Abstract: Low-intensity pulsed ultrasound (LIPUS) has emerged as a novel non-invasive neuromodulation technique capable of transcranial penetration and precise targeting of deep brain regions, exhibiting unique advantages in the intervention of neurodegenerative dementia. This review systematically summarizes the research progress of LIPUS in improving cognitive and physical dysfunction in Alzheimer’s disease, Parkinson’s disease, vascular dementia, traumatic brain injury-related dementia, as well as Lewy body dementia and frontotemporal dementia, with a particular focus on the internal correlation among disease types, intervention targets, acoustic parameters, and therapeutic efficacy. It further elaborates on the potential neural mechanisms of LIPUS-mediated cognitive regulation from the perspective of cognitive neuropsychology, and clarifies the application value, existing deficiencies and future transformation prospects of this technology in cognitive impairment intervention.
The core innovation of this review lies in establishing a standardized analytical framework of “disease-target-parameter-efficacy” for LIPUS intervention in dementia. By sorting out existing preclinical and clinical evidence, this paper systematically delineates the optimal intervention targets for different dementia subtypes: the hippocampus, prefrontal cortex and precuneus are the dominant targets for Alzheimer’s disease intervention; the striatum, subthalamic nucleus, substantia nigra and primary motor cortex serve as core regulatory regions for Parkinson’s disease-related motor and cognitive dysfunction; the medial prefrontal cortex, barrel cortex and hippocampus are effective intervention sites for vascular dementia; and the injured cerebral cortex is the key target for improving post-traumatic cognitive impairment. This review further classifies and summarizes the effective intensity range of ultrasound parameters across animal models and human subjects, clarifying that spatial peak temporal average intensity and duty cycle are the core parameters determining neuroprotective and neuromodulatory effects, while fundamental frequency and pulse repetition frequency mainly play auxiliary regulatory roles. It quantitatively refines the effective parameter intervals of different disease subtypes, and highlights the significant parameter differences between animal experiments and human clinical applications, providing an important reference for subsequent parameter optimization and clinical conversion.
In terms of mechanism innovation, this review integrates multi-level pathological evidence and reveals multiple shared pathways by which LIPUS improves cognitive and physical dysfunction: upregulating the expression of brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor and nerve growth factor to maintain synaptic plasticity; inhibiting neuroinflammation by regulating microglial activation and pro-inflammatory cytokine secretion; ameliorating abnormal neural oscillations and functional connectivity disorders in cognitive-related neural circuits; promoting the clearance of amyloid-β plaques and α-synuclein aggregation; activating the Fndc5/irisin signaling pathway to repair neuronal damage; and improving cerebral blood perfusion and white matter integrity to alleviate brain pathological degeneration. In addition, this review proposes that LIPUS can modulate neuronal autophagy pathways, which provides a new mechanistic explanation for the potential intervention of Lewy body dementia and frontotemporal dementia lacking direct experimental evidence.
From the perspective of cognitive neuropsychology, this study complements the theoretical system of non-invasive physical intervention on cognitive function, clarifies the specificity of target-cognitive domain matching and the dependence of parameter-efficacy response, and fills the research gap of psychological perspective integration in the field of ultrasonic neuromodulation. At present, the limitations of this field include insufficient high-quality clinical trials, inconsistent parameter standards, unclear long-term efficacy and safety, and prominent interspecies transformation barriers. Future research should focus on optimizing individualized target and parameter schemes, establishing human-adapted ultrasound parameter evaluation systems, revealing in-depth molecular neural mechanisms, and conducting multi-center controlled clinical trials. Collectively, LIPUS exhibits broad application prospects in the precise intervention of cognitive and physical dysfunction in dementia, and its standardized clinical translation will provide a safe, non-invasive and innovative intervention strategy for reducing the global burden of dementia.

Key words: dementia, low-intensity pulsed ultrasound, cognitive impairment, neuromodulation, Alzheimer's disease