Interactions between cathodic- and anodic-pulses during high-frequency stimulations with the monophasic-pulses alternating in polarity at axons—experiment and simulation studies

Abstract

Abstract Background. Electrical neuromodulation therapies commonly utilize high-frequency stimulations (HFS) of biphasic-pulses to treat neurological disorders. The biphasic pulse consists of a leading cathodic-phase to activate neurons and a lagging anodic-phase to balance electrical charges. Because both monophasic cathodic- and anodic-pulses can depolarize neuronal membranes, splitting biphasic-pulses into alternate cathodic- and anodic-pulses could be a feasible strategy to improve stimulation efficiency. Objective. We speculated that neurons in the volume initially activated by both polarity pulses could change to be activated only by anodic-pulses during sustained HFS of alternate monophasic-pulses. To verify the hypothesis, we investigated the interactions of the monophasic pulses during HFS and revealed possible underlying mechanisms. Approach. Different types of pulse stimulations were applied at the alvear fibers (i.e. the axons of CA1 pyramidal neurons) to antidromically activate the neuronal cell bodies in the hippocampal CA1 region of anesthetized rats in-vivo. Sequences of antidromic HFS (A-HFS) were applied with alternate monophasic-pulses or biphasic-pulses. The pulse frequency in the A-HFS sequences was 50 or 100 Hz. The A-HFS duration was 120 s. The amplitude of antidromically-evoked population spike was measured to evaluate the neuronal firing induced by each pulse. A computational model of axon was used to explore the possible mechanisms of neuronal modulations. The changes of model variables during sustained A-HFS were analyzed. Main results. In rat experiments, with a same pulse intensity, the activation volume of a cathodic-pulse was greater than that of an anodic-pulse. In paired-pulse tests, a preceding cathodic-pulse was able to prevent a following anodic-pulse from activating neurons due to refractory period. This indicated that the activation volume of a cathodic-pulse covered that of an anodic-pulse. However, during sustained A-HFS of alternate monophasic-pulses, the anodic-pulses were able to prevail over the cathodic-pulses in activating neurons in the overlapped activation volume. Model simulation results show the mechanisms of the activation failures of cathodic-pulses. They include the excessive membrane depolarization caused by an accumulation of potassium ions, the obstacle of hyperpolarization in the conduction pathway and the interactions from anodic-pulses. Significance. The study firstly showed the domination of anodic-pulses over cathodic-pulses in their competitions to activate neurons during sustained HFS. The finding provides new clues for designing HFS paradigms to improve the efficiency of neuromodulation therapies.