Musselman Eric D, Raha Ishani, Pelot Nicole A, Grill Warren M
Department of Biomedical Engineering, Duke University, Durham, NC, USA.
Department of Electrical and Computer Engineering, Duke University, Durham, NC, USA.
Bioelectron Med. 2025 May 16;11(1):11. doi: 10.1186/s42234-025-00174-9.
Previous efforts to translate vagus nerve stimulation (VNS) therapies from preclinical studies to human clinical applications (e.g., for stroke, heart failure, and inflammatory diseases) did not account for individual- or species-specific differences in nerve responses when selecting stimulation parameters. Lack of explicit consideration for producing equivalent nerve responses could contribute to clinical outcomes not replicating promising results from preclinical animal studies.
We used models of VNS built with ASCENT (Musselman, PLoS Comput Biol 17:e1009285, 2021) to quantify nerve responses across species and simulate translation of VNS therapies via either recycling or linear scaling of stimulation parameters. For humans (n = 9) and pigs (n = 12), we used previously validated computational models with the standard clinical helical cuff electrode on individual-specific nerve morphologies (Musselman, J Neural Eng 20:acda64, 2023b). We also modeled rat VNS (n = 9) with the Micro-Leads Neuro bipolar cuff. We calculated thresholds for fiber activation (A-, B-, and C-fibers) with biphasic rectangular pulses (0.13, 0.25, 0.5 ms). We defined "K" as the ratio of activation thresholds between a pair of individuals. We used a mixed model ANOVA on the natural logarithm of K to test for differences in inter-species Ks across fiber types and pulse widths. Lastly, using the same nerve morphologies and application-specific device design (cuff and waveform), we developed models to predict nerve responses in chronic human and rat VNS studies for treatment of stroke, inflammation, and heart failure.
Depending on the individual and species, the activation amplitude required to produce a given nerve response varied widely. Thus, applying the same VNS parameters across individuals within a species produced a large range of nerve responses. Further, applying the same or linearly scaled stimulation amplitudes across species also produced highly variable responses. Ks were greater for B fibers than A fibers (p < 0.0001) and decreased with longer pulse widths (p < 0.0001 between consecutive pairs).
The results highlight the need for systematic approaches to select stimulation parameters that account for individual- and species-specific differences in nerve responses to stimulation. Such parameter tuning may lead to higher response rates and greater therapeutic benefits from VNS therapies.
先前将迷走神经刺激（VNS）疗法从临床前研究转化为人类临床应用（如用于中风、心力衰竭和炎症性疾病）的努力，在选择刺激参数时未考虑神经反应的个体或物种特异性差异。在产生等效神经反应方面缺乏明确的考虑，可能导致临床结果无法复制临床前动物研究中的良好结果。
我们使用ASCENT构建的VNS模型（Musselman，《公共科学图书馆·计算生物学》17：e1009285，2021）来量化不同物种的神经反应，并通过刺激参数的循环利用或线性缩放来模拟VNS疗法的转化。对于人类（n = 9）和猪（n = 12），我们使用先前经过验证的计算模型，将标准临床螺旋袖带电极应用于个体特异性神经形态（Musselman，《神经工程学杂志》20：acda64，2023b）。我们还使用微型引线神经双极袖带对大鼠VNS（n = 9）进行建模。我们用双相矩形脉冲（0.13、0.25、0.5毫秒）计算纤维激活（A、B和C纤维）的阈值。我们将“K”定义为一对个体之间激活阈值的比率。我们对K的自然对数进行混合模型方差分析，以测试不同纤维类型和脉冲宽度的种间K值差异。最后，使用相同的神经形态和特定应用的设备设计（袖带和波形），我们开发了模型来预测慢性人类和大鼠VNS研究中治疗中风、炎症和心力衰竭的神经反应。
根据个体和物种的不同，产生给定神经反应所需的激活幅度差异很大。因此，在一个物种内对个体应用相同的VNS参数会产生大范围的神经反应。此外，在不同物种间应用相同或线性缩放的刺激幅度也会产生高度可变的反应。B纤维的K值大于A纤维（p < 0.0001），并且随着脉冲宽度的增加而降低（连续对之间p < 0.0001）。
结果强调需要采用系统方法来选择刺激参数，以考虑神经对刺激反应的个体和物种特异性差异。这种参数调整可能会提高VNS疗法的反应率并带来更大的治疗益处。
