Theta-gamma phase-amplitude coupling as a promising neurophysiological biomarker for evaluating the efficacy of low-intensity focused ultrasound stimulation on vascular dementia treatment.

Low-intensity focused ultrasound stimulation (LIFUS) has garnered attention for its potential in vascular dementia (VD) treatment. However, the lack of sufficient data supporting its efficacy and elucidating its mechanisms of action limits its further clinical translation and application. Considerable researches support the idea that LIFUS can improve the disturbance of neural oscillation modes caused by a variety of neurological diseases. However, the effect of LIFUS on neural oscillation modes in VD remains unclear. Therefore, this study aims to investigate the therapeutic effects of LIFUS on neural oscillation modes in VD. To achieve this purpose, the VD model was established via the bilateral common carotid artery occlusion, followed by two weeks of LIFUS treatment targeting the bilateral hippocampus. The therapeutic effects of LIFUS were evaluated by behavioral tests and cerebral blood flow measurement. Electrophysiological signals were recorded from the hippocampal CA1 and CA3 and medial prefrontal cortex (mPFC). The results indicated LIFUS could effectively improve cognitive dysfunction in VD rats. The underlying electrophysiological mechanisms involved the restoration of phase-amplitude coupling (PAC) of theta-gamma oscillations within both the CA3-CA1 local circuit and the hippocampus-mPFC cross-brain circuit. Classification results based on PAC characteristics suggested that PAC metrics are effective for evaluating the efficacy of LIFUS in treating VD, with optimal recognition performance observed in the hippocampus-mPFC cross-brain circuit. Our findings provide neuroelectrophysiological insights into the mechanisms of LIFUS in VD treatment and propose a promising diagnostic biomarker for evaluating LIFUS efficacy in future applications.