Critical slowing down at the neuromuscular junction: an early-warning framework for amyotrophic lateral sclerosis

Abstract Objective. In amyotrophic lateral sclerosis (ALS), disease is monitored largely through accumulated loss. We develop the hypothesis that the stability of the compensation offsetting that loss carries an earlier signal than the level of loss itself, readable as a critical-slowing-down (CSD) signature from instability measures already recorded serially. Methods. We set out a two-tier framework. Tier 1 treats the joint trajectory of single-fibre electromyography (SFEMG) jitter and fibre density as a coupling between instability and compensation, analysed with a multivariate early-warning estimator. Tier 2 is an immediately runnable screen on existing serial motor unit number index (MUNIX) and compound muscle action potential (CMAP) cohorts, analysing the directly measured signals rather than the derived motor unit size index (MUSIX) ratio, and benchmarking the dynamical metric against CMAP slope under a pre-registered plan. Two generative simulations support the design: a division-artefact analysis with measurement noise fixed to published reliability, and a feasibility analysis of detection power under realistic sparse sampling. Results. With biological fluctuation held flat, serial variance analysis of MUSIX manufactured a spurious rising-variance signature (relative variance rising ~4.7-fold toward the transition), conditional on the MUNIX measurement floor, and large enough to swamp the effect being sought. Within-patient detection of a planted CSD signal was at chance (area under the curve 0.52–0.56). Stage-aligned cohort-level detection was recoverable but noise-limited, requiring on the order of 80–160 patients at well-standardised noise and underpowered at worst-case noise. Conclusions. The framework is hypothesis-generating; its most likely outcome on real data is a pre-registered null, itself informative, whereas a positive Tier 2 result would be novel and would discriminate the underlying transition type. Significance. This is the first application of critical slowing down to the neuromuscular junction — a cheap, retrospective test on existing serial electrophysiology, for which measurement standardisation, not data collection, is the rate-limiting step.