The vagus nerve (VN), the principal nerve of the parasympathetic nervous system, occupies a crucial role in the reflex control of physiological homeostasis (Berthoud and Neuhuber, 2000). The roles of VN reflexes in controlling the cardiovascular, pulmonary, and gastrointestinal systems have been studied for more than 100 years, but only recently has the role of VN reflexes been studied in controlling inflammation (Pavlov et al., 2020; Pavlov et al., 2018; Tracey, 2009; Tracey, 2002). We and others have defined VN mechanisms, termed ‘the inflammatory reflex (IR),’ which inhibit cytokine production in the spleen, and attenuates inflammation in preclinical and clinical studies (Borovikova et al., 2000; Rosas-Ballina et al., 2008; Rosas-Ballina et al., 2011). Clinical VN stimulating devices are used in the treatment of epilepsy (The Vagus Nerve Stimulation Study Group, 1995) and depression (Rush et al., 2000), and are being studied in the treatment of brain disorders such as tinnitus (Tyler et al., 2017; Vanneste et al., 2017), stroke (Engineer et al., 2019; Kimberley et al., 2018), and Alzheimer’s disease (Merrill et al., 2006; Sjögren et al., 2002), as well as peripheral organ and systemic diseases, such as heart failure (De Ferrari et al., 2017), cardiac arrhythmias (Huang et al., 2015; Nasi-Er et al., 2019; Stavrakis et al., 2015; Yamaguchi et al., 2018), pulmonary hypertension (Ntiloudi et al., 2019; Yoshida et al., 2018), rheumatoid arthritis (Koopman et al., 2016), Crohn’s disease (Bonaz et al., 2016), and lupus (Aranow, 2018). Additional possible indications for vagus nerve stimulation (VNS) include common disorders in which inflammation is implicated, such as type 2 diabetes, obesity, and atherosclerosis (Couzin-Frankel, 2010; Furman et al., 2019; Slavich, 2015; Strowig et al., 2012).

Optimal preclinical studies of VNS in models of chronic disease require long-term implantation of a VNS device optimized for small animals, but to date the majority of chronically implanted VN devices have been limited to neurological and cardiovascular diseases in rats, pigs, dogs, and other large animals (Nasi-Er et al., 2019; Yamaguchi et al., 2018; Yoshida et al., 2018; Annoni et al., 2019; Beaumont et al., 2016; Chinda et al., 2016; Farrand et al., 2017; Li et al., 2004; Meyers et al., 2018; Nuntaphum et al., 2018; Yamakawa et al., 2015; Ganzer et al., 2018). The mouse is currently the species of choice in the study of disease pathophysiology, genetic mechanisms, and drug screening (Bryda, 2013; Perlman, 2016). However, VNS research in mice has been limited to acute stimulation (Bansal et al., 2012; Caravaca et al., 2019; de Lucas-Cerrillo et al., 2011; Huffman et al., 2019; Huston et al., 2006; Meneses et al., 2016; Saeed et al., 2005; Shukla et al., 2015; The et al., 2007), primarily because of significant surgical and technical challenges that accompany a mechanically (Cuoco and Durand, 2000; Prasad et al., 2014; Rydevik et al., 1981) and electrochemically (McCreery et al., 1992; Negi et al., 2010) stable long-term interface with the microscopic anatomy of the mouse VN. As a consequence, the therapeutic role of VNS in chronic inflammatory diseases and the long-term effects on neural mechanisms are largely unexplored. A functional and reliable long-term VNS implant in the mouse is necessary to broaden the translational potential of VNS in chronic diseases and provides an experimental tool to probe the long-term effects of VN neuromodulation on autonomic and neuroimmune circuits.

Here, we describe a surgical technique to permanently implant a micro-cuff electrode onto the mouse cervical vagus for long-term VNS—developed, refined, and validated through a collaboration between four research labs (two labs at Feinstein Institutes, University of Colorado, and New York University). This produced a standardized, long-lasting, functionally consistent implant with expected stimulus-elicited physiological responses that persist for at least 4 weeks. Because the implant does not interfere with physiological VN-mediated reflexes, including baroreflex, lung stretch reflex, and feeding reflexes, and successfully inhibits serum TNF levels in acute endotoxemia, this method may be useful in facilitating mechanistic studies of long-term VN neuromodulation.

