Extracellular stimulation of central neurons: influence of stimulus waveform and frequency on neuronal output

The objective of this project was to examine the influence of stimulus waveform and frequency on extracellular stimulation of neurons with their cell bodies near the electrode (local cells) and fibers of passage in the CNS. Detailed computer-based models of CNS cells and axons were developed that accurately reproduced the dynamic firing properties of mammalian motoneurons including afterpotential shape, spike-frequency adaptation, and firing frequency as a function of stimulus amplitude. The neuron models were coupled to a three-dimensional finite element model of the spinal cord that solved for the potentials generated in the tissue medium by an extracellular electrode. Extracellular stimulation of the CNS with symmetrical charge balanced biphasic stimuli resulted in activation of fibers of passage, axon terminals, and local cells around the electrode at similar thresholds. While high stimulus frequencies enhanced activation of fibers of passage, a much more robust technique to achieve selective activation of targeted neuronal populations was via alterations in the stimulus waveform. Asymmetrical charge-balanced biphasic stimuli, consisting of a long-duration low-amplitude cathodic prepulse phase followed by a short-duration high-amplitude anodic stimulus phase, enabled selective activation of local cells. Conversely, an anodic prepulse phase followed by a cathodic stimulus phase enabled selective activation of fibers of passage. The threshold for activation of axon terminals in the vicinity of the electrode was lower than the threshold for direct activation of local cells, independent of the stimulus waveform. As a result, stimulation induced trans-synaptic influences (indirect depolarization/hyperpolarization) on local cells altered their neural output, and this indirect effect was dependent on stimulus frequency. If the indirect activation of local cells was inhibitory, there was little effect on the stimulation induced neural output of the local cells. However, if the indirect activation of the local cells was excitatory, attempts to activate selectively fibers of passage over local cells was limited. These outcomes provide a biophysical basis for understanding frequency-dependent outputs during CNS stimulation and provide useful tools for selective stimulation of the CNS.