A cross-species, direction-aware transcriptomic framework identifies a TMS-rescuable synaptic gene program in the Parkinsonian substantia nigra: from stratification signature to precision neuromodulation

Abstract Repetitive transcranial magnetic stimulation (rTMS) ameliorates motor symptoms in Parkinson’s disease (PD), yet its molecular mechanism remains poorly defined and individual responses vary widely. Using publicly available transcriptomic resources, we pre-specified and tested a cross-species, direction-aware framework linking the genes activated by rTMS to the synaptic programs lost in the PD substantia nigra. A literature-anchored, direction-annotated TMS-responsive gene set (TMSgs-up, n = 63 genes from 8 independent evidence sources) significantly overlapped the PD-down-regulated synaptic plasticity-related gene program (OR = 249.4, 95% CI 101.8–609.5, FDR = 6.2 × 10 − 24, 13/27 genes) with complete direction specificity (overlap with PD-up: OR = 0.33, FDR = 0.949). Three-way intersection of human PD-down, MPTP-down, and TMS-up genes defined a 15-gene rescuable core (S_rescue) enriched in the AGTR1 + ventral-tier dopamine neurons selectively lost in PD (OR = 36.1, P = 3.4 × 10 − 10), forming a tightly interconnected protein network (STRING: 48 edges vs 2 expected, P < 10 − 16) and enriched in dopaminergic synapse (FDR = 4.1 × 10 − 10) and synaptic vesicle cycle (FDR = 6.7 × 10 − 8) pathways. TMSgs-up was enriched in long-term potentiation (FDR = 3.4 × 10 − 24), and CREB1 ChIP-seq targets were over-represented (FDR = 8.4 × 10 − 7), supporting a Ca2+–CaMKII–CREB axis; ISR–LTP antagonism was not significant at bulk level, reported as a pre-specified exploratory negative. This framework places PD pathology and TMS mechanism in a single gene-coordinate system, providing a falsifiable molecular interface from stratification toward precision neuromodulation.