# Temporal summation of subthreshold stimuli in human motor axons: Implications for intraoperative neuromonitoring

## TL;DR

This study shows how repeated low-level nerve stimulation can trigger muscle responses, offering guidelines to prevent unintended activation during brain surgery monitoring.

## Contribution

The study introduces a subthreshold superexcitability index to guide safe stimulation parameters during intraoperative neuromonitoring.

## Key findings

- Higher stimulus amplitudes and wider pulse widths significantly increase the probability of compound muscle action potentials.
- Persistent sodium current levels correlate with individual susceptibility to subthreshold stimulation.
- Subthreshold trains activate motor axons predictably based on amplitude, width, and train length.

## Abstract

•Subthreshold stimulus trains can depolarize axons to firing threshold.•Subthreshold superexcitability index (5% CMAP criterion) guides “safe” amplitude-width-train length combinations.•Higher individual susceptibility is associated with larger persistent sodium currents.

Subthreshold stimulus trains can depolarize axons to firing threshold.

Subthreshold superexcitability index (5% CMAP criterion) guides “safe” amplitude-width-train length combinations.

Higher individual susceptibility is associated with larger persistent sodium currents.

To examine how stimulus amplitude and width influence subthreshold superexcitability of peripheral axons and to provide evidence-based recommendations for minimizing inadvertent compound muscle action potential (CMAP) generation during intraoperative corticobulbar monitoring.

Fifteen healthy participants received median nerve stimulation under nine conditions combining three amplitudes (80 %, 85 %, and 90 % of threshold) and three pulse widths (0.1 ms, 0.5 ms, 1.0 ms). Trains of 1–7 subthreshold pulses (2 ms interpulse interval) were delivered 10 times per condition. CMAPs were recorded from the abductor pollicis brevis (APB), and the probability of a response exceeding 100 µV (baseline-to-negative-peak) was calculated. Persistent sodium current was estimated using the latent addition test (LAh).

Higher pulse amplitudes and wider pulse widths significantly increased CMAP probability, with a significant interaction (F(4,56) = 4.853, p = 0.002, partial η2 = 0.257). All pairwise comparisons were significant (p ≤ 0.023). When controlling for rheobase, LAh was positively correlated with response probability (rpartial(12) = 0.539, p = 0.047).

Subthreshold trains activate motor axons in a predictable manner depending on amplitude, width, and train length. These findings challenge current IONM assumptions and highlight the need for threshold-referenced, standardized protocols.