VNS is an emerging bioelectronic therapy with possible applications in many chronic diseases. However, its translational potential is hindered by the lack of a reliable long-term VNS implant in mice—the preferred species in the preclinical study of human diseases (Vandenbergh, 2008). Development of a simple, well-characterized, and reliable long-term VNS interface in mice will allow for standardized assessment of long-term VNS efficacy, as well as potential adverse effects, in various models of chronic disease. It will also allow mechanistic studies of autonomic tone alterations that might accompany long-term VNS. Here, we describe a surgical approach to permanently implant a micro-cuff electrode onto the mouse cervical VN. In addition, we provide a systematic method to assess its functionality and standardize stimulation dosing over time. Our data demonstrate a robust and reproducible interface with the VN capable of producing characteristic physiological responses for at least 4 weeks post-implantation, while causing no large-scale axonal damage. We also provide functional evidence of intact vagal reflexes and anti-inflammatory action.

To maximize the applicability of our tool in various research programs carried out by teams with different areas of expertise, we tried to accomplish two goals: ease of assembly and use, and reproducibility. Assembly of the implant makes use of only off-the-shelf supplies and materials, including commercially available micro-cuffs and common physiological sensors. For example, determining HRT requires the use of a simple rodent heart monitor. The surgical technique, which reflects the aggregate experience of three research groups, was refined and simplified over the course of several animal cohorts. Finally, validation of the longitudinal performance of this implant by three research groups supports the reproducibility of this method when exercised by different investigators.

Previous research using VNS in mouse models of disease has been limited to acute, single-event, stimulation (Huffman et al., 2019; The et al., 2007; Ji et al., 2014). These studies, although of significant translational value, provide less insight into the possible role of VNS in the treatment of chronic conditions. Moreover, acute stimulation studies are carried out under anesthesia, which confounds the results due to the effects of some anesthetics, such as isoflurane, on decreasing vagal tone (Marano et al., 1996; Picker et al., 2001) and suppressing the immune response (Cruz et al., 2017). For these reasons, a long-term interface to deliver stimulation to the VN is needed. However, to date, reported attempts at a stable and functional interface with the VN in mice either focused on long-term neural recordings with no longitudinal stimulation data (Caravaca et al., 2017; Falcone et al., 2020), or provided insufficient evidence of long-term implant functionality and effectiveness (Ten Hove et al., 2020). For example, while Caravaca et al., 2017 reported longitudinal neural recordings, VNS was delivered to a separate subset of animals 3 hr post-implantation in a terminal model of endotoxemia, essentially an acute procedure. Falcone et al., 2020 used their long-term microwire interface to collect neural signals but did not provide longitudinal stimulus-elicited physiological responses to demonstrate continued stimulation functionality. In a recent study by Ten Hove et al., 2020, VNS was delivered in mice for 12 days via a commercial cuff electrode to study its effects on ACE2 expression in intestinal cells. Although the authors provided histological evidence for an intact nerve structure, but without showing viable nerve fibers, they relied on visual observation of stimulus-elicited breathing and movement changes to confirm electrode functionality, an unreliable method for assessing nerve fiber engagement, as pain or irritation could produce a similar behavior. They also used electrical impedance to determine implant functionality, which, as shown in this report, is not well correlated to functional performance. Therefore, the reported lack of effect may be related to nonfunctioning implants that went undetected, given their method of testing. In this study, we established the feasibility of a long-term vagus interface in mice capable of producing stimulus-elicited responses for at least 4 weeks, a period that allows for therapeutic assessment in many models of chronic disease. Importantly, almost all animals achieved a full recovery from the implantation procedure during the first week and maintained a stable implant after the second week. This is evident from the slow attrition of functional cuffs over time seen in randomly selected subsets of animals (Figure 3F). We also showed that this approach can be used to deliver dose-controlled VNS in conscious animals without repeated exposure to anesthetics, while ensuring consistent stimulation longitudinally and across different animals (Video 1). VNS in two conscious animals produced comparable changes in HR as those seen in anesthetized animals and implant longevity in those two animals ranged between 2 and 3 weeks. To our knowledge, this report is the first demonstration of chronic VNS in the mouse that provides longitudinal evidence of stimulus-elicited physiological responses.

