Harnessing Theta-Gamma Coupled Brainwave Using Ultrasound for Spinal Astrocyte Revitalization and Sustained Neuropathic Pain Relief

Ultrasound stimulation is a promising non-invasive method for pain treatment, but comprehending its long-lasting impact and mechanisms remains challenging. Here, we investigate the neuromodulation effects of patterned ultrasound, focusing on spinal astrocytes in a partial sciatic nerve crush injury (PCI) model. Low-intensity continuous theta burst ultrasound stimulation with gamma bursts (LI-cTBUS) provides significant pain relief during and after application. LI-cTBUS enhances extracellular BDNF uptake by spinal astrocytes, restoring balance in the spinal BDNF/TrkB/KCC2 pathway, and reduces reactive astrogliosis by activating the TRPA1 ion channel, suggesting its role in ultrasound-induced analgesia. PCI alters the spinal cord transcriptomics, but LI-cTBUS normalizes these changes by attenuating inflammatory pathways, downregulating BDNF/TrkB signaling, and regulating GABA neurotransmission. Overall, LI-cTBUS revitalizes reactive astrocytes, reducing astrogliosis and nociceptive responses, highlighting its efficacy in alleviating mechanical allodynia and providing sustained neuropathic pain relief, underscoring its therapeutic potential.