Cervical vagus nerve morphometry and vascularity in the context of nerve stimulation - A cadaveric study

Hammer, Niels; Löffler, Sabine; Cakmak, Yusuf Özgür; Ondruschka, Benjamin; Planitzer, Uwe; Schultz, Michael; Winkler, Dirk; Weise, David

doi:10.1038/s41598-018-26135-8

Cited by 66 publications

(67 citation statements)

References 51 publications

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“…[46] throughout the protocol, by locating the carotid artery as an anatomical reference. Although variation exists regarding the location and topographical anatomy of the cervical vagus nerve, a recent cadaveric study reports that cervical vagus nerve can be visualized in a 35 Â 35 mm distance lateral of the laryngeal eminence and posterior to the skin of the neck, which typically falls under the area the electrodes are placed [107].…”

Section: Limitationsmentioning

confidence: 99%

Quantifying acute physiological biomarkers of transcutaneous cervical vagal nerve stimulation in the context of psychological stress

et al. 2020

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Background: Stress is associated with activation of the sympathetic nervous system, and can lead to lasting alterations in autonomic function and in extreme cases symptoms of posttraumatic stress disorder (PTSD). Vagal nerve stimulation (VNS) is a potentially useful tool as a modulator of autonomic nervous system function, however currently available implantable devices are limited by cost and inconvenience. Objective: The purpose of this study was to assess the effects of transcutaneous cervical VNS (tcVNS) on autonomic responses to stress. Methods: Using a double-blind approach, we investigated the effects of active or sham tcVNS on peripheral cardiovascular and autonomic responses to stress using wearable sensing devices in 24 healthy human participants with a history of exposure to psychological trauma. Participants were exposed to acute stressors over a three-day period, including personalized scripts of traumatic events, public speech, and mental arithmetic tasks. Results: tcVNS relative to sham applied immediately after traumatic stress resulted in a decrease in sympathetic function and modulated parasympathetic/sympathetic autonomic tone as measured by increased pre-ejection period (PEP) of the heart (a marker of cardiac sympathetic function) of 4.2 ms (95% CI 1.6e6.8 ms, p < 0.01), decreased peripheral sympathetic function as measured by increased photoplethysmogram (PPG) amplitude (decreased vasoconstriction) by 47.9% (1.4e94.5%, p < 0.05), a 9% decrease in respiratory rate (À14.3 to À3.7%, p < 0.01). Similar effects were seen when tcVNS was applied after other stressors and in the absence of a stressor. Conclusion: Wearable sensing modalities are feasible to use in experiments in human participants, and tcVNS modulates cardiovascular and peripheral autonomic responses to stress.

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Section: Limitationsmentioning

confidence: 99%

Quantifying acute physiological biomarkers of transcutaneous cervical vagal nerve stimulation in the context of psychological stress

et al. 2020

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“…As compared to other animal models, the domestic pig best approximated the diameter of the human vagus (Hammer et al 2018), which is an important point of emphasis for preclinical testing of electrodes and stimulation approaches to minimize off-target effects at human scale. When comparing the surgical window in humans to that of the pig, the presence of the nodose (inferior) ganglion within the surgical window in pig but not in humans has two important implications.…”

Section: Vagotopymentioning

confidence: 99%

Functional Vagotopy in the Cervical Vagus Nerve of the Domestic Pig: Implications for the Study of Vagus Nerve Stimulation

