Mechanistic Insights into Skin Sympathetic Nerve Activity Dynamics in Healthy Subjects Through a Two-Layer Signal-Analytical and Closed-Loop Physiological Modeling Framework

Objective Skin sympathetic nerve activity (SKNA) has emerged as a promising non-invasive surrogate measure of sympathetic drive, but its relevant physiological characteristics remain ill-defined. This observational study aims to investigate its regulatory patterns during rest and Valsalva maneuver (VM) in healthy participants. Method Using a two-layer strategy integrating signal analysis and physiological modelling, we analyzed data recorded from 41 subjects performing repeated VMs. The observational layer includes time-domain feature comparisons using linear mixed-effect models, and time-varying spectral coherence analysis. The mechanistic layer proposes a mathematical model to investigate whether baroreflex and respiratory modulation are sufficient to reproduce the observed HR and average SKNA (aSKNA) dynamics. Main Results Mean integrated SKNA (iSKNA) showed more significant change than HRV for VM induced effects. We also found mean iSKNA increase during VM varies with BMI and sex. The coherence analysis indicated that iSKNA strongly synchronized with EDR under resting conditions. The proposed model successfully reproduced main characteristics of aSKNA dynamics, yielding a high median Pearson correlation coefficient of 0.80 ([Q 1 , Q 3 ] = [0.60, 0.91]). In contrast, HR dynamics were only partially captured, with a median PCC of 0.37 ([Q 1 , Q 3 ] = [0.16, 0.55]). These results likely suggest SKNA provides a more direct representation of sympathetic burst dynamics during VM in healthy subjects. Significance This study provides convergent evidence that SKNA reflects known autonomic regulatory influences in healthy subjects. These findings strengthen the physiological interpretability of SKNA while clarifying its appropriate use as a practical biomarker of sympathetic function.