Moving beyond belief: A narrative review of potential biomarkers for transcutaneous vagus nerve stimulation

Abstract

Transcutaneous vagus nerve stimulation or tVNS is a non-invasive neurostimulation technique that is currently being tested as a potential treatment for a myriad of neurological and psychiatric disorders.However, the working mechanisms underlying tVNS are poorly understood, and it remains unclear whether stimulation activates the vagus nerve for every participant. Finding a biological marker of tVNS is imperative, as it can help guide research on clinical applications, and can inform researchers on optimal stimulation sites and parameters to further optimize treatment efficacy. In this narrative review, we discuss five potential biomarkers for tVNS, and review currently available evidence for these markers for both invasive and transcutaneous VNS. While some of these biomarkers hold promise from a theoretical perspective, none of the potential biomarkers provide clear and definitive indications that tVNS increases vagal activity or augments activity in the locus coeruleus-noradrenaline network. We conclude the review by providing several recommendations for how to tackle the challenges and opportunities when researching potential biomarkers for the effects of tVNS.

Digital Cardiovascular Biomarker Responses to Transcutaneous Cervical Vagus Nerve Stimulation: State-Space Modeling, Prediction, and Simulation

“…Heart rate is a cardiac measure originating centrally from the heart, whereas the PPG signals measured in this study were sensed at the periphery—in particular, transmissively at the fingertip. As described in the Methods section, a clear physiological distinction exists; these differences may in fact explain the relative contrasts observed in this study, as well as the previous difficulties encountered in identifying a trustworthy biomarker derived from the heart (eg, heart rate variability measures) [ 37 ].…”

“…PPG amplitude may thus be a more trackable dynamic marker of the physiological responsiveness to tcVNS than those previously investigated. Notably, such biomarkers have thus far remained elusive in the existing tVNS literature [ 37 ]. Hence, in conjunction with the consistency of PPG amplitude discovered in previous work [ 5 , 12 ], the finding that PPG amplitude remains more amenable to our modeling approach suggests that PPG amplitude may serve as a superior biomarker for real-time tcVNS systems, and thus should be given precedence in a multimodal sensing setting.…”

Neuro-cardiac coupling predicts transcutaneous auricular vagus nerve stimulation effects

“…Any biomarkers that are reproducibly associated with -but not necessarily caused by -the condition of interest (Mischak et al, 2010), could be used to titrate stimulation parameters (i.e., current intensity, pulse width, stimulation frequency), identify optimal stimulation targets within the auricle and/or detect susceptible physiological states, e.g., during the respiratory cycle (Burger et al, 2020;Gurel et al, 2019;Sclocco et al, 2019).…”

“…Candidate taVNS biomarkers include cardiac, neurophysiological, and biochemical readouts (Burger et al, 2020). Electrocardiographic (ECG) metrics are considered to be among the most promising candidate biomarkers (Clancy et al, 2014;Gurel et al, 2020), for two reasons: Firstly, ECG is inexpensive, and quickly and safely applicable in virtually all patient subpopulations, unlike, for example, magnetic resonance imaging-based biomarkers (Mithani et al, 2019;Yakunina et al, 2017).…”

Transcutaneous Vagus Nerve Stimulation Modulates EEG Microstates and Delta Activity in Healthy Subjects

“…In detail, the nucleus of the solitary tract is a pivotal structure as it represents the target of major afferent vagal inputs and because it presents widespread projections toward a variety of key cerebral areas, including amygdala, thalamus, hippocampus and neocortex [ 8 ]. Still, the mechanism of action and potential effectiveness of tVNS with respect to diagnostics and the therapy of neurological and psychiatric disorders remains to be verified, and the functional neurobiology of how VNS, invasive or non-invasive, works is poorly understood [ 9 , 10 , 11 ]. Therefore, there is a need to further explore the potential influence of tVNS on cortical functional dynamics.…”