BACKGROUND 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). OBJECTIVE 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. METHODS 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. RESULTS 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. CONCLUSIONS The absence of FUS-related histologic findings suggests that the neuromodulation and MR-ARFI protocols evaluated do not cause tissue damage.

中文翻译：

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恒河猴和绵羊经颅聚焦超声神经调节和磁共振声辐射力成像的组织学安全性

背景技术通过经颅聚焦超声（FUS）进行的神经调节提供了非侵入性治疗特定大脑区域的潜力，治疗位置由磁共振声辐射力成像（MR-ARFI）验证。目的 为了在广泛临床使用之前调查这些方法的安全性，我们报告了 FUS 神经调节和 MR-ARFI 后两种大型动物模型的组织学发现。方法对两只恒河猴和13只多赛特绵羊进行了研究。FUS 神经调节针对恒河猴的初级视觉皮层和皮层下位置，经 MR-ARFI 验证，在 11 只绵羊中。恒河猴和五只羊都接受了一次 FUS 治疗，而六只羊则间隔三到六天接受了重复治疗。剩下的两只对照羊没有接受超声检查，但在其他方面与 11 只实验羊进行了相同的麻醉和 MRI 程序。对脑组织的苏木精和伊红染色切片（在 FUS 后 0 至 11 天收获）评估 FUS 和对照位置以及 FUS 光束路径内的组织的组织损伤。TUNEL 染色用于评估接受高剂量 FUS 的绵羊是否存在细胞凋亡。结果 在恒河猴或任何受检绵羊中均未观察到与 FUS 相关的死前组织学发现。无论治疗组如何，所有绵羊的脑膜内都存在血管外红细胞 (RBC)。相似地，在 FUS 治疗 (8/11) 和未治疗 (2/2) 绵羊的神经实质的非目标区域中很少注意到血管周围红细胞的小聚集体。然而，没有观察到并发的组织学异常，这与作为脑提取后验尸伪影发生的红细胞外渗一致。高剂量 FUS 组中的绵羊在 FUS 的目标部位是 TUNEL 阴性的。结论 FUS 相关组织学检查结果的缺失表明所评估的神经调节和 MR-ARFI 协议不会导致组织损伤。