professor Department of Rehabilitation Medicine, Affiliated Hospital of Guizhou Medical University Guiyang, Guizhou, China (People's Republic)
Objectives : Spinal cord injury (SCI) leads to severe and often permanent neurological deficits. While neuromodulation techniques like intermittent theta burst stimulation (iTBS) show promise, the efficacy of multi-target approaches and their underlying mechanisms remain poorly explored. This study aimed to investigate the therapeutic effect of combining transcranial and trans-spinal iTBS (dual-target iTBS) in a rat model of SCI and to elucidate the involved molecular pathway.
Design: A C6 contusive SCI model was established in rats, randomly assigned to Sham, SCI, or SCI groups receiving transcranial, trans-spinal, or dual-target iTBS for 28 days. A separate cohort received lentiviral-mediated PDE1A knockdown. Outcomes were assessed via behavioral tests, electrophysiology, histology, transmission electron microscopy, and multi-omics sequencing. In vitro studies used primary neurons.
Results: Dual-target iTBS demonstrated superior efficacy compared to single-target stimulation, leading to significant improvements in motor coordination, grip strength, and gait. Electrophysiological recordings revealed enhanced neural transmission, evidenced by increased amplitudes and shortened latencies of MEPs and SEPs. Histologically, dual-target iTBS reduced lesion volume, promoted dendritic arborization, and increased expression of neuronal markers (MAP2, TUJ1, NF-H/L). Crucially, it enhanced synaptic remodeling, increasing the density and improving the structure of synapses and upregulating key synaptic proteins (PSD-95, Synaptophysin, CaMKII). Mechanistically, multi-omics analysis identified PDE1A as a central player. Dual-target iTBS downregulated the injury-induced overexpression of PDE1A, consequently elevating cAMP levels and the expression of its downstream effector, PRKACA. Confirmatory experiments showed that PDE1A knockdown replicated the benefits of dual-target iTBS, promoting neurite outgrowth, synaptic protein expression in neurons, and improving functional and structural recovery after SCI.
Conclusion: Dual-target iTBS is more effective than single-target stimulation for SCI recovery, mechanistically involving the inhibition of PDE1A and activation of the cAMP/PKA pathway to drive synaptic and neural repair. PDE1A is a novel therapeutic target.
