Measurement of activity-dependent response to electrical stimulation in small unmyelinated axons

Abstract

One of the most fundamental aspects of neurophysiology is that neurons are electrically excitable- that is, provided the appropriate electrical or sensory stimulus, they will respond by firing an action potential. This is well understood in both theoretical and practical terms for a single application of an electrical pulse to an otherwise inactive neuron. However, responses to sequences of stimuli, such as those used by clinical neural stimulators, can quickly become extremely difficult to predict. The problem emerges as each responding action potential activates a set of activity-dependent mechanisms, which in turn may al- ter the excitability of the neuron and therefore the number of action potentials evoked by stimulation. As these activity-dependent processes are usually unmeasured, differ between neurons, and vary in their sensitivity to activity as well as their impact on excitability, the problem of predicting response to sequences of electrical stimuli is difficult to constrain. Here, we show how techniques using high-density microelectrode arrays, a novel electro- physiology tool, can be adapted to measure intermittent response to electrical stimulation. We then use these tools to probe the impact of the stimulus location relative to the neuron on intermittent response, and investigate the role of the delay between stimulus and action potential initiation in measurements of response latency. Based on these studies, we argue that intermittent responsiveness to stimulation is a phenomena governed by spatially local dynamics, rather than cell-wide dynamics. We then discuss implications of this claim for clinical neural stimulation, as well as the interpretation of antidromic latency measurements as evidence of timing plasticity.