Therapeutic ultrasound for the treatment of demyelinating diseases.

Demyelinating diseases, such as multiple sclerosis, result from the progressive loss of myelin sheaths in the central and peripheral nervous systems, leading to impaired neural conduction and disability. Current disease-modifying therapies focus on immunosuppression to limit inflammation but fail to restore lost myelin. This lack of regenerative capacity underscores the need for strategies that actively promote remyelination. Recent advances highlight neuromodulation, and in particular low-intensity ultrasound (US), as a promising approach to stimulate both neuronal activity and glial responses essential for myelin repair. Ultrasound noninvasively promotes remyelination through complementary mechanisms: indirectly, by enhancing activity-dependent myelination via neuronal firing, and directly, by exerting mechanical bioeffects on oligodendrocyte precursor cells, oligodendrocytes, astrocytes, microglia, and Schwann cells. Experimental studies show US activation of key signaling cascades (PI3K/Akt, MAPK/ERK, NF-κB, TGF-β1), promoting oligodendrocyte survival, differentiation, and myelin repair, alongside microglial polarization, astrocytic neurotrophic support, and functional recovery in central and peripheral models. Converging data from neuromodulation research indicate that activation of cholinergic and noradrenergic circuits-such as those engaged by vagus nerve stimulation-can enhance OPC differentiation, attenuate neuroinflammation, and support remyelination, raising the possibility that ultrasound-based stimulation of these pathways may synergistically amplify regenerative outcomes while avoiding the need for implanted devices. Ultrasound holds transformative potential for central nervous system repair and can also promote regenerative processes in the peripheral nervous system. Cutting-edge ultrasound technologies enable noninvasive penetration of the skull, precise modulation of deep brain circuits with millimeter accuracy, and fine temporal control without inducing systemic side effects. When combined with advanced imaging techniques (e.g., MR-guided US), ultrasound achieves increasingly effective therapeutic outcomes by enhancing beam-targeting precision and enabling real-time monitoring. Moreover, emerging approaches such as sonogenetics and magneto-acoustic stimulation further expand its specificity and therapeutic potential. Collectively, current evidence establishes therapeutic ultrasound as a transformative, noninvasive strategy for treating demyelinating diseases.