Low intensity focused ultrasound: a new prospect for the treatment of Parkinson’s disease

Figures & data

Table 1. Summary of the neuro-modulatory effects of LIFU/LIPU in PD model.

Authors & Year	Species	model	Ultrasound parameters	Stimulation site	Consequence
Hui Zhou et al. 2019	C57BL/6 mice	MPTP	FF 800 kHz, PRF 100 Hz, TBD 1 ms, SD 6 s, DC 10%, ISI 10 s, TST 40 min, 7 day, 76 mW/cm^2	Motor cortex	Motor behavior ↑ Striatal T-SOD and GSH-PX ↑
Yi Yuan et al. 2020	C57/BL6 mice	MPTP	FF 500 kHz, PRF 1 kHz, DC 5%, SD 50 ms, ISI 1s, TST 5 min, 0.255 W/cm^2	Subthalamic nucleus	Motor behavior ↑
Tian Xu et al.2020	C57/BL6 mice	MPTP	FF1MHz, 5 min/day, 10 day, 0.3 W/cm^2	–	Motor behavior ↑ DA levels ↑ Dopaminergic neuron regeneration ↑
Hui Zhou et al. 2021	C57/BL6 mice	MPTP	FF 3.8 MHz, 1 kHz PRF, 50% DC, TST 30 min/day, 3.5-day intervals for 5 weeks, 430 mW/cm^2(Ispta)	Subthalamic nucleus	Motor behavior ↑ Chronic inflammatory response of microglia and astrocytes ↓
Xueying Chen et al.2021	C57/BL6 mice	MPTP/N2a cells	FF 1 MHz, 1 kHz PRF, 20% DC, TST10 min/day, 5 day	–	Motor behavior ↑ Tyrosine hydroxylase positive neurons ↑ MPP+-induced reactive oxygen species (ROS) ↑ MPP+-induced mitochondrial membrane potential ↑
Lu Zhao et al. 2016	PC12 cells	MPP+	FF 1 MHz, PRF 100 Hz, DC 20%, TST 10 min, 30 or 50 mW/cm^2	–	MPP+-induced neurotoxicity ↓ NGF-induced neurite outgrowth ↑
Lu Zhao et al. 2017	PC12 cells	MPP+	FF 1 MHz,100Hz PRF,20% DC, TST 10 min, 50 mW/cm^2	–	MPP+-induced neurotoxicity ↓ MPP+-induced oxidative stress↓
Karmacharya et al. 2017	PC12 cells	MPP+	FF 1 MHz, TST 10 min, 30, 50, or 100mW/cm^2	–	Mitochondrial complex I activity ↑ CK2 expression ↓ MPP+-induced mitochondrial ROS generation↓ phosphorylation/ aggregation of α-synuclein↓

FF: fundamental frequency PRF: pulsed repetition frequency DC: duty cycle TBD: time of burst duration SD: stimulation duration ISI: interstimulus interval TST: total stimulation time.

Figure 1. The strategy and effect of low intensity focused ultrasound in the treatment of PD. 1. LIFU combined with MBs opens the BBB. 2. LIFU acts on specific parts of the mice brain, such as the motor cortex, substantia nigra, striatum and other specific sites. 3. Microvesicles or nanoparticles deliver relevant genes or therapeutic drugs such as polymeric nanoparticle, dendrimer, nanogel, magnetic nanoparticle, viral-based nanoparticle, micelle and liposome. 4. Therapeutic substances typically pass through an open BBB in two ways: the paracellular route and the transcellular route.

Table 2. Summary of different strategies for FUS-mediated Permeabilization of the BBB in PD model.

Authors & Year	Species	Model	Ultrasound parameters	Delivery vehicle	Delievable	Dose&time	Consequence
Gesthimani Samiotaki et al. 2015	C57BL/6 mice	–	FF 10 MHz, PRF 10 Hz, TST 60s	Microbubbles	NTN	5 μg/g	NTN bioavailability↑
Chung-Yin Lin et al. 2016	Balb/c mice	MPTP	FF 500 kHz, TBD 10 ms, DC 1%, RPF 1 Hz, TST 60 s	gene-liposome-microbubbles	GFP/GDNF	27μg;21days	LpDNA-MBs complexes administration↑
Ling Long et al. 2017	SD rats	6-OHDA	FF 0.5 MHz, TST 30 s	pDC315 nanoparticles	Nrf2	0.01 mg/kg; 14 days	Nrf2 gene transfection efficiency↑ Oxygen species levels↓
Brian P. Mead et al. 2017	SD rats	6-OHDA	FF 1.15 MHz, PNP 0.6 MPa	Brain penetrating nanoparticles	GDNF	0.5 μg/g body weight	GDNF protein content ↑
Peijian Yue et al.2018	SD rats	6-OHDA	FF 1 MHz, DC 20%, 2 W/cm^2	PEGylated liposomes-coupled microbubbles	GDNF	5μg; 3 weeks	PLs-GDNF-MBs delivery↑ Behavioral deficits ↓ Neuron loss ↓
Kristiana Xhima et al. 2019	Transgenic mice	–	FF 1.68 MHz, TBD 10 ms, PRF 1 Hz, TST 120 s.	AAV9 vectors	shRNA sequence targeting human α-syn	1.25 × 10^10 VG/g	Viral vectors targeting α-synuclein delivery↑
Maria Eleni Karakatsani et al. 2019	C57BL/6 mice	MPTP	FF 1.5 MHz, PRF 10 Hz, TST 60 s, PNP 0.45 MPa.	Microbubbles, AAV1-CAG-eGFP-GDNF vectors	GDNF, NTN	Neurturn 20 μg/g οf body mass);100μl diluted AAV; 12 weeks	Intravenous neurotrophic delivery↑ Nigrostriatal dopaminergic pathway’s damage↓
Chung-Yin Lin et al. 2020	Balb/c mice	MPTP	FF 1.0 MHz, TBD 10 ms, PRF 10 Hz, TST 3 min.	Microbubble (MB)-liposome complex	GDNF, BDNF, and concurrent GDNF/BDNF gene delivery	60μg; twice a week for 3 weeks	BDNF or GDNF gene delivery↑ Behavioral deficit↓ Dopaminergic neuronal loss↓ Calcium influx, GFAP and caspase 3 expression↓

FF: fundamental frequency PRF: pulsed repetition frequency DC: duty cycle TBD: time of burst duration. SD: stimulation duration ISI: interstimulus interval TST: total stimulation time.

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials. Data sharing is not applicable to this article as no new data were created or analyzed in this study. The source of the figure and table provided in the article were original.