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Abstract Objective.Transcutaneous electrical stimulation of peripheral nerves is a common technique to assist or rehabilitate impaired muscle activation. However, conventional stimulation paradigms activate nerve fibers synchronously with action potentials time-locked with stimulation pulses. Such synchronous activation limits fine control of muscle force due to synchronized force twitches. Accordingly, we developed a subthreshold high-frequency stimulation waveform with the goal of activating axons asynchronously.Approach.We evaluated our waveform experimentally and through model simulations. During the experiment, we delivered continuous subthreshold pulses at frequencies of 16.67, 12.5, or 10 kHz transcutaneously to the median and ulnar nerves. We obtained high-density electromyographic (EMG) signals and fingertip forces to quantify the axonal activation patterns. We used a conventional 30 Hz stimulation waveform and the associated voluntary muscle activation for comparison. We modeled stimulation of biophysically realistic myelinated mammalian axons using a simplified volume conductor model to solve for extracellular electric potentials. We compared the firing properties under kHz and conventional 30 Hz stimulation.Main results.EMG activity evoked by kHz stimulation showed high entropy values similar to voluntary EMG activity, indicating asynchronous axon firing activity. In contrast, we observed low entropy values in EMG evoked by conventional 30 Hz stimulation. The muscle forces evoked by kHz stimulation also showed more stable force profiles across repeated trials compared with 30 Hz stimulation. Our simulation results provide direct evidence of asynchronous firing patterns across a population of axons in response to kHz frequency stimulation, while 30 Hz stimulation elicited synchronized time-locked responses across the population.Significance.We demonstrate that the continuous subthreshold high-frequency stimulation waveform can elicit asynchronous axon firing patterns, which can lead to finer control of muscle forces.
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This content will become publicly available on August 1, 2026
Dentate gyrus granule cell activation following extracellular electrical stimulation: a multi-scale computational model to guide hippocampal neurostimulation strategies
IntroductionThe effectiveness of neural interfacing devices depends on the anatomical and physiological properties of the target region. Multielectrode arrays, used for neural recording and stimulation, are influenced by electrode placement and stimulation parameters, which critically impact tissue response. This study presents a multiscale computational model that predicts responses of neurons in the hippocampus—a key brain structure primarily involved in memory formation, especially the conversion of short-term memories into long-term storage—to extracellular electrical stimulation, providing insights into the effects of electrode positioning and stimulation strategies on neuronal response. MethodsWe modeled the rat hippocampus with highly detailed axonal projections, integrating the Admittance Method to model propagation of the electric field in the tissue with the NEURON simulation platform. The resulting model simulates electric fields generated by virtual electrodes in the perforant path of entorhinal cortical (EC) axons projecting to the dentate gyrus (DG) and predicts DG granule cell activation via synaptic inputs. ResultsWe determined stimulation amplitude thresholds required for granule cell activation at different electrode placements along the perforant path. Membrane potential changes during synaptic activation were validated against experimental recordings. Additionally, we assessed the effects of bipolar electrode placements and stimulation amplitudes on direct and indirect activation. ConclusionStimulation amplitudes above 750 μA consistently activate DG granule cells. Lower stimulation amplitudes are required for axonal activation and downstream synaptic transmission when electrodes are placed in the molecular layer, infra-pyramidal region, and DG crest. SignificanceThe study and underlying methodology provide useful insights to guide the stimulation protocol required to activate DG granule cells following the stimulation of EC axons; the complete realistic 3D model presented constitutes an invaluable tool to strengthen our understanding of hippocampal response to electrical stimulation and guide the development and placement of prospective stimulation devices and strategies.
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- Award ID(s):
- 2121164
- PAR ID:
- 10638131
- Publisher / Repository:
- Frontiers
- Date Published:
- Journal Name:
- Frontiers in Computational Neuroscience
- Volume:
- 19
- ISSN:
- 1662-5188
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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