An Anodic Phase Can Facilitate Rather Than Weaken a Cathodic Phase to Activate Neurons in Biphasic-Pulse Axonal Stimulations

Abstract

Electrical pulses have been promisingly utilized in neural stimulations to treat various diseases. Usually, charge-balanced biphasic pulses are applied in the clinic to eliminate the possible side effects caused by charge accumulations. Because of its reversal action to the preceding cathodic phase, the subsequent anodic phase has been commonly considered to lower the activation efficiency of biphasic pulses. However, an anodic pulse itself can also activate axons with its “virtual cathode” effect. Therefore, we hypothesized that the anodic phase of a biphasic pulse could facilitate neuronal activation in some circumstances. To verify the hypothesis, we compared the activation efficiencies of cathodic pulse, biphasic pulse, and anodic pulse applied in both monopolar and bipolar modes in the axonal stimulation of alveus in rat hippocampal CA1 region in vivo. The antidromically evoked population spikes (APS) were recorded and used to evaluate the amount of integrated firing of pyramidal neurons induced by pulse stimulations. We also used a computational model to investigate the pulse effects on axons at various distances from the stimulation electrode. The experimental results showed that, with a small pulse intensity, a cathodic pulse recruited more neurons to fire than a biphasic pulse. However, the situation was reversed with an increased pulse intensity. In addition, setting an inter-phase gap of 100 μs was able to increase the activation efficiency of a biphasic pulse to exceed a cathodic pulse even with a relatively small pulse intensity. Furthermore, the latency of APS evoked by a cathodic pulse was always longer than that of APS evoked by a biphasic pulse, indicating different initial sites of the neuronal firing evoked by the different types of pulses. The computational results of axon modeling showed that the subsequent anodic phase was able to relieve the hyperpolarization block in the flanking regions generated by the preceding cathodic phase, thereby increasing rather than decreasing the activation efficiency of a biphasic pulse with a relatively great intensity. These results of both rat experiments and computational modeling firstly reveal a facilitation rather than an attenuation effect of the anodic phase on biphasic-pulse stimulations, which provides important information for designing electrical stimulations for neural therapies.

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

“…The above experimental results and our previous study (Feng et al 2022) have shown that the A-HFS ⊤⊥ -induced suppression of the neuronal activations must have generated at the axons instead of the somata. Otherwise, the somata would not have distinguished the APs induced initially on axons by the two types of pulses and made distinct suppressions of APS ⊤ and APS ⊥ .…”

“…The experimental results presented here and in our previous studies (Feng et al 2013(Feng et al , 2022 have shown that the HFS-induced suppressions of neuronal activations mainly occur at axons instead of somata. Therefore, to focus on the investigation of axonal mechanisms, here we utilized an axonal model without other neuronal elements such as axonal initial segment, soma and dendrites.…”

“…During sustained HFS of pulses in DBS, axonal membranes can be excessively depolarized, resulting in an intermittent block at axons (Jensen and Durand 2009, Zheng et al 2011, Feng et al 2013, 2014. Under the situation of partial axon block, we recently found that the activation of anodic-pulses was not weaker than that of cathodicpulses during a type of HFS with alternate cathodicand anodic-pulses (Feng et al 2022). In addition, the two types of monophasic pulses were found to activate distinct sub-populations of neurons, respectively.…”