcranial brain stimulation — such as transcranial alternating current (tACS), direct current (tDCS), and magnetic (tMS) stimulation — share a common fundamental limitation: a trade-off between brain depth, neural target focality, and activating field intensity. The TIS approach has the potential to circumvent this trade-off, enabling deep and focal neural activation. TIS leverages two “carrier” frequencies offset by a small frequency difference that produced a neuromodulatory “beat” pattern at the difference frequence. This beat field can peak deep in the brain, can be more focal than conventional stimulation, and can be steered into specific regions by adjusting the relative intensities of the carrier fields. Modeling such stimulation onto biophysically realistic single cell models is the first step to understanding the effects, possible applications, and potential limitations of TIS.
Materials and
Methods: In this study, we utilized the NEURON software implemented within a Python Integrated Development Environment to simulate model neurons in three dimensions. These model cells were either generated by our researchers or obtained from previous research archived in the ModelDB repository. The selection of the latter models was guided by target neurons within the region of interest for coordinated experimental efforts in both humans and non-human primates. As one example, we thoroughly explored TIS in a morphologically correct model of a layer 2 pyramidal cell in human hippocampus (Panel A). The model used had multiple components derived from Deitcher Y et al [1]. Their study characterized a comprehensive set of electrophysiological and biophysical properties this model, including mean action potential (AP) amplitude, half-width, rise time, after-hyperpolarization (AHP) depth, first spike latency, spike frequency, inter-spike interval coefficient of variation (ISI-CV), mean ISI, threshold current for spike generation, membrane time constant (τm), input resistance (RN), and sag ratio.
We simplified the TIS field by assuming that beat-field stimulation originated from a point source, and calculated the resulting extracellular potential {V} at every location in space {x, y, z} from the equation: V=(I/(4*π*ρ))/√(x^2+y^2+z^2 ) , where I represents the current generated by the point source, and ρ denotes the tissue conductivity.
This comprehensive approach, combining the use of NEURON software, three-dimensional model cells, and a well-defined mathematical framework, allows for a detailed investigation of the neuronal responses to the simulated beat field stimulation, contributing to a deeper understanding of the underlying neurophysiological mechanisms.
Results, Conclusions, and Discussions: This study utilized a computational model with a point source positioned 0, 60 and 120 m away, in the x, y and z coordinates respectively from the soma of the neuron, represented as the red sphere in Figure 1 A. The stimulation vector ranged from 50 mV to 320 mV, depending on the position of the small segments within the model. Sufficiently large simulation revealed both hyperpolarization and depolarization in different regions of the neuronal dendritic arbor. For most configurations, the net effect on the cell body was depolarization, supporting that the neuron can be biased toward activation. The level of activation can be modulated with the intensity of the TIS. The next step in this research is to extend the model to include use specific and clinically accurate stimulation values and positions and apply the same simulation methodology to observe the response characteristics for pyramidal neurons in the hippocampus and throughout the cortical sheet.
This comprehensive computational approach, combining detailed neuron modeling, realistic stimulation parameters, and validation through experimental data, provides a robust framework for investigating the neurophysiological mechanisms underlying the propagation of action potentials and the potential applications of TIS in a controlled and systematic manner. Subsequent testing on non-human primates, will contribute to a deeper understanding of the complex dynamics of neuronal networks and inform the development of more effective neuromodulation techniques.