Settell

Knudsen

Dingle

et al. 2019

Preprint

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Given current clinical interest in vagus nerve stimulation, there are surprisingly few studies characterizing the anatomy of the vagus nerve in large animal models as it pertains to on-and off-target engagement of local fibers. We sought to address this gap by evaluating vagal anatomy in the domestic pig, whose vagus nerve organization and size approximates the human cervical vagus nerve. We provide data on key features across the cervical vagus nerve including diameter, number and diameter of fascicles, and distance of fascicles from the epineural surface where stimulating electrodes are placed. We also characterized the relative locations of the superior and recurrent laryngeal branches of the vagus nerve that have been implicated in therapy limiting side effects with common electrode placement. We identified key variants across the cohort that may be important for vagus nerve stimulation with respect to changing sympathetic/parasympathetic tone, such as cross-connections to the sympathetic trunk. We discovered that cell bodies of pseudo-unipolar cells aggregate together to form a very distinct grouping within the nodose ganglion. This distinct grouping gives rise to a larger number of smaller fascicles as one moves caudally down the cervical vagus nerve. This often leads to a distinct bimodal organization, or ‘vagotopy’ that may be advantageous to exploit in design of electrodes/stimulation paradigms. Finally, we placed our data in context of historic and recent histology spanning mouse, rat, canine, pig, non-human primate and human models, thus providing a comprehensive resource to understand similarities and differences across species.

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“…There are published descriptions of vagal morphology, including from the human cervical VN ( Seki et al, 2014 ; Hammer et al, 2015 , 2018 ; Verlinden et al, 2016 ), human subdiaphragmatic VN ( Tailai et al, 1980 ), rat cervical VN ( Fazan and Lachat, 1997 ; Licursi de Alcântara et al, 2008 ), and rat subdiaphragmatic VN ( Prechtl and Powley, 1985 ). However, each study focused on a single species, typically a single nerve level (e.g., cervical or subdiaphragmatic), and included only a subset of morphological metrics; further, there is a dearth of data on VN morphology in large animals.…”

Section: Introductionmentioning

confidence: 99%

Quantified Morphology of the Cervical and Subdiaphragmatic Vagus Nerves of Human, Pig, and Rat

et al. 2020

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It is necessary to understand the morphology of the vagus nerve (VN) to design and deliver effective and selective vagus nerve stimulation (VNS) because nerve morphology influences fiber responses to electrical stimulation. Specifically, nerve diameter (and thus, electrode-fiber distance), fascicle diameter, fascicular organization, and perineurium thickness all significantly affect the responses of nerve fibers to electrical signals delivered through a cuff electrode. We quantified the morphology of cervical and subdiaphragmatic VNs in humans, pigs, and rats: effective nerve diameter, number of fascicles, effective fascicle diameters, proportions of endoneurial, perineurial, and epineurial tissues, and perineurium thickness. The human and pig VNs were comparable sizes (∼2 mm cervically; ∼1.6 mm subdiaphragmatically), while the rat nerves were ten times smaller. The pig nerves had ten times more fascicles—and the fascicles were smaller—than in human nerves (47 vs. 7 fascicles cervically; 38 vs. 5 fascicles subdiaphragmatically). Comparing the cervical to the subdiaphragmatic VNs, the nerves and fascicles were larger at the cervical level for all species and there were more fascicles for pigs. Human morphology generally exhibited greater variability across samples than pigs and rats. A prior study of human somatic nerves indicated that the ratio of perineurium thickness to fascicle diameter was approximately constant across fascicle diameters. However, our data found thicker human and pig VN perineurium than those prior data: the VNs had thicker perineurium for larger fascicles and thicker perineurium normalized by fascicle diameter for smaller fascicles. Understanding these differences in VN morphology between preclinical models and the clinical target, as well as the variability across individuals of a species, is essential for designing suitable cuff electrodes and stimulation parameters and for informing translation of preclinical results to clinical application to advance the therapeutic efficacy of VNS.

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Cervical vagus nerve morphometry and vascularity in the context of nerve stimulation - A cadaveric study

Cited by 66 publications

References 51 publications

Quantifying acute physiological biomarkers of transcutaneous cervical vagal nerve stimulation in the context of psychological stress

Quantifying acute physiological biomarkers of transcutaneous cervical vagal nerve stimulation in the context of psychological stress

Functional Vagotopy in the Cervical Vagus Nerve of the Domestic Pig: Implications for the Study of Vagus Nerve Stimulation

Quantified Morphology of the Cervical and Subdiaphragmatic Vagus Nerves of Human, Pig, and Rat

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