Transsynaptic modulation of cerebellar nuclear cells: theta AC-burst stimulation

Objectives. Transcranial alternating current stimulation (tACS) and its variants are being tested in clinical trials for treatment of neurological disorders, and cerebellar tACS (ctACS) in particular has garnered much interest because of the involvement of the cerebellum in these disorders. The main objective of this study was to investigate the frequency tuning curves for the entrainment of the Purkinje cells (PCs) and the cerebellar nuclear (CN) cells by their axonal projections. In addition, we aimed to investigate the temporal and steady-state characteristics of the PC-CN transsynaptic modulation under clinically relevant stimulation waveforms. Approach. Experiments were conducted in anesthetized rats with the electrical stimulations applied to the cerebellar cortex while the spiking activity of PC and CN cells were recorded extracellularly. The PC-CN modulation was tested in a wide range of AC frequencies (1-1000 Hz). Furthermore, high-frequency AC stimulation (40-400 Hz) repeated at 4 Hz, that we termed theta AC-Burst Stimulation, was tested for its transient and steady-state responses. Main results. The CN cell firing patterns suggest that the population of projecting PCs that is entrained by the surface stimulation consists of the cells that are entrained in 180° opposite phases to each other. The CN cell spiking activity in general follows the entrainment pattern of the projecting PCs in the transient response. The CN entrainment during the steady-state turns into suppression at high frequencies of the stimulation. The PC responses could be explained with a simple statistical model that suggested that low-frequency (as well as DC) and high-frequency AC modulation may be operating through different neural mechanisms. Significance. High-frequency AC stimulation with a low-frequency envelope can be leveraged to induce CN modulation at theta frequencies. These results may explain some of the clinical findings and provide insight for future clinical trials of ctACS.