Cerebellar output controls generalized spike-and-wave discharge occurrence.

OBJECTIVE: Disrupting thalamocortical activity patterns has proven to be a promising approach to stop generalized spike-and-wave discharges (GSWDs) characteristic of absence seizures. Here, we investigated to what extent modulation of neuronal firing in cerebellar nuclei (CN), which are anatomically in an advantageous position to disrupt cortical oscillations through their innervation of a wide variety of thalamic nuclei, is effective in controlling absence seizures. METHODS: Two unrelated mouse models of generalized absence seizures were used: the natural mutant tottering, which is characterized by a missense mutation in Cacna1a, and inbred C3H/HeOuJ. While simultaneously recording single CN neuron activity and electrocorticogram in awake animals, we investigated to what extent pharmacologically increased or decreased CN neuron activity could modulate GSWD occurrence as well as short-lasting, on-demand CN stimulation could disrupt epileptic seizures. RESULTS: We found that a subset of CN neurons show phase-locked oscillatory firing during GSWDs and that manipulating this activity modulates GSWD occurrence. Inhibiting CN neuron action potential firing by local application of the γ-aminobutyric acid type A (GABA-A) agonist muscimol increased GSWD occurrence up to 37-fold, whereas increasing the frequency and regularity of CN neuron firing with the use of GABA-A antagonist gabazine decimated its occurrence. A single short-lasting (30-300 milliseconds) optogenetic stimulation of CN neuron activity abruptly stopped GSWDs, even when applied unilaterally. Using a closed-loop system, GSWDs were detected and stopped within 500 milliseconds. INTERPRETATION: CN neurons are potent modulators of pathological oscillations in thalamocortical network activity during absence seizures, and their potential therapeutic benefit for controlling other types of generalized epilepsies should be evaluated.

A Power-Efficient Multichannel Neural Stimulator Using High-Frequency Pulsed Excitation From an Unfiltered Dynamic Supply.

This paper presents a neural stimulator system that employs a fundamentally different way of stimulating neural tissue compared to classical constant current stimulation. A stimulation pulse is composed of a sequence of current pulses injected at a frequency of 1 MHz for which the duty cycle is used to control the stimulation intensity. The system features 8 independent channels that connect to any of the 16 electrodes at the output. A sophisticated control system allows for individual control of each channel's stimulation and timing parameters. This flexibility makes the system suitable for complex electrode configurations and current steering applications. Simultaneous multichannel stimulation is implemented using a high frequency alternating technique, which reduces the amount of electrode switches by a factor 8. The system has the advantage of requiring a single inductor as its only external component. Furthermore it offers a high power efficiency, which is nearly independent on both the voltage over the load as well as on the number of simultaneously operated channels. Measurements confirm this: in multichannel mode the power efficiency can be increased for specific cases to 40% compared to 20% that is achieved by state-of-the-art classical constant current stimulators with adaptive power supply.

Does a coupling capacitor enhance the charge balance during neural stimulation? An empirical study.

Due to their DC-blocking characteristic, coupling capacitors are widely used to prevent potentially harmful charge buildup at the electrode-tissue interface. Although the capacitors can be an effective safety measure, it often seems overlooked that coupling capacitors actually introduce an offset voltage over the electrode-tissue interface as well. This work investigates this offset voltage both analytically and experimentally. The calculations as well as the experiments using bipolar-driven platinum electrodes in a saline solution confirm that coupling capacitors introduce an offset, while they barely contribute to the passive charge balancing. In particular cases, this offset is shown to reach potentially dangerous voltage levels that could induce irreversible electrochemical reactions. This work therefore suggests that when the use of coupling capacitors is required, the offset voltage should be analyzed for all operating conditions to ensure it remains within safe boundaries.

High frequency switched-mode stimulation can evoke post synaptic responses in cerebellar principal neurons.

This paper investigates the efficacy of high frequency switched-mode neural stimulation. Instead of using a constant stimulation amplitude, the stimulus is switched on and off repeatedly with a high frequency (up to 100 kHz) duty cycled signal. By means of tissue modeling that includes the dynamic properties of both the tissue material as well as the axon membrane, it is first shown that switched-mode stimulation depolarizes the cell membrane in a similar way as classical constant amplitude stimulation. These findings are subsequently verified using in vitro experiments in which the response of a Purkinje cell is measured due to a stimulation signal in the molecular layer of the cerebellum of a mouse. For this purpose a stimulator circuit is developed that is able to produce a monophasic high frequency switched-mode stimulation signal. The results confirm the modeling by showing that switched-mode stimulation is able to induce similar responses in the Purkinje cell as classical stimulation using a constant current source. This conclusion opens up possibilities for novel stimulation designs that can improve the performance of the stimulator circuitry. Care has to be taken to avoid losses in the system due to the higher operating frequency.