VNS causes reduction in HR, mainly through activation of efferent cardioinhibitory fibers (Buschman et al., 2006). In a functional neural interface, increasing stimulation intensity leads to recruitment of more fibers, and hence a larger stimulus-evoked response (Chang et al., 2020; Zaaimi et al., 2008). This is consistent with our observation wherein changes in stimulation intensity resulted in a dose-dependent decrease in HR (Figure 2B). Additionally, higher stimulation intensities lead to the ordered recruitment of different fiber types according to size: from large A, to intermediate-size B, to small C fibers (Blair and Erlanger, 1933). The variable changes in BR we observed at different stimulation intensities (Figure 2A, Figure 3A) can be explained by activation of either A or C fibers, which differentially affect breathing in mice (Chang et al., 2015) and in rats (Chang et al., 2020). In addition, a functional nerve interface exhibits a characteristic relationship between intensity and PW (strength-duration): to produce a response, lower stimulation intensities are required at longer PWs, and vice versa (Geddes and Bourland, 1985). Our long-term implants produced HR responses at lower intensities with longer PWs, a relationship that remains consistent with time (Figure 3C). These findings indicate a robust electrode-tissue interface with the VN.

An effective approach to delivering long-term VNS must include standardized methods for verifying implant functionality and controlling stimulation dose over the course of treatment. To evaluate electrode performance across time, we used HRT as a quick and accessible measure of fiber recruitment in real time (Yoo et al., 2016). Initial threshold values were variable among animals and increased over the first week post-implantation in almost all mice (Figure 3—figure supplement 1A). The variability in baseline thresholds at the time of implantation is not explained by differences in pre-implantation impedance and is likely due to variability in electrode placement, which affects fiber engagement. The gradual increase in HRT over time can be attributed to fibrotic encapsulation of electrode surfaces, a process that evolves over days to weeks and is known to reduce the efficacy of implanted neural interfaces by increasing tissue resistivity and the distance between the nerve and the electrode contact surface (Anderson et al., 2008; Grill and Mortimer, 1994; Farah et al., 2019; Vasudevan et al., 2017). We observed increased tissue growth within the cuff, which, upon histological examination, comprised fibrotic tissue around the nerve (Figure 6). This may explain why longer PWs were more effective in eliciting HRT in aged implants: the effect of distance on activation threshold is weaker for long pulses than for short pulses (Grill and Mortimer, 1995). In addition to assessing performance, HRT was used as a method to estimate individualized stimulation doses. Since animals exhibit variable threshold values at baseline and across time, employing fixed parameters would result in variable fiber recruitment, inconsistent therapeutic dosing, and, possibly, undesirable off-target effects. This is of particular importance when VNS is delivered therapeutically, wherein standardized doses are desirable within and in between animals, and across time. Previous reports from rat and large animal models implemented a similar approach to adjust stimulation intensity using respiratory twitching (Yoshida et al., 2018; Nishizaki et al., 2016), and HR (Huffman et al., 2019; Chapleau et al., 2016; Yu et al., 2014) to standardize stimulation protocols, but not on a dose-by-dose basis. Notably, electrical impedance, which is commonly used as a measure of electrode integrity and performance (Straka et al., 2018), did not always correlate with changes in HRT on an individual implant basis as implants aged (Figure 3E). In fact, impedance tended to decrease over the period of implantation as HRT increased (Figure 3B, D). Moreover, several nonfunctional cuffs had relatively low impedance values (Figure 3E). For these reasons, we rely on HRT values as a reliable indicator of electrode integrity and a method to estimate stimulation dosage (Qing et al., 2018).

