The cranial nerves are the pathways through which environmental information (sensation) is directly communicated to the brain, leading to perception, and giving rise to higher cognition. Because cranial nerves determine and modulate brain function, invasive and non-invasive cranial nerve electrical stimulation methods have applications in the clinical, behavioral, and cognitive domains. Among other neuromodulation approaches such as peripheral, transcranial and deep brain stimulation, cranial nerve stimulation is unique in allowing axon pathway-specific engagement of brain circuits, including thalamo-cortical networks. In this review we amalgamate relevant knowledge of 1) cranial nerve anatomy and biophysics; 2) evidence of the modulatory effects of cranial nerves on cognition; 3) clinical and behavioral outcomes of cranial nerve stimulation; and 4) biomarkers of nerve target engagement including physiology, electroencephalography, neuroimaging, and behavioral metrics. Existing non-invasive stimulation methods cannot feasibly activate the axons of only individual cranial nerves. Even with invasive stimulation methods, selective targeting of one nerve fiber type requires nuance since each nerve is composed of functionally distinct axon-types that differentially branch and can anastomose onto other nerves. None-the-less, precisely controlling stimulation parameters can aid in affecting distinct sets of axons, thus supporting specific actions on cognition and behavior. To this end, a rubric for reproducible dose-response stimulation parameters is defined here. Given that afferent cranial nerve axons project directly to the brain, targeting structures (e.g. thalamus, cortex) that are critical nodes in higher order brain networks, potent effects on cognition are plausible. We propose an intervention design framework based on driving cranial nerve pathways in targeted brain circuits, which are in turn linked to specific higher cognitive processes. State-of-the-art current flow models that are used to explain and design cranial-nerve-activating stimulation technology require multi-scale detail that includes: gross anatomy; skull foramina and superficial tissue layers; and precise nerve morphology. Detailed simulations also predict that some non-invasive electrical or magnetic stimulation approaches that do not intend to modulate cranial nerves per se, such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS), may also modulate activity of specific cranial nerves. Much prior cranial nerve stimulation work was conceptually limited to the production of sensory perception, with individual titration of intensity based on the level of perception and tolerability. However, disregarding sensory emulation allows consideration of temporal stimulation patterns (axon recruitment) that modulate the tone of cortical networks independent of sensory cortices, without necessarily titrating perception. For example, leveraging the role of the thalamus as a gatekeeper for information to the cerebral cortex, preventing or enhancing the passage of specific information depending on the behavioral state. We show that properly parameterized computational models at multiple scales are needed to rationally optimize neuromodulation that target sets of cranial nerves, determining which and how specific brain circuitries are modulated, which can in turn influence cognition in a designed manner.

中文翻译：

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脑神经电刺激在认知和疾病中的作用

脑神经是环境信息（感觉）直接传达到大脑的途径，导致感知，并产生更高的认知。由于脑神经决定和调节大脑功能，因此侵入性和非侵入性脑神经电刺激方法在临床、行为和认知领域都有应用。在外周、经颅和深部脑刺激等其他神经调节方法中，颅神经刺激的独特之处在于允许轴突通路特异性参与大脑回路，包括丘脑皮质网络。在这篇综述中，我们合并了以下方面的相关知识：1）颅神经解剖学和生物物理学；2）脑神经对认知的调节作用的证据；3）脑神经刺激的临床和行为结果；4) 神经靶标参与的生物标志物，包括生理学、脑电图、神经影像和行为指标。现有的非侵入性刺激方法无法仅激活单个脑神经的轴突。即使采用侵入性刺激方法，选择性靶向一种神经纤维类型也需要细微差别，因为每条神经都是由功能不同的轴突类型组成，这些轴突类型有差异性分支并且可以吻合到其他神经上。尽管如此，精确控制刺激参数可以帮助影响不同的轴突组，从而支持对认知和行为的特定作用。为此，这里定义了可重复的剂量反应刺激参数的标题。鉴于传入颅神经轴突直接投射到大脑，目标结构（例如丘脑、皮质）是高阶大脑网络中的关键节点，对认知的潜在影响是合理的。我们提出了一种基于驱动目标大脑回路中的脑神经通路的干预设计框架，这些通路又与特定的高级认知过程相关。用于解释和设计脑神经激活刺激技术的最先进的电流模型需要多尺度细节，包括：大体解剖学；颅骨孔和浅表组织层；和精确的神经形态。详细的模拟还预测，一些本身并不打算调节脑神经的非侵入性电或磁刺激方法，例如经颅直流电刺激（tDCS）和经颅磁刺激（TMS），也可能调节特定脑神经的活动。许多先前的脑神经刺激工作在概念上仅限于产生感觉知觉，根据知觉和耐受性水平进行个体滴定强度。然而，忽略感觉模拟可以考虑时间刺激模式（轴突募集），该模式独立于感觉皮层调节皮质网络的音调，而不必滴定感知。例如，利用丘脑作为大脑皮层信息看门人的作用，根据行为状态阻止或增强特定信息的传递。我们表明，需要在多个尺度上正确参数化的计算模型来合理优化针对脑神经组的神经调节，确定哪些特定的大脑回路以及如何调节，这反过来又可以以设计的方式影响认知。