Hellman Abigail, Maietta Teresa, Clum Alicia, Byraju Kanakaharini, Raviv Nataly, Staudt Michael D, Jeannotte Erin, Ghoshal Goutam, Shin Damian, Neubauer Paul, Williams Emery, Heffter Tamas, Burdette Clif, Qian Jiang, Nalwalk Julia, Pilitsis Julie G
2Neuroscience and Experimental Therapeutics, and.
Departments of1Neurosurgery.
J Neurosurg. 2021 Apr 16;135(5):1508-1515. doi: 10.3171/2020.9.JNS202962. Print 2021 Nov 1.
The authors' laboratory has previously demonstrated beneficial effects of noninvasive low intensity focused ultrasound (liFUS), targeted at the dorsal root ganglion (DRG), for reducing allodynia in rodent neuropathic pain models. However, in rats the DRG is 5 mm below the skin when approached laterally, while in humans the DRG is typically 5-8 cm deep. Here, using a modified liFUS probe, the authors demonstrated the feasibility of using external liFUS for modulation of antinociceptive responses in neuropathic swine.
Two cohorts of swine underwent a common peroneal nerve injury (CPNI) to induce neuropathic pain. In the first cohort, pigs (14 kg) were iteratively tested to determine treatment parameters. liFUS penetration to the L5 DRG was verified by using a thermocouple to monitor tissue temperature changes and by measuring nerve conduction velocity (NCV) at the corresponding common peroneal nerve (CPN). Pain behaviors were monitored before and after treatment. DRG was evaluated for tissue damage postmortem. Based on data from the first cohort, a treatment algorithm was developed, parameter predictions were verified, and neuropathic pain was significantly modified in a second cohort of larger swine (20 kg).
The authors performed a dose-response curve analysis in 14-kg CPNI swine. Specifically, after confirming that the liFUS probe could reach 5 cm in ex vivo tissue experiments, the authors tested liFUS in 14-kg CPNI swine. The mean ± SEM DRG depth was 3.79 ± 0.09 cm in this initial cohort. The parameters were determined and then extrapolated to larger animals (20 kg), and predictions were verified. Tissue temperature elevations at the treatment site did not exceed 2°C, and the expected increases in the CPN NCV were observed. liFUS treatment eliminated pain guarding in all animals for the duration of follow-up (up to 1 month) and improved allodynia for 5 days postprocedure. No evidence of histological damage was seen using Fluoro-Jade and H&E staining.
The results demonstrate that a 5-cm depth can be reached with external liFUS and alters pain behavior and allodynia in a large-animal model of neuropathic pain.
作者所在实验室先前已证明，针对背根神经节（DRG）的无创低强度聚焦超声（liFUS）在啮齿动物神经性疼痛模型中具有减轻异常性疼痛的有益效果。然而，在大鼠中，从侧面接近时DRG位于皮肤下方5毫米处，而在人类中，DRG通常深达5 - 8厘米。在此，作者使用改良的liFUS探头，证明了使用外部liFUS调节神经性猪抗伤害感受反应的可行性。
两组猪接受腓总神经损伤（CPNI）以诱导神经性疼痛。在第一组中，对猪（14千克）进行反复测试以确定治疗参数。通过使用热电偶监测组织温度变化以及测量相应腓总神经（CPN）的神经传导速度（NCV），验证liFUS对L5 DRG的穿透情况。在治疗前后监测疼痛行为。在尸检时评估DRG的组织损伤情况。根据第一组的数据，制定了治疗算法，验证了参数预测，并在第二组较大的猪（20千克）中显著改善了神经性疼痛。
作者在14千克CPNI猪中进行了剂量反应曲线分析。具体而言，在体外组织实验中确认liFUS探头可达到5厘米深度后，作者在14千克CPNI猪中测试了liFUS。在这个初始组中，DRG的平均深度±标准误为3.79±0.09厘米。确定参数后将其外推至较大动物（20千克），并验证了预测结果。治疗部位的组织温度升高未超过2°C，并且观察到CPN的NCV有预期的增加。liFUS治疗在随访期间（长达1个月）消除了所有动物的疼痛防护，并在术后5天改善了异常性疼痛。使用Fluoro - Jade和苏木精 - 伊红染色未发现组织学损伤的证据。
结果表明，外部liFUS可达到5厘米深度，并在神经性疼痛的大型动物模型中改变疼痛行为和异常性疼痛。
