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Latest Views on the Mechanisms of Action of Surgically Implanted Cervical Vagal Nerve Stimulation in Epilepsy

Open AccessPublished:September 02, 2022DOI:https://doi.org/10.1016/j.neurom.2022.08.447

      Abstract

      Background

      Vagus nerve stimulation (VNS) is approved as an adjunctive treatment for drug-resistant epilepsy. Although there is a substantial amount of literature aiming at unraveling the mechanisms of action of VNS in epilepsy, it is still unclear how the cascade of events triggered by VNS leads to its antiepileptic effect.

      Objective

      In this review, we integrated available peer-reviewed data on the effects of VNS in clinical and experimental research to identify those that are putatively responsible for its therapeutic effect. The topic of transcutaneous VNS will not be covered owing to the current lack of data supporting the differences and commonalities of its mechanisms of action in relation to invasive VNS.

      Summary of the Main Findings

      There is compelling evidence that the effect is obtained through the stimulation of large-diameter afferent myelinated fibers that project to the solitary tract nucleus, then to the parabrachial nucleus, which in turn alters the activity of the limbic system, thalamus, and cortex. VNS-induced catecholamine release from the locus coeruleus in the brainstem plays a pivotal role. Functional imaging studies tend to point toward a common vagal network that comes into play, made up of the amygdalo-hippocampal regions, left thalamus, and insular cortex.

      Conclusions

      Even though some crucial pieces are missing, neurochemical, molecular, cellular, and electrophysiological changes occur within the vagal afferent network at three main levels (the brainstem, the limbic system [amygdala and hippocampus], and the cortex). At this final level, VNS notably alters functional connectivity, which is known to be abnormally high within the epileptic zone and was shown to be significantly decreased by VNS in responders. The effect of crucial VNS parameters such as frequency or current amplitude on functional connectivity metrics is of utmost importance and requires further investigation.

