Low-intensity transcranial ultrasound neuromodulation promotes neuronal regeneration: A new hope for noninvasive treatment of neurodegenerative diseases

Neurodegenerative diseases, which are characterized by progressive neuronal loss and the lack of disease-modifying therapies, are becoming a major global health challenge. The existing neuromodulation techniques, such as deep brain stimulation and transcranial magnetic stimulation, show limitations such as invasiveness, restricted cortical targeting, and irreversible tissue effects. In this context, low-intensity transcranial ultrasound has emerged as a promising noninvasive alternative that can penetrate deep into the brain and modulate neuroplasticity. This review comprehensively assesses the therapeutic mechanisms, efficacy, and translational potential of low-intensity transcranial ultrasound in treating neurodegenerative diseases, with emphasis on its role in promoting neuronal regeneration, modulating neuroinflammation, and enhancing functional recovery. We summarize the findings of previous studies and systematically illustrate the potential of low-intensity transcranial ultrasound in regulating cell death mechanisms, enhancing neural repair and regeneration, and alleviating symptoms associated with neurodegenerative diseases. Preclinical findings indicate that low-intensity transcranial ultrasound can enhance the release of neurotrophic factors (e.g., brain-derived neurotrophic factor), promote autophagy to clear protein aggregates, modulate microglial activation, and temporarily open the blood-brain barrier to facilitate targeted drug delivery. Existing clinical trial data show that low-intensity transcranial ultrasound can reduce amyloid-? plaques, improve motor and cognitive deficits, and promote remyelination in various disease models. Early clinical trials suggest that low-intensity transcranial ultrasound may enhance cognitive scores in Alzheimer's disease and alleviate motor symptoms in Parkinson's disease, all while demonstrating a favorable safety profile. Past studies support the notion that by integrating safety, precision, and reversibility, low-intensity transcranial ultrasound can transform the treatment landscape for neurodegenerative disease. However, more advancements are necessary for future clinical application of low-intensity transcranial ultrasound, including optimizing parameters such as frequency, intensity, and duty cycle; considering individual anatomical differences; and confirming long-term efficacy. We believe establishing standardized protocols, conducting larger trials, and investigating the underlying mechanisms to clarify dose-response relationships and refine personalized application strategies are essential in this regard. Future research should focus on translating preclinical findings into clinical practice, addressing technical challenges, and exploring combination therapies with pharmacological or gene interventions.