Department of Radiology, Stanford University, Stanford, CA, USA.
Department of Comparative Medicine, Stanford University, Stanford, CA, USA.
Brain Stimul. 2020 May-Jun;13(3):804-814. doi: 10.1016/j.brs.2020.02.017. Epub 2020 Feb 21.
Neuromodulation by transcranial focused ultrasound (FUS) offers the potential to non-invasively treat specific brain regions, with treatment location verified by magnetic resonance acoustic radiation force imaging (MR-ARFI).
To investigate the safety of these methods prior to widespread clinical use, we report histologic findings in two large animal models following FUS neuromodulation and MR-ARFI.
Two rhesus macaques and thirteen Dorset sheep were studied. FUS neuromodulation was targeted to the primary visual cortex in rhesus macaques and to subcortical locations, verified by MR-ARFI, in eleven sheep. Both rhesus macaques and five sheep received a single FUS session, whereas six sheep received repeated sessions three to six days apart. The remaining two control sheep did not receive ultrasound but otherwise underwent the same anesthetic and MRI procedures as the eleven experimental sheep. Hematoxylin and eosin-stained sections of brain tissue (harvested zero to eleven days following FUS) were evaluated for tissue damage at FUS and control locations as well as tissue within the path of the FUS beam. TUNEL staining was used to evaluate for the presence of apoptosis in sheep receiving high dose FUS.
No FUS-related pre-mortem histologic findings were observed in the rhesus macaques or in any of the examined sheep. Extravascular red blood cells (RBCs) were present within the meninges of all sheep, regardless of treatment group. Similarly, small aggregates of perivascular RBCs were rarely noted in non-target regions of neural parenchyma of FUS-treated (8/11) and untreated (2/2) sheep. However, no concurrent histologic abnormalities were observed, consistent with RBC extravasation occurring as post-mortem artifact following brain extraction. Sheep within the high dose FUS group were TUNEL-negative at the targeted site of FUS.
The absence of FUS-related histologic findings suggests that the neuromodulation and MR-ARFI protocols evaluated do not cause tissue damage.
经颅聚焦超声（FUS）的神经调节具有非侵入性地治疗特定脑区的潜力，其治疗位置可通过磁共振声辐射力成像（MR-ARFI）进行验证。
在广泛的临床应用之前，为了研究这些方法的安全性，我们报告了在 FUS 神经调节和 MR-ARFI 后两种大动物模型中的组织学发现。
对两只恒河猴和十三只 Dorset 绵羊进行了研究。FUS 神经调节的靶点是恒河猴的初级视觉皮层，以及通过 MR-ARFI 验证的十一只绵羊的皮质下位置。两只恒河猴和五只绵羊接受了单次 FUS 治疗，而六只绵羊则接受了间隔三到六天的重复治疗。另外两只对照绵羊没有接受超声治疗，但接受了与十一只实验绵羊相同的麻醉和 MRI 程序。对脑组织（FUS 治疗后零到十一天采集）的苏木精和伊红染色切片进行评估，以确定 FUS 和对照部位以及 FUS 光束路径内的组织是否有损伤。TUNEL 染色用于评估接受高剂量 FUS 的绵羊是否存在凋亡。
在恒河猴或任何接受检查的绵羊中，均未观察到与 FUS 相关的生前组织学发现。所有绵羊的脑膜中均存在血管外红细胞（RBC），无论治疗组如何。同样，在 FUS 治疗（11/11）和未治疗（2/2）绵羊的非靶区神经实质中，也很少观察到小的血管周围 RBC 聚集。然而，没有观察到同时发生的组织学异常，这与从大脑中提取后血红细胞外渗是死后人为因素的结果一致。高剂量 FUS 组的绵羊在 FUS 靶点处 TUNEL 呈阴性。
没有发现与 FUS 相关的组织学发现表明，评估的神经调节和 MR-ARFI 方案不会造成组织损伤。