      Keywords

      Introduction

      James Corning, an American neurologist, was the first to propose vagal nerve stimulation as a treatment for seizures in 1880. At that time, epilepsy was thought to arise from cerebral hyperemia. Corning aimed at decreasing cerebral blood flow by compression of the carotid arteries while attempting to reduce cardiac output through transcutaneous electrical stimulation of the vagus nerve.
      • Clancy J.A.
      • Deuchars S.A.
      • Deuchars J.
      The wonders of the Wanderer.
      Direct electrical stimulation of the cervical vagus nerve was later shown to reduce strychnine-induced seizures in cats in 1937.
      • Schweitzer A.
      • Wright S.
      The anti-strychnine action of acetylcholine, prostigmine and related substances, and of central vagus stimulation.
      It was subsequently shown that stimulation of vagal afferents could modulate cortical activity independently of any cardiovascular alterations.
      • Zanchetti A.
      • Wang S.C.
      • Moruzzi G.
      The effect of vagal afferent stimulation on the EEG pattern of the cat.
      • Chase M.H.
      • Nakamura Y.
      • Clemente C.D.
      • Sterman M.B.
      Afferent vagal stimulation: neurographic correlates of induced EEG synchronization and desynchronization.
      • Chase M.H.
      • Sterman M.B.
      • Clemente C.D.
      Cortical and subcortical patterns of response to afferent vagal stimulation.
      The first commercial vagus nerve stimulator for use in humans, the Vagus Nerve Stimulation (VNS) Therapy System® (LivaNova PLC, London, United Kingdom), was approved in the EU in 1994 as an adjunctive therapy for drug-resistant epilepsy. Efficacy has been shown in controlled and numerous open-label studies.
      • FineSmith R.B.
      • Zampella E.
      • Devinsky O.
      Vagal nerve stimulator: a new approach to medically refractory epilepsy.
      • Ben-Menachem E.
      Vagus-nerve stimulation for the treatment of epilepsy.
      • Penry J.K.
      • Dean J.C.
      Prevention of intractable partial seizures by intermittent vagal stimulation in humans: preliminary results.
      Cardiac-based seizure detection (CBSD) was later introduced to VNS Therapy Systems. CBSD involves monitoring heart rate to elicit an additional train of stimulation when rapid heart-rate accelerations, often associated with seizures, are detected. The objective is thus to try to abort a seizure or reduce its propagation and thereby improve the clinical results.
      • Hamilton P.
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      Clinical outcomes of VNS therapy with AspireSR® (including cardiac-based seizure detection) at a large complex epilepsy and surgery centre.
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      • Harush A.
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      • Feldman Z.
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      Clinical outcomes of closed-loop vagal nerve stimulation in patients with refractory epilepsy.
      • Muthiah N.
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      • Vodovotz L.
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      Comparison of traditional and closed loop vagus nerve stimulation for treatment of pediatric drug-resistant epilepsy: a propensity-matched retrospective cohort study.
      • Santhumayor B.
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      • Rodgers S.
      Evaluating vagus nerve stimulation treatment with heart rate monitoring in pediatric patients with intractable epilepsy.
      Similarly to deep brain stimulation (DBS), whose mechanisms of action are still not entirely understood,
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      Deep brain stimulation mechanisms: the control of network activity via neurochemistry modulation.
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      Closing the loop of deep brain stimulation.
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      • Hess C.W.
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      A comprehensive review of brain connectomics and imaging to improve deep brain stimulation outcomes.
      • Hammond C.
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      Latest view on the mechanism of action of deep brain stimulation.