Implant longevity can be influenced by abiotic factors (Prasad et al., 2014; Vasudevan et al., 2017), such as lead breakage and electrode degradation. We observed three cases of lead wire breakage out of nine nonfunctional implants in three groups of animals. In all three cases, breakage occurred at the junction between the lead wire and electrode, exposing a mechanically weak point that should be reinforced during manufacturing. Neural electrodes can degrade with long-term use (Negi et al., 2010). This process is accelerated at stimulation intensities that exceed the electrode’s ability to transfer charge without undergoing irreversible damage (CIC) (Negi et al., 2010; Merrill et al., 2005). The damage imparted by exceeding this threshold is not limited to the electrode but can affect the nerve as well (Cogan et al., 2016). Although we did not examine explanted electrodes for morphological or electrochemical changes, we did take note of platinum-iridium’s maximum charge capacity (Cogan, 2008), which was not exceeded in most animals (Figure 3B, Figure 3—figure supplement 1A). On the few occasions when ICIC was exceeded, it likely did not cause significant damage to the electrode as the stimulation events were brief (10 s) and limited in number. This becomes important when VNS is administered therapeutically in chronic models, wherein stimulation protocols may be employed on a daily basis for up to several weeks. In such settings, care should be taken not to exceed ICIC. Standardizing stimulation dose could prevent exceeding CIC while still delivering therapeutic stimulation. Mechanical forces generated by chronic cuffing can also damage nerves (Agnew and McCreery, 1990; Larsen et al., 1998; Somann et al., 2018). Our histological analysis revealed viable nerve tissue with no obvious fiber loss or axonal fragmentation. Therefore, damage to the nerve is unlikely to be a contributing factor to increased HRT over time. However, we interpret this preliminary analysis with caution, in part, due to the lack of small-fiber detail in these relatively thick sections (5 and 50 μm). Future studies will rely on higher resolution images with resin-embedding and electron microscopic analysis, which is the gold standard of peripheral nerve examination. Apart from electrode- and tissue-related factors, we found that surgical proficiency contributed greatly to implant success, which is evident from the increase in successful implantations over successive groups of animals (Table 1, cohorts 1–3, from earlier to later) completed over several months by an initially inexperienced surgeon. Over time, fine adjustments to electrode placement, surgical approach, and post-surgical care lead to higher success rates.

The VN maintains homeostasis by controlling many bodily functions, including appetite, respiration, and BP (Paintal, 1973). Chronic cuffing of the vagus could, in principle, cause damage to the nerve, thereby affecting these functions. For example, severing the VN causes weight loss in mice (Kral and Görtz, 1981) by affecting appetite and gastric transit times among other factors (Dezfuli et al., 2018; Khound et al., 2017). We did not observe weight loss or changes in food intake in our implanted animals compared with controls, which suggests that those vagal pathways were not affected (Figure 4A, B). The VN also mediates the afferent and the efferent-parasympathetic component of the baroreflex, a homeostatic mechanism that maintains BP within normal range by modulating HR (Glick and Braunwald, 1965). In an intact system, an increase in BP causes a reflexive decrease in HR by increasing vagal activity, which is consistent with our observations in implanted animals. The responsiveness of this system can be quantified using the baroreflex sensitivity index or the ratio of change in HR to change in BP, which we found in implanted mice to be comparable to naive controls (Figure 4C, D). The vagus also carries vital sensory information from the lung to regulate breathing (Carr and Undem, 2003). Recent evidence has shown that this is mediated by large, myelinated A fibers that cause slowing down of breathing and small, unmyelinated C fibers that cause rapid shallow breathing (Chang et al., 2015). These sensory pathways control respiration by reflexive activity that changes BR, such as the Herring–Breuer inflation and deflation reflexes (Schelegle and Green, 2001; Siniaia et al., 2000; Yu, 2016). In our studies, we were able to evoke similar changes in BR using VNS in anesthetized animals (Figure 4F). We, however, did not observe visible changes to BR during awake VNS. Even though there may still exist small alterations in BR that went unnoticed visually, changes in BR in awake animals may be more difficult to visually inspect due to movement, higher baseline BR compared to anesthetized mice, and compensatory mechanisms that are suppressed during anesthesia. Patients receiving VNS for epilepsy do not show changes in tidal volume or BR during wakefulness (Banzett et al., 1999), yet exhibit decreases in air flow when VNS is activated during sleep (Murray et al., 2001). Taken together, these data strongly suggest that the long-term implant does not cause damage to the nerve to the degree that would affect vital bodily functions. Importantly, the fact that these preserved reflexes are mediated by large, myelinated fibers further supports the viability of the nerve after chronic cuffing as large fibers are the most sensitive to chronic compression injury (Dahlin et al., 1989).

