W2 Gating Failure in Motor Neurone Disease: TRN Gate Coherence Loss as a Proposed Upstream Cause of Motor Cortical Hyperexcitability — A Pre-Symptomatic Intervention Hypothesis

Version 3.3 — 26 July 2026 Five citation corrections applied. Conway (2026a) status updated from 'submitted to Consciousness and Cognition' to 'under review' throughout — the journal is not named. Wehmeyer et al. year corrected from 2025 to 2026 throughout. Condition count updated to twelve conditions across ten levels; prior conditions updated from eight to eleven; MND designation updated from ninth to twelfth application. CCT disclosure third paragraph added to Acknowledgements: 'The author is an independent researcher without institutional affiliation. No funding was received for this work.' Benatar citations corrected — two separate 2018 papers now correctly distinguished: Benatar et al. (2018a) Ann Neurol 84(1):130–139 DOI 10.1002/ana.25276 for the NfL/phenoconversion claim; Benatar et al. (2018b) JNNP 89(4):404–411 for neuromuscular characterisation. No changes to scientific content, hypotheses, predictions, or locked claims. What this paper proposes Motor neurone disease (MND/ALS) is characterised by progressive degeneration of upper and lower motor neurons. The dying forward hypothesis correctly identifies motor cortical hyperexcitability as an early driver of lower motor neurone death via glutamate excitotoxicity, but does not identify why motor cortex becomes hyperexcitable. This paper proposes that the thalamic reticular nucleus (TRN) alpha gate is progressively deprived of its primary drive source as Betz cells degenerate — removing the mechanism that normally prevents motor cortex from entering pathological excitation. Two independently confirmed anatomical facts establish this: Layer 5 Betz cells are the primary drivers of TRN motor sector activity via monosynaptic corticothalamic projections (Hadinger et al., 2023; Carroll et al., 2022); and Betz cells are among the first and most severely affected neurons in sporadic ALS, confirmed from gross neuropathology through single-cell transcriptomics to the most recent authoritative synthesis (Braak et al., 2013; Pineda et al., 2024; Eisen, Vucic, and Kiernan, 2025). The connection between these two facts — gate coherence failure upstream of motor cortical hyperexcitability — has not previously been stated in the ALS literature. Four convergent findings published since v2.1 strengthen the account: Sunahara et al. (2026) confirm TRN motor sector neurons are active dynamic control elements; Cotto et al. (2026) establish that ALS-vulnerable and ALS-resilient Layer 5 neurons are metabolically divergent, explaining why surviving neurons cannot compensate; Wehmeyer et al. (2026, Molecular Psychiatry) independently confirmed the TRN gate mechanism in Tourette syndrome without knowledge of this programme; and Lang et al. (2026, Journal of Clinical Investigation) demonstrated motor-sector-specific TRN disruption in presymptomatic ALS gene carriers — sleep spindle RMS reduced at C3/C4 but not F3/F4 before any clinical motor onset — partially confirming Prediction 1 before the proposed study has been conducted. Four falsifiable predictions follow. The most immediately testable requires no new device and can be assessed in existing presymptomatic cohorts using TMS-EEG. A companion evidence register documenting 43 independent sources across eight evidential branches is uploaded with this record. Figure 1 (W2 gate failure in MND — self-amplifying loop and circuit rescue) is uploaded as a separate file on this record.