Neural Circuit Model of Long-Term Potentiation from Intermittent Theta Burst Stimulation

Abstract

Neural circuits have explained motor learning observed in animal populations, and plastic synaptic reorganization, but simulation of network modeling at larger scales lacks circuit organization. As a result, while large scale models capture general population behavior, there remains no canonical circuit, or simplest circuit-based functional subunit, that can be studied to determine the most discrete level of neuromodulation effect. The purpose of this study was to integrate a canonical neural circuit of the motor cortex with mathematical representation of membrane potentials across multiple neurons. The circuit model was evaluated by comparing changes in modeled resting outputter cell spike rate to changes in empirically recorded motor evoked potential amplitudes following intermittent theta burst stimulation (iTBS) delivered via transcranial magnetic stimulation. Effect sizes measured the magnitude of effect in both modeled and experimental data. The model successfully showed an increase in resting spike rate with relation to increased AMPA receptor permeability, scaled by simulated effects of iTBS to induce long-term potentiation (LTP), in an excitatory change similar to that seen in empirically recorded motor evoked potentials from human subjects. Thus, the model captured the mechanism of LTP in its simplest form. The representation is incomplete, however, as the model overestimated the responsivity based on the increased effect size relative to empirical data and noise. The overestimation is likely due to the lack of the disinhibition mechanism being fully represented in this iteration of the circuit, the simplicity of the cellular compartments modeled relative to the physiological complexity of neurons, and model parameter approximations of values controlling AMPA receptors. The circuit model is a building block for wider and more complex cortical networks that can be used to test mechanisms and applications of neuromodulation modalities.