The potential wide therapeutic applicability of VNS lies in part in its ability to modulate inflammation, a process fundamental to the pathogenesis of many diseases (Couzin-Frankel, 2010; Furman et al., 2019; Slavich, 2015; Strowig et al., 2012). VNS controls inflammation by activating the IR, defined as an afferent arm that responds to inflammation in the periphery via vagal sensory neurons and an efferent arm that suppresses activation of macrophages via vagal motor neurons that project to the spleen (Tracey, 2009; Tracey, 2002). This effect was first described in a model of LPS endotoxemia, wherein acute VNS suppressed TNF release (Borovikova et al., 2000), and has since been established as a standard functional read-out of the anti-inflammatory effects of VNS (Caravaca et al., 2019). For these reasons, we sought to determine whether stimulation through long-term implants could reproduce that effect. We found that delivering three doses of stimulation to the animals over 2 days using 9- to 17-day-old implants significantly decreased serum TNF compared to sham-stimulated and sham surgery animals. In contrast, delivering a single stimulation dose, using older implants (about 3–6 weeks old) did not result in significant reduction in TNF. However, we observed a considerable decrease in serum TNF (>~40% compared to mean TNF in sham stimulation controls) in four out of seven animals with functional cuffs, as demonstrated by VNS-elicited HR responses (Figure 5E). The lack of an anti-inflammatory response in the single-dose group could have several explanations. Chronic cuffing of the VN might suppress efferent signaling that could reduce the anti-inflammatory actions of VNS (Somann et al., 2018) due to loss of nerve fibers smaller than what we could detect histologically (Nitz et al., 1986; Szabo and Sharkey, 1993). Alternatively, some animals in the single-dose group could be non-responders, a common occurrence in these studies (Caravaca et al., 2019; Huffman et al., 2019). Our data indicate that a HR response does not necessarily mean engagement of the IR, consistent with previous findings in acute studies (Huffman et al., 2019; Huston et al., 2007). Anatomically, vagal cholinergic fibers signaling to the spleen via abdominal sympathetic ganglia to suppress inflammation (Kressel et al., 2020) may lie in distinct parts of the nerve from those innervating the heart to cause drops in HR (Rajendran et al., 2019). It is unknown if the IR is activated by engagement of efferent fibers, or additionally by afferent fibers, some of which are activated by lower VNS intensities. Recent reports implicate both afferent and efferent pathways (Kressel et al., 2020; Murray et al., 2021; Olofsson et al., 2015) in the anti-inflammatory actions of VNS, and in a study by Huffman et al., 2019, TNF was suppressed using 90% of HRT, without reduction in HR. Moreover, stimulating at or above HRT could activate compensatory reflexes that might alter the anti-inflammatory effect of VNS, as shown in one report where stimulation at higher frequencies and amplitudes resulted in an increase in TNF in healthy animals (Tsaava et al., 2020). We suggest using HRT as a practical method to estimate stimulation dose required to achieve consistent efferent, parasympathetic fiber recruitment in an implant, thereby reducing variability related to the nerve anatomy itself and the nerve-electrode interface. Stimulus intensities required to engage specific circuits and organs could then be determined experimentally relative to HRT (Huffman et al., 2019). A fixed set of parameters could still be used in recovered animals beyond the first week when the procedure is optimized, and variability minimized, as we show in the endotoxemia experiment with multiple doses (Figure 5). In this experiment, animals received VNS with 250 μs PW, compared with the 500 μs PW used in other validation cohorts. This shorter PW could explain why 1 mA did not usually result in HR changes (Figure 5C), as HRT is generally greater for shorter PWs (Figure 3C). Future studies could focus on empirically determining reliable stimulation doses to chronically engage the anti-inflammatory pathway.

