Systematic characterization of inhibitory subpopulations activated by spinal cord stimulation using a targeted strategy

项目总结

Project Summary Spinal cord stimulation is an opioid-sparing neuromodulation therapy commonly used for the treatment of intractable chronic pain of the back and limbs. There is a substantial need to understand the fundamental biological mechanisms of SCS in order to improve clinical delivery and outcomes. It has proven challenging to characterize the inhibitory populations engaged by SCS, as electrophysiological recordings are vulnerable to interference from stimulation artifacts and only sample a sparse subset of active neurons. Immediate-early gene (c-fos) expression studies have been equivocal and did not distinguish excitatory and inhibitory populations. Therefore, it remains unknown whether SCS drives activation of distinct inhibitory subpopulations in a stimulation amplitude- and frequency-dependent manner. An innovative mouse model will be used to tag activated neurons during prolonged SCS delivered via chronically implanted miniaturized bipolar electrodes. A wide range of clinically-relevant SCS waveforms will be employed, and activated neurons will be molecularly phenotyped and visualized in situ via multiplexed RNA hybridization. Probes against specific molecular markers will be used to classify neurons in distinct inhibitory clusters, and statistical models will developed to characterize effects of stimulation parameters on neuronal clusters. This project will spatially and molecularly identify the inhibitory subpopulations activated by the full spectrum of clinically-relevant SCS waveforms. This information will dramatically improve the ability to design waveforms targeting specific spinal cord circuits, and have direct translational relevance, opening the door to rational implementation of SCS for distinct clinical pathologies.