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      • Kiening K.L.
      Cellular, molecular, and clinical mechanisms of action of deep brain stimulation-a systematic review on established indications and outlook on future developments.
      the full mechanisms by which VNS exerts its antiepileptic effect are still elusive. Many mechanisms in humans and in various animal models have been described.
      • Henry T.R.
      Therapeutic mechanisms of vagus nerve stimulation.
      • Hamdi H.
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      • Lagarde S.
      • et al.
      Use of polyvinyl alcohol sponge cubes for vagal nerve stimulation: a suggestion for the wrapping step. Technical note and step-by-step operative technique.
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      • Wilder B.J.
      • et al.
      Neurochemical effects of vagus nerve stimulation in humans.
      • Vonck K.
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      • Boon P.
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      • Groves D.A.
      • Brown V.J.
      Vagal nerve stimulation: a review of its applications and potential mechanisms that mediate its clinical effects.
      When discussing the mechanisms of action of VNS, the comparison with DBS is far from being irrelevant. Indeed, DBS may be regarded as a peculiar extraphysiological situation in which a lead is inserted within the brain to stimulate excitable structures in the vicinity of the electrode. This complicates the situation because different types of neural elements may be affected by the current, such as neuronal cell bodies and myelinated axons of different diameters and origins (afferent, efferent, passing by fibers, dendrites). However, the pulse width (60 μs) speaks for a predominant effect on fibers.
      • Ranck J.B.
      Which elements are excited in electrical stimulation of mammalian central nervous system: a review.
      • Holsheimer J.
      • Dijkstra E.A.
      • Demeulemeester H.
      • Nuttin B.
      Chronaxie calculated from current-duration and voltage-duration data.
      • Nowak L.G.
      • Bullier J.
      Axons, but not cell bodies, are activated by electrical stimulation in cortical gray matter. I. Evidence from chronaxie measurements.
      In the case of VNS, the situation seems simpler because of the fascicular structure of the nerve itself that implies that only fiber bundles will be affected. However, the different types of fibers making up the trunk of the nerve may be differently organized across individuals and affected differently by the stimulation depending on pulse width, output current, and electrode design, as modeling simulation suggests.
      • Helmers S.L.
      • Begnaud J.
      • Cowley A.
      • et al.
      Application of a computational model of vagus nerve stimulation.
      The coverage of the nerve by the helical electrode used by the VNS Therapy® indeed affects the current density decay from the edge of the electrodes to the center of the nerve.
      • Bucksot J.E.
      • Wells A.J.
      • Rahebi K.C.
      • et al.
      Flat electrode contacts for vagus nerve stimulation.
      The current helical design is designed to cover approximately 75% (270°) of its circumference. Regardless of this, the downstream effects toward the brain nuclei are not easy to disentangle.
      In this review, the authors, after a short review of key concepts of vagal fascicular and functional anatomy, present a global overview of the existing literature, updated since the seminal paper by Henry et al
      • Henry T.R.
      Therapeutic mechanisms of vagus nerve stimulation.
      reviewing successively functional imaging, neurotransmitter release, or electroencephalogram (EEG) studies. Secondly, the authors—based on their own functional connectivity studies in patients with epilepsy—intend to shed light on the putative mechanisms of action of VNS.
      For clarity, the authors will not discuss the mechanisms at work for indications other than epilepsy. The topic of transcutaneous VNS will not be covered either in this review owing to the current lack of data supporting the differences and commonalities of its mechanisms of action in relation to invasive VNS.