Therefore, we have developed a surgical approach to implant micro-cuff electrodes onto the mouse cervical VN to deliver chronic electrical stimulation. Our findings demonstrate a stable and robust interface with the nerve capable of producing stimulus-evoked responses for at least 4 weeks. We also provide a method to standardized stimulation doses between animals and across time. Given the wide range of illnesses studied in the mouse, this implant methodology provides a previously unavailable tool for screening of long-term VNS in disease models.

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 2, 3, and 4.

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Author details

1. Ibrahim T Mughrabi

   Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing

   Contributed equally with

   Jordan Hickman

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8057-6146

2. Jordan Hickman

   1. Departments of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, United States
   2. Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, United States

   Contribution

   Data curation, Validation, Investigation, Visualization, Methodology, Writing - review and editing

   Contributed equally with

   Ibrahim T Mughrabi

   Competing interests

   No competing interests declared

3. Naveen Jayaprakash

   Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, United States

   Contribution

   Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

4. Dane Thompson

   1. Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, United States
   2. The Elmezzi Graduate School of Molecular Medicine, Manhasset, United States

   Contribution

   Formal analysis, Validation, Investigation, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

5. Umair Ahmed

   Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, United States

   Contribution

   Data curation, Investigation, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

6. Eleni S Papadoyannis

   1. Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York University, New York, United States
   2. Department of Neuroscience and Physiology, Neuroscience Institute, Center for Neural Science, New York University School of Medicine, New York University, New York, United States
   3. Department of Otolaryngology, New York University School of Medicine, New York University, New York, United States
   4. Howard Hughes Medical Institute Faculty Scholar, New York University School of Medicine, New York University, New York, United States

   Contribution

   Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

7. Yao-Chuan Chang

   Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, United States

   Contribution

   Software, Formal analysis, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0340-4652

8. Adam Abbas

   Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, United States

   Contribution

   Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

9. Timir Datta-Chaudhuri

   Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, United States

   Contribution

   Writing - review and editing

   Competing interests

   No competing interests declared

10. Eric H Chang

    Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, United States

    Contribution

    Writing - review and editing

    Competing interests

    No competing interests declared

11. Theodoros P Zanos

    Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, United States

    Contribution

    Writing - review and editing

    Competing interests

    No competing interests declared

12. Sunhee C Lee

    Institute of Molecular Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, United States

    Contribution

    Formal analysis, Methodology, Writing - review and editing

    Competing interests

    No competing interests declared

13. Robert C Froemke

    1. Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York University, New York, United States
    2. Department of Neuroscience and Physiology, Neuroscience Institute, Center for Neural Science, New York University School of Medicine, New York University, New York, United States
    3. Department of Otolaryngology, New York University School of Medicine, New York University, New York, United States
    4. Howard Hughes Medical Institute Faculty Scholar, New York University School of Medicine, New York University, New York, United States

    Contribution

    Conceptualization, Funding acquisition, Writing - review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-1230-6811

14. Kevin J Tracey

    Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, United States

    Contribution

    Conceptualization, Funding acquisition, Writing - review and editing

    Competing interests

    holds patents broadly related to this work. He has assigned all rights to the Feinstein Institutes for Medical Research.

15. Cristin Welle

    1. Departments of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, United States
    2. Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, United States

    Contribution

    Conceptualization, Funding acquisition, Writing - review and editing

    For correspondence

    cristin.welle@cuanschutz.edu

    Competing interests

    No competing interests declared

16. Yousef Al-Abed

    Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, United States

    Contribution

    Conceptualization, Funding acquisition, Writing - review and editing

    Competing interests

    No competing interests declared

17. Stavros Zanos

    Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, United States

    Contribution

    Conceptualization, Data curation, Software, Formal analysis, Supervision, Funding acquisition, Visualization, Methodology, Writing - original draft, Project administration, Writing - review and editing

    For correspondence

    szanos@northwell.edu

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-3967-8164

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