BMEF：Low intensity focused ultrasound assisted treatment of ischemic stroke
Research Article | Open Access
Volume 2022 |Article ID 9864910 |
https://doi.org/10.34133/2022/9864910
Ischemic stroke can lead to disability and death, and patients often exhibit poor prognosis. Surgical thrombectomy performed after Large Vessel Occlusion (LVO) in the hyperacute phase of ischemic stroke is the best intervention to clear the primary obstruction and restore cerebral blood flow (CBF) in the penumbra. Intravenous injection of thrombolytic agents (rt PA) for systemic treatment of LVO has little effect, so other interventions need to be supplemented before and after thrombectomy surgery.
Focused Ultrasound (FUS) has good skull penetration, which can enhance thrombolysis and reduce cerebral infarction. Among various ultrasound techniques, Low Intensity Focused Ultrasound (LIFU) has become a non-invasive therapy that can be used to treat various diseases. Studies have shown that in animal models of heart disease, vascular dementia, and Alzheimer's disease, this therapy can upregulate neurotrophic factors and produce long-term effects through angiogenesis and neurogenesis.
In order to investigate how LIFU affects neuroprotection and vascular changes after stroke, the author's team used a non thrombotic adult male CD1 mouse model with permanent middle cerebral artery occlusion (pMCAO) as the research object, and performed transcranial LIFU on the model mice using a 1.1 MHz voxel FUS transducer to evaluate whether directed LIFU can promote the acute neuroprotective effect of the experimental mouse model and verify whether LIFU has adverse effects on the brain under ischemic conditions.
The author first studied the safety and efficacy of LIFU treatment. They compared the effects of LIFU with two peak negative pressures of 1.8 MPa and 3.5 MPa on pMCAO group and control (sham) group mice. All groups underwent transcranial LIFU treatment for 30 minutes after surgery (Figure 1). Among them, 1 mouse died and 1 mouse bled in the 3.5 MPa pmCAO group, and 1 mouse died and 1 mouse bled in the 3.5 MPa sham group. The site of bleeding showed damage to the cerebral artery and pia mater artery; However, there were no deaths or bleeding in the two groups at 1.8 MPa (Figure 2), so the authors used a peak negative pressure of 2.0 MPa in subsequent experiments to maximize the therapeutic effect of LIFU and minimize the risk to the experimental subjects.
Figure 1: Experimental setup for focused ultrasound therapy after ischemic stroke. (SD: Duration of Ultrasound, ISI: Inter Stimulus Interval), TBD：tone-burst duration， Pulse duration, PRF：pulse repetition frequency， Pulse repetition frequency)
Figure 2: The tissue after LIFU treatment with peak negative pressure of 1.8 MPa and 3.5 MPa. A-B: 1.8 MPa sham group brain, no bleeding; C: The vascular images of the 1.8MPa sham group showed no damage caused by ultrasound; D-E: In the 3.5 MPa sham group, there is bleeding in the brain; F: The vascular images of the 3.5 MPa shot group showed significant tissue damage.
Vasogenic edema is a major problem after ischemic stroke, caused by the disruption of the blood-brain barrier (BBB), and IgG deposition can indirectly measure BBB function. Therefore, the author continued to apply LIFU or mock LIFU at 1.1MHz and 2.0 MPa for 30 minutes to the pMCAO mouse model, and evaluated the infarct volume and quantified the area of IgG deposition 24 hours later. It was found that compared with the mock group, the infarct volume and IgG deposition in the LIFU treatment group were significantly reduced (Figure 3, Figure 4), indicating that LIFU can prevent cortical tissue damage, extracellular fluid accumulation, and BBB destruction after pMCAO.
Figure 4: Mice treated with LIFU showed reduced IgG deposition after pMCAO. (A: Stock group, B: LIFU treatment group)
In addition, the author stained mouse coronal sections with the vascular marker CD31 and measured the diameter of microvessels in the ipsilateral cortex. Compared with the mock group, the LIFU treatment group showed an increase in cortical microvascular diameter (Figure 5), indicating that the acute vasodilation effect of ultrasound may help prevent pMCAO induced ischemic stroke. In fact, previous research on humans has shown that non-invasive percutaneous low-frequency ultrasound can cause vasodilation of the brachial artery. Focused ultrasound can trigger endothelial cells to release nitric oxide, leading to vasodilation, and the activation of endothelial cells supports VEGF signaling, angiogenesis, and BBB recovery. These changes may play a core role in the neuroprotection of LIFU during ischemic stroke.
Figure 5: After ischemic stroke, the microvascular size of mice treated with LIFU increased. (B, D: mock group, C, E: LIFU treatment group; Green: CD31， Microvascular, red: Nissl， neuron
Figure 6: LIFU treatment did not significantly alter the size of cerebellar collateral vessels
Soft meningeal anastomosis of blood vessels or collateral circulation provides an alternative pathway for post-stroke blood flow into the infarcted area, which has a certain effect on protecting the ischemic penumbra. The evaluation of collateral circulation has also become an important imaging marker in the selection of stroke treatment strategies.
The author quantified the diameter and quantity of collateral circulation in mice treated with pMCAO for 24 hours on the same and opposite sides, mock LIFU, and LIFU (representative confocal images in Figures 6A-B and C-D). The diameter of the ipsilateral MCA-ACA (middle cerebral artery anterior cerebral artery) bypass was significantly increased in the mock group and LIFU treatment group compared to the contralateral group, but there was no difference between the mock group and LIFU treatment group, and there was no difference in the number of collateral branches between the groups. Similar results were observed in MCA-PCA (posterior cerebral artery) and all MCA bypass pathways (Figure 6E-H).
The author also calculated the size distribution of collateral vessels, which were divided into five segments according to vessel diameter:<20 μ m, 21-30 μ m, 31-40 μ m, 41-50 μ m, and>50 μ m. Among all MCA collateral vessels, the proportion of ipsilateral collateral vessels in the LIFU treatment group increased compared to the contralateral 31-40 μ m and 41-50 μ m segments, while the mock group only increased the proportion of the 31-40 μ m segment. The proportion of<20 μ m segment vessels on the same side decreased compared to the contralateral side in both groups of mice, and similar results were observed in the MCA-ACA bypass (Figure 61-J). Although there was no significant change in collateral size within 24 hours in the LIFU treatment group, it is not ruled out that LIFU treatment can improve or alter vascular dilation in collateral circulation, which may affect neuroprotection. These blood vessels did not dilate possibly due to the short duration of LIFU treatment, indicating that neuroprotection may be related to capillary dilation rather than collateral circulation.
In summary, these findings suggest that LIFU may provide important neuroprotection through alternative mechanisms of arterial generation.
The results of this study indicate that there is an urgent need for a transcranial LIFU device that can provide the optimal parameter range as a treatment strategy for ischemic stroke. The 1.1MHz system used by the author can provide transcranial LIFU and safely induce significant neuroprotective effects within 30 minutes after ischemic stroke.
Overall, this work demonstrates the neuroprotective properties of LIFU in a mouse stroke model and suggests its potential as a novel neural therapy for treating cerebral ischemia.
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BMEF： Low intensity focused ultrasound assisted treatment of ischemic stroke
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