Abstract
Experimental electrophysiological assessment of evoked responses from regenerating nerves is challenging due to the typical complex response of events dispersed over various latencies and poor signal-to-noise ratio. Our objective was to automate the detection of compound action potential events and derive their latencies and magnitudes using a simple cross-correlation template comparison approach. For this, we developed an algorithm called Waveform Similarity Analysis. To test the algorithm, challenging signals were generated in vivo by stimulating sural and sciatic nerves, whilst recording evoked potentials at the sciatic nerve and tibialis anterior muscle, respectively, in animals recovering from sciatic nerve transection. Our template for the algorithm was generated based on responses evoked from the intact side. We also simulated noisy signals and examined the output of the Waveform Similarity Analysis algorithm with imperfect templates. Signals were detected and quantified using Waveform Similarity Analysis, which was compared to event detection, latency and magnitude measurements of the same signals performed by a trained observer, a process we called Trained Eye Analysis. The Waveform Similarity Analysis algorithm could successfully detect and quantify simple or complex responses from nerve and muscle compound action potentials of intact or regenerated nerves. Incorrectly specifying the template outperformed Trained Eye Analysis for predicting signal amplitude, but produced consistent latency errors for the simulated signals examined. Compared to the trained eye, Waveform Similarity Analysis is automatic, objective, does not rely on the observer to identify and/or measure peaks, and can detect small clustered events even when signal-to-noise ratio is poor. Waveform Similarity Analysis provides a simple, reliable and convenient approach to quantify latencies and magnitudes of complex waveforms and therefore serves as a useful tool for studying evoked compound action potentials in neural regeneration studies.
Highlights
Peripheral nerve injury can lead to severe sensory and motor functional deficits
CNAPs from the intact side had predominantly simple response morphologies, with the occasional animal demonstrating a complex response, while all CNAPs evoked from regenerating nerves always displayed complex response morphologies
There was a relatively poor signal-tonoise ratio associated with responses from regenerated nerves, due to their typically small response magnitudes, compared to background noise levels
Summary
Peripheral nerve injury can lead to severe sensory and motor functional deficits. Progress in developing new treatments heavily relies on the evaluation of nerve function, and an objective, reliable and sensitive measure of nerve functional integrity is essential to accurately assess treatment outcomes. During nerve regeneration that follows injury, the nerve compound action potential (CAP) is fragmented, resulting in a noisy and complex CAP response comprised of smaller multiple compound events with sporadic latencies [1,2]. Despite the reproducibility of events evoked from regenerating nerves, there is little consistency among responses evoked from the regenerating nerves of different animals of the same species, and often very little resemblance to responses evoked from an intact nerve, at least during the earlier stages of recovery [2] Amplitudes of these events are of the same order of magnitude as background noise levels, and this problem is classically overcome by averaging multiple evoked responses. It may be necessary to average up to 500 evoked responses in order to reveal the response from the background noise [2,3], and test protocols with such large numbers of repeated stimuli risk compromising the functional integrity of regenerating nerves
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