Title

Estimation and modulation of persistent inward currents in human spinal motoneurons

Author Identifiers

Ricardo Mesquita

https://orcid.org/0000-0002-0327-3253

Date of Award

2022

Degree Type

Thesis

Degree Name

Doctor of Philosophy

School

School of Medical and Health Sciences

First Advisor

Anthony Blazevich

Second Advisor

Janet Taylor

Third Advisor

Gabriel Trajano

Abstract

The manner in which motoneurons respond to excitatory and inhibitory input depends strongly on how their intrinsic properties are influenced by neuromodulators. Importantly, activation of voltage-gated channels that generate persistent (long-lasting) inward currents (PICs) is crucial for initiation, acceleration, and maintenance of firing. The overall aim of this thesis was to develop new ways to both estimate and modulate PIC contributions to motoneuron firing in humans.

Hypothetically, PIC estimation in humans might be possible by examining muscle force and electromyographic activity responses to tendon vibration superimposed with bursts of neuromuscular electrical stimulation (NMES) in an otherwise-inactive muscle (VibStim). Such activation produces involuntary muscle contractions with PIC-like behaviours (e.g., muscle-length dependence, warm-up, and self-sustained activity). In Study 1, the effect of NMES parameters on torque magnitude was examined. Bouts of 5 x 2-s NMES with wide pulse width eliciting 20% of maximal voluntary force provided the most robust responses when compared to bouts with different NMES intensity, pattern, and pulse width. This combination may therefore be useful for research or clinical applications, and these parameters were thus used in the subsequent studies.

As PICs are highly sensitive to inhibition but enhanced by serotonin and noradrenaline, it was hypothesised that both reciprocal inhibition (RI) and whole-body relaxation (WBR; which might decrease serotonin and noradrenaline release) would reduce PICs. Thus, in Study 2, PICs were estimated using both VibStim and the well-established paired motor unit (MU) technique, in which high-density surface electromyography captured MU firings during ramp contractions and delta frequency (ΔF) was calculated. ΔF is a measure of recruitment-derecruitment firing hysteresis, which is assumed to be an estimate of PIC activity. ΔF was decreased by both RI and WBR. However, only some variables were decreased during WBR in VibStim and all variables remained unaltered in RI. ΔF results demonstrate the effects of inhibition on PICs in multiple MUs and show the potential to reduce PICs through non-pharmacological, neuromodulatory interventions such as WBR. The lack of consistency between techniques suggests that VibStim is not sufficiently sensitive to detect PIC changes under some physiological conditions; that is, there may be insufficient scope for VibStim variables to decrease adequately to detect PIC suppression.

Accordingly, a comparison of PIC estimates measured with both techniques during neuromodulatory interventions that should facilitate PICs is also of interest. In Study 3, the effects of jaw clenching (JC) and mental stress (MS) on PICs were examined. ΔF was not altered by JC or MS. In VibStim, all variables were increased in JC while some were increased in MS. This suggests that increased neuromodulation may have little effect during voluntary contractions (as when computing ΔF) but be more notable when voluntary drive is eliminated (VibStim).

In conclusion, this thesis (1) elucidates strengths and limitations of an alternative method (VibStim) to estimate motoneuronal PICs, (2) improves our understanding of the mechanisms of PIC depression in human motoneurons, and (3) suggests that effects of increased serotonin and noradrenaline release on PICs depend on whether PICs are estimated at rest or during voluntary contractions.

Comments

Author also known as Ricardo Mesquita

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