A geometric approach to quantifying the neuromodulatory effects of persistent inward currents on individual motor unit discharge patterns

Abstract

Objective: All motor commands flow through motoneurons, which entrain control of their innervated muscle fibers, forming a motor unit (MU). Owing to the high fidelity of action potentials within MUs, their discharge profiles detail the organization of ionotropic excitatory/inhibitory as well as metabotropic neuromodulatory commands to motoneurons. Neuromodulatory inputs (e.g., norepinephrine, serotonin) enhance motoneuron excitability and facilitate persistent inward currents (PICs). PICs introduce quantifiable properties in MU discharge profiles by augmenting depolarizing currents upon activation (i.e., PIC amplification) and facilitating discharge at lower levels of excitatory input than required for recruitment (i.e., PIC prolongation). Approach: Here, we introduce a novel geometric approach to estimate neuromodulatory and inhibitory contributions to MU discharge by exploiting discharge non-linearities introduced by PIC amplification during time-varying linear tasks. In specific, we quantify the deviation from linear discharge (“brace height”) and the rate of change in discharge (i.e., acceleration slope, attenuation slope, angle). We further characterize these metrics on a simulated motoneuron pool with known excitatory, inhibitory, and neuromodulatory inputs and on human MUs (Number of MUs; Tibialis Anterior: 1448, Medial Gastrocnemius: 2100, Soleus: 1062, First Dorsal Interosseus: 2296). Main Result: In the simulated motor pool, we found brace height and attenuation slope to consistently indicate changes in neuromodulation and the pattern of inhibition (excitation-inhibition coupling), respectively, whereas the paired MU analysis (ΔF) was dependent on both neuromodulation and inhibition pattern. Furthermore, we provide estimates of these metrics in human MUs and show comparable variability in ΔF and brace height measures for MUs matched across multiple trials. Significance: Spanning both datasets, we found brace height quantification to provide an intuitive method for achieving graded estimates of neuromodulatory and inhibitory drive to individual MUs. This complements common techniques and provides an avenue for decoupling changes in the level of neuromodulatory and pattern of inhibitory motor commands.

The effects of biological sex on estimates of persistent inward currents in the human lower limb

“…The paired MU analysis technique to estimate PIC magnitude in humans has been well-validated, but it is possible that the mechanisms behind the observed sex differences in ΔF are not solely due to changes in monoaminergic drive. For example, differences in the patterns of inhibitory inputs, monoamine release, monoaminergic receptor activity and/or sensitivity differences between the sexes could possibly account for differences in MU discharge patterns (Beauchamp et al ., 2023). Future studies which include a comprehensive array of contractions, that complement the isometric triangular ramps utilized herein, and allow inferences about the biophysical properties of motoneurons (Khurram et al ., 2022) or that use electrical stimulation or vibration protocols to probe excitatory and inhibitory circuits (Mesquita et al ., 2021, Pearcey et al ., 2022, Orssatto et al ., 2022), may reveal further insight into the mechanism behind these sex differences.…”

“…The paired MU analysis technique to estimate PIC magnitude in humans has been well-validated, but it is possible that the mechanisms behind the observed sex differences in ΔF are not solely due to changes in monoaminergic drive. For example, differences in the patterns of inhibitory inputs, monoamine release, monoaminergic receptor activity and/or sensitivity differences between the sexes could possibly account for differences in MU discharge patterns (Beauchamp et al, 2023).…”

Can local vibration alter the contribution of persistent inward currents to human motoneuron firing?

“…Moreover, the F scores calculated in this study are an estimation of contribution of PICs to a specific motoneuron firing pattern -firing rate hysteresis or 'PIC prolongation' . Thus, the effects of LV in this study cannot be directly extrapolated to other non-linearities in the motoneuronal input-output properties (Beauchamp et al, 2023;Binder et al, 2020) either, such as acceleration, saturation, warm-up and self-sustained firing. Other limitations of this methodological approach are that F scores cannot estimate the contribution of subthreshold PICs to motoneuron firing (Afsharipour et al, 2020), are generally confined to relatively higher threshold MUs (Beauchamp et al, 2023), and can be contaminated by spike frequency adaptation (Vandenberk & Kalmar, 2014) or by alterations in the firing rate profile of the control units.…”

“…Thus, the effects of LV in this study cannot be directly extrapolated to other non-linearities in the motoneuronal input-output properties (Beauchamp et al, 2023;Binder et al, 2020) either, such as acceleration, saturation, warm-up and self-sustained firing. Other limitations of this methodological approach are that F scores cannot estimate the contribution of subthreshold PICs to motoneuron firing (Afsharipour et al, 2020), are generally confined to relatively higher threshold MUs (Beauchamp et al, 2023), and can be contaminated by spike frequency adaptation (Vandenberk & Kalmar, 2014) or by alterations in the firing rate profile of the control units. Finally, it remains unclear whether the magnitude of changes in F reported during ramp contractions in this study has meaningful implications in motor control.…”

Ageing reduces persistent inward current contribution to motor neurone firing: Potential mechanisms and the role of exercise

“…Calcium PICs are activated after recruitment and enable motor neurone self‐sustained firing, prompting firing rate hysteresis (Heckman et al., 2005), which is measured by the Δ F technique (Powers & Heckman, 2015). Recent developments in the estimation of the PIC contribution to motor neurone firing rate acceleration (Beauchamp et al., 2023), along with Δ F calculations, will enable the investigation of resistance training‐related adaptations on estimates of sodium and calcium PICs in future experiments.…”