      Anatomical Reminder: The Vagus Nerve and Its Projection

      The tenth cranial nerve is the longest cranial nerve
      • Pearce J.M.S.
      Samuel Thomas Soemmerring (1755–1830): the naming of cranial nerves.
      and constitutes the main parasympathetic output of the autonomic nervous system. However, recent literature shows more sympathetic fibers in the vagus nerve than previously assumed.
      • Verlinden T.J.M.
      • Rijkers K.
      • Hoogland G.
      • Herrler A.
      Morphology of the human cervical vagus nerve: implications for vagus nerve stimulation treatment.
      Based on early studies in cats, unmyelinated C-fibers seem to predominate over fast-conducting intermediate and large-caliber myelinated fibers (B- or A-fibers) in the cervical portion of the vagus nerve.
      • Agostoni E.
      • Chinnock J.E.
      • De Daly M.B.
      • Murray J.G.
      Functional and histological studies of the vagus nerve and its branches to the heart, lungs and abdominal viscera in the cat.
      Moreover, in cats,
      • Foley J.O.
      • DuBois F.S.
      Quantitative studies of the vagus nerve in the cat. I. The ratio of sensory to motor fibers.
      the nerve is made up of approximately 80% afferent fibers, mostly unmyelinated, and 20% efferent fibers, predominantly unmyelinated parasympathetic fibers to viscera, with some myelinated fibers to vocal muscles. In mice, pigs, and humans, it has recently been shown that the percentage of myelinated fibers was 54% ± 7% in the cervical vagus nerve compared with the abdominal vagus nerve, which contains mostly unmyelinated fibers. In humans, the myelinated fibers consist predominantly of small-diameter (63%), medium-diameter (33%), and large-diameter fibers (4%). The number of fibers within the cervical vagus nerve is approximately 50,000 (±10,000).
      • Stakenborg N.
      • Gomez-Pinilla P.J.
      • Verlinden T.J.M.
      • et al.
      Comparison between the cervical and abdominal vagus nerves in mice, pigs, and humans.
      As mentioned by Henry et al,
      • Henry T.R.
      Therapeutic mechanisms of vagus nerve stimulation.
      the two vagus nerves are asymmetric with regard to cardiac innervation: the left vagus nerve primarily innervates the AV node, whereas the right vagus nerve innervates the SA node. Moreover, the right vagus nerve carries most of the parasympathetic fibers that densely innervate the cardiac atria.
      In addition, 80% of the nerve afferent fibers terminate in the nucleus of tractus solitarius (NTS), which represents the main gateway and processing center for information reaching the brainstem through the vagus nerve.
      • Odekunle A.
      • Bower A.J.
      Brainstem connections of vagal afferent nerves in the ferret: an autoradiographic study.
      Each vagus nerve connects bilaterally on that key center. The afferent fibers of the left vagus nerve synapse on several other nuclei of the dorsal medulla ipsilaterally. The vagus nerve projects to the nucleus ambiguus, the dorsal motor nucleus of the vagus nerve, the area postrema, spinal trigeminal nucleus, and medial reticular formation. In turn, the NTS has a wide range of projections to several key structures in the brainstem such as the noradrenergic locus coeruleus (LC), serotoninergic raphe nucleus (RN), cerebellum, periaqueducal gray matter, and parabrachial nuclei (PBN). The PBN appears as a key node because of its connections to the insula, thalamus, hippocampus, and amygdala. The ascending vago-solitario-parabrachial pathways provide dense innervation to the limbic system. Vagal-LC and vagal-RN interactions may play an important role, given the widespread noradrenergic and serotoninergic dense cortical innervation stemming respectively from those two brainstem nuclei with potential antiseizure effects in rodents.
      • Dailey J.W.
      • Yan Q.S.
      • Adams-Curtis L.E.
      • et al.
      Neurochemical correlates of antiepileptic drugs in the genetically epilepsy-prone rat (GEPR).
      • Stanton P.K.
      • Mody I.
      • Zigmond D.
      • Sejnowski T.
      • Heinemann U.
      Noradrenergic modulation of excitability in acute and chronic model epilepsies.
      • Krahl S.E.
      • Clark K.B.
      • Smith D.C.
      • Browning R.A.
      Locus coeruleus lesions suppress the seizure-attenuating effects of vagus nerve stimulation.
      • Krahl S.E.
      • Senanayake S.S.
      • Handforth A.
      Seizure suppression by systemic epinephrine is mediated by the vagus nerve.

      Which Fibers Are Involved, and Which Are the Actual Targets of VNS?

      VNS efficacy was shown to be mainly mediated by fast afferent myelinated A- and B-fibers. Indeed, lesioning below the site of VNS electrode in a canine model of epilepsy did not result in loss of efficacy.
      • Zabara J.
      Inhibition of experimental seizures in canines by repetitive vagal stimulation.
      No loss of seizure-suppressing effects was reported when C-fibers were chemically inactivated by capsaicin.
      • Krahl S.E.
      • Senanayake S.S.
      • Handforth A.
      Destruction of peripheral C-fibers does not alter subsequent vagus nerve stimulation-induced seizure suppression in rats.
      Moreover, efficacious stimulation amplitudes are in the order of magnitude of 1.5 mA (starting from 0.75 mA), which corresponds to an amplitude that lies below the threshold of slow unmyelinated C-fibers. Fiber-type recruitment follows a size principle (large and heavily myelinated A-fiber being recruited first, followed by myelinated medium-sized B, then C). Computational models indicate that output current between 0.75 and 1.75 mA with pulse width of 250 or 500 microseconds will result in predominant activation of the myelinated fibers.
      • Helmers S.L.
      • Begnaud J.
      • Cowley A.
      • et al.
      Application of a computational model of vagus nerve stimulation.
      Castoro et al
      • Castoro M.A.
      • Yoo P.B.
      • Hincapie J.G.
      • et al.
      Excitation properties of the right cervical vagus nerve in adult dogs.
      studied the excitation properties of the vagus nerve in dogs across a wide range of stimulation parameters. The rheobase currents of A- and B-fibers were 0.4 mA and 0.7 mA, respectively, and the chronaxie of both types of fibers was 180 microseconds.
      Recent evidence derived from experiments conducted in rodents by Chang et al
      • Chang Y.C.
      • Cracchiolo M.
      • Ahmed U.
      • et al.
      Quantitative estimation of nerve fiber engagement by vagus nerve stimulation using physiological markers.
      showed a correlation between the type of physiological response and the type of fibers involved. C-fiber activation was, for instance, strongly associated with breathing changes and apnea. It is unlikely that the amplitude required to recruit C-fibers could be attained in humans without also giving rise to significant adverse effects. Their rodent model suggests that quantitative estimation of nerve fiber engagement could prove pertinent to refine VNS therapy by tailoring the desired type of fiber involvement to the indication (predominant C-fiber activation when antiinflammatory effect is searched for or predominant B-fibers for heart failure).
      Further evidence on the fibers activated in humans by VNS is provided by several studies based on intraoperative compound action potentials (CAPs).
      Evans et al
      • Evans M.S.
      • Verma-Ahuja S.
      • Naritoku D.K.
      • Espinosa J.A.
      Intraoperative human vagus nerve compound action potentials.
      measured CAPs of the vagus nerve fiber intraoperatively. A-fiber potentials were recordable and activated by very low stimulus currents, A-delta and C-fibers being less reliably elicited, with C-fibers requiring the highest intensities.
      Usami et al
      • Usami K.
      • Kawai K.
      • Sonoo M.
      • Saito N.
      Scalp-recorded evoked potentials as a marker for afferent nerve impulse in clinical vagus nerve stimulation.
      recorded scalp-evoked potential as a marker of the afferent impulse in clinical vagal nerve stimulation. The short-latency components of the vagus nerve–evoked potential (estimated conduction velocity conduction of 27.4 ± 10.2 m/s) were regarded as directly resulting from the involvement of A-fibers of the nerve.
      Vespa et al
      • Vespa S.
      • Stumpp L.
      • Bouckaert C.
      • et al.
      Vagus nerve stimulation-induced laryngeal motor evoked potentials: a possible biomarker of effective nerve activation.
      showed the ability to noninvasively record the laryngeal motor–evoked potentials (LMEPs) induced by VNS that could serve as a biomarker of nerve activation and enable better titration of the parameters. As shown by Chang et al, these data are suggestive of selective involvement of A-α fiber activations, but no significant differences in VNS-induced LMEPs were found between responders and nonresponders.
      • Chang Y.C.
      • Cracchiolo M.
      • Ahmed U.
      • et al.
      Quantitative estimation of nerve fiber engagement by vagus nerve stimulation using physiological markers.

      VNS Therapy and Neurotransmitter and Cytokines Release

      Early studies have shown that VNS therapy induces significant alterations of neurotransmitter release. Roosevelt et al
      • Roosevelt R.W.
      • Smith D.C.
      • Clough R.W.
      • Jensen R.A.
      • Browning R.A.
      Increased extracellular concentrations of norepinephrine in cortex and hippocampus following vagus nerve stimulation in the rat.
      found increased extracellular concentrations of noradrenaline (NA) in the rat cortex and hippocampus after vagus nerve stimulation at 1 mA. Interestingly, the increase remained confined to the period of stimulation. No increase of NA release occurred <0.5 mA. Using in vivo microdialysis in rats, Hassert et al
      • Hassert D.L.
      • Miyashita T.
      • Williams C.L.
      The effects of peripheral vagal nerve stimulation at a memory-modulating intensity on norepinephrine output in the basolateral amygdala.
      also showed that VNS caused a 98% increase of NA.
      The amplitude of the P3 component of the event-related potential, a marker of LC activity associated with NA release in the brain, was shown to be significantly increased in responders.
      • De Taeye L.
      • Vonck K.
      • van Bochove M.
      • et al.
      The P3 event-related potential is a biomarker for the efficacy of vagus nerve stimulation in patients with epilepsy.
      In an animal model of limbic seizures, VNS-induced changes in extracellular hippocampal levels of NA, dopamine, serotonin, and γ-amino butyric acid (GABA) were measured in freely moving rats. A strong positive correlation was found between the noradrenergic and antiseizure effects of VNS.
      • Berger A.
      • Vespa S.
      • Dricot L.
      • et al.
      How is the norepinephrine system involved in the antiepileptic effects of vagus nerve stimulation?.
      Blockade of hippocampal α(2)-receptors reversed the seizure-suppressing effect of VNS.
      • Raedt R.
      • Clinckers R.
      • Mollet L.
      • et al.
      Increased hippocampal noradrenaline is a biomarker for efficacy of vagus nerve stimulation in a limbic seizure model.
      Other neurotransmitters such as GABA, glycine, and various amino-acid pools were found to be modified by VNS in the brain.
      • Hammond E.J.
      • Uthman B.M.
      • Wilder B.J.
      • et al.
      Neurochemical effects of vagus nerve stimulation in humans.
      ,
      • Woodbury D.M.
      • Woodbury J.W.
      Effects of vagal stimulation on experimentally induced seizures in rats.
      ,
      • Ben-Menachem E.
      • Hamberger A.
      • Hedner T.
      • et al.
      Effects of vagus nerve stimulation on amino acids and other metabolites in the CSF of patients with partial seizures.
      These studies are of interest for two reasons: first, they were conducted in human patients, and second, they investigated the chronic effect as opposed to studies focusing on acute alterations of neurotransmitter release. Furthermore, it has been postulated that immunologic and antiinflammatory action could play a role in the beneficial effects of VNS. A few studies investigated the changes of proinflammatory cytokines and tryptophane metabolites induced by VNS in peripheral blood.
      • Aalbers M.W.
      • Klinkenberg S.
      • Rijkers K.
      • et al.
      The effects of vagus nerve stimulation on pro- and anti-inflammatory cytokines in children with refractory epilepsy: an exploratory study.
      • Majoie H.J.M.
      • Rijkers K.
      • Berfelo M.W.
      • et al.
      Vagus nerve stimulation in refractory epilepsy: effects on pro- and anti-inflammatory cytokines in peripheral blood.
      • Klinkenberg S.
      • van den Borne C.J.H.
      • Aalbers M.W.
      • et al.
      The effects of vagus nerve stimulation on tryptophan metabolites in children with intractable epilepsy.

      Functional Imaging Studies

      Functional imaging studies have shown that VNS induces significant changes in cerebral blood flow. Studies showed regional increase of cerebral blood flow, mainly in the thalamus and the cerebral cortex. Ko et al
      • Ko D.
      • Heck C.
      • Grafton S.
      • et al.
      Vagus nerve stimulation activates central nervous system structures in epileptic patients during PET H2(15)O blood flow imaging.
      found, using positron emission tomography (PET) H2O blood flow imaging, that VNS caused activation of several central areas, including the contralateral thalamus.
      Henry et al
      • Henry T.R.
      • Bakay R.A.E.
      • Pennell P.B.
      • Epstein C.M.
      • Votaw J.R.
      Brain blood-flow alterations induced by therapeutic vagus nerve stimulation in partial epilepsy: II. Prolonged effects at high and low levels of stimulation.
      showed VNS-induced cerebral blood flow increase in bilateral thalami, hypothalami, and inferior cerebellar hemispheres. These alterations were found to occur immediately but also were shown to persist at three months. Functional magnetic resonance imaging (fMRI) studies also have shown bilateral activation, maximal in thalami (left more than right) and insular cortices.
      • Narayanan J.T.
      • Watts R.
      • Haddad N.
      • Labar D.R.
      • Li P.M.
      • Filippi C.G.
      Cerebral activation during vagus nerve stimulation: a functional MR study.
      Marrosu et al
      • Marrosu F.
      • Serra A.
      • Maleci A.
      • Puligheddu M.
      • Biggio G.
      • Piga M.
      Correlation between GABA(A) receptor density and vagus nerve stimulation in individuals with drug-resistant partial epilepsy.
      applied single-photon emission computerized tomography with the benzodiazepine receptor inverse agonist [123I]iomazenil to examine cortical GABA(A) receptor density (GRD) before and one year after VNS implant. VNS therapeutic responses were significantly correlated with the normalization of GRD.
      Recently, a resting state–fMRI functional connectivity study on the brainstem-cortical/subcortical structures in eight controls and eight VNS responder patients led to the conclusion that VNS could reorganize the altered functional connectivity (Fc) between the brainstem and insula, precuneus, and cerebellum.
      • Zhu J.
      • Wang J.
      • Xu C.
      • et al.
      The functional connectivity study on the brainstem-cortical/subcortical structures in responders following cervical vagus nerve stimulation.
      Similarly, in 66 children with epilepsy who had VNS, Yu et al
      • Yu R.
      • Park H.J.
      • Cho H.
      • et al.
      Interregional metabolic connectivity of 2-deoxy-2[18 F]fluoro-D-glucose positron emission tomography in vagus nerve stimulation for pediatric patients with epilepsy: a retrospective cross-sectional study.
      compared metabolic connectivity between responders and nonresponders (≥50% seizure frequency decrease) using preoperative fluorodeoxyglucose PET. Relative changes in glucose metabolism were strongly connected among the areas of the brainstem, cingulate gyrus, cerebellum, bilateral insula, and putamen in patients with ≥50% seizure frequency reduction after VNS. These results support the existence of specific preexisting connectivity patterns in responders vs nonresponders. As suggested by Hachem et al,
      • Hachem L.D.
      • Wong S.M.
      • Ibrahim G.M.
      The vagus afferent network: emerging role in translational connectomics.
      preoperative connectivity studies not only may serve as biomarkers for selection of patients but also may provide insights as to VNS action mechanisms.
      • Workewych A.M.
      • Arski O.N.
      • Mithani K.
      • Ibrahim G.M.
      Biomarkers of seizure response to vagus nerve stimulation: a scoping review.
      More recent studies aiming at predicting VNS response based on structural and functional connectomic profiling have offered insights. VNS responders showed greater fractional anisotropy in the left thalamocortical, limbic, and association fibers and greater connectivity in a functional network encompassing the left thalamic, insular, and temporal nodes, pointing toward a similar network to that of early functional imaging studies.
      • Mithani K.
      • Mikhail M.
      • Morgan B.R.
      • et al.
      Connectomic profiling identifies responders to vagus nerve stimulation.
      A similar study from the same group had first shown that thalamocortical intrinsic connectivity could play a key role in the preoperative estimated response to VNS, supporting further the existence of a specific network coming into play and affected by VNS.
      • Ibrahim G.M.
      • Sharma P.
      • Hyslop A.
      • et al.
      Presurgical thalamocortical connectivity is associated with response to vagus nerve stimulation in children with intractable epilepsy.

      Impact on Brain Electrophysiological Signals

      EEG Synchronization and Power Spectral Analysis

      Early animal studies dating back to the 1960s sought to determine the effect of acute vagal nerve stimulation on the EEG. These studies showed that the effect was highly dependent on stimulation parameters and particularly on the amplitude and frequency
      • Chase M.H.
      • Nakamura Y.
      • Clemente C.D.
      • Sterman M.B.
      Afferent vagal stimulation: neurographic correlates of induced EEG synchronization and desynchronization.
      : Synchronization (spindle-like activity) could be observed at 1 to 17 Hz, whereas desynchronization seemed to be associated with higher stimulation frequencies (>30 Hz).
      Chase et al
      • Chase M.H.
      • Sterman M.B.
      • Clemente C.D.
      Cortical and subcortical patterns of response to afferent vagal stimulation.
      reported that much higher frequency and voltage gave rise to synchronization (100 Hz or 200 Hz), whereas 25 Hz resulted in desynchronization. Salinsky et al
      • Salinsky M.C.
      • Burchiel K.J.
      Vagus nerve stimulation has no effect on awake EEG rhythms in humans.
      analyzed the effect of acute VNS on awake EEG rhythms in humans. They found no effects on spectral analysis, even in patients showing apparent response to VNS.
      Marrosu et al
      • Marrosu F.
      • Santoni F.
      • Puligheddu M.
