Abstract
Ultrasound (US) has emerged as a noninvasive neurostimulation method for motor control in Parkinson's disease (PD). Previous in vivo US neuromodulation studies for PD were single-target stimulation. However, the motor symptoms of PD are linked with neural circuit dysfunction, and multi-target stimulation is conducted in clinical treatment for PD. Thus, in the present study, we achieved multi-target US stimulation using holographic lens transducer based on the Rayleigh-Sommerfeld diffraction integral and time-reversal methods. We demonstrated that holographic US stimulation of the bilateral dorsal striatum (DS) could improve the motor function in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. The holographic US wave (fundamental frequency: 3 MHz, pulse repetition frequency: 500 Hz, duty cycle: 20%, tone-burst duration: 0.4 ms, sonication duration: 1 s, interstimulus interval: 4 s, spatial-peak temporal-average intensity: 180 mw/cm(2)) was delivered to the bilateral DS 20 min per day for consecutive 10 d after the last injection of MPTP. Immunohistochemical c-Fos staining demonstrated that holographic US significantly increased the c-Fos-positive neurons in the bilateral DS compared with the sham group (P = 0.003). Moreover, our results suggested that holographic US stimulation of the bilateral DS ameliorated motor dysfunction (P < 0.05) and protected the dopaminergic (DA) neurons (P < 0.001). The neuroprotective effect of holographic US was associated with the prevention of axon degeneration and the reinforcement of postsynaptic densities [growth associated protein-43 (P < 0.001), phosphorylated Akt (P = 0.001), β3-tubulin (P < 0.001), phosphorylated CRMP2 (P = 0.037), postsynaptic density (P = 0.023)]. These data suggested that holographic US-induced acoustic radiation force has the potential to achieve multi-target neuromodulation and could serve as a reliable tool for the treatment of PD.