Maintenance Plasticity Rescue Slows ALS Progression in a Pruning-Continuum Model: Implications for Early Intervention in Motor and Mood Circuits

Background: Major depressive disorder and amyotrophic lateral sclerosis share intriguing comorbidity, with depression often appearing months before motor symptoms in 10–34% of ALS patients. Our prior genomic analyses identified microglial-mediated synaptic pruning as the sole consistent cross-disorder pathway, with autophagy failure acting as an ALS-specific amplifier. To test whether this continuum could explain dynamic progression and treatment responses, we built a mesoscale neural network model in which all clinical features emerge from architectural state changes. Methods: A layered feed-forward network (prefrontal-limbic to motor sub-layers) underwent progressive pruning (complement-biased plus activity-dependent), weight corruption (modelling aggregate spread), and sparsity-driven excitotoxicity. Autophagy inefficiency limited clearance. Ketamine-like treatment induced gradient-guided regrowth with noise and pruning reduction; riluzole provided excitotoxicity damping only. Simulations ran for 30 cycles (~45 months) across standard, bulbar-onset, limb-onset, ALS-MDD comorbid, pure MDD, and control profiles. Symptoms and biomarkers (including neurofilament proxy from weight instability) were derived directly from network state. Results: Untreated ALS reproduced preclinical stability, symptomatic acceleration, and advanced plateau, with stochastic flares mimicking clinical exacerbations. Bulbar- and limb-onset subtypes emerged naturally from sub-layer pruning biases. Maintenance ketamine slowed decline most effectively (terminal ALSFRS-R proxy 13–14 vs 11–12 untreated/riluzole; respiratory risk 85–89%; 10–15% higher motor integrity). Riluzole offered modest early slowing but converged to similar end-state. In comorbid runs, prefrontal pruning produced early depression as a prodromal signal, with ketamine providing dual mood-motor benefit. Conclusions: The model validates pruning as the upstream shared vulnerability and demonstrates that regular plasticity promotion can partially modify ALS trajectory, particularly in limb-onset or mood-comorbid cases. It offers a computational scaffold for testing early-intervention strategies and PRS-stratified trials. Keywords: amyotrophic lateral sclerosis, synaptic pruning, computational modelling, ketamine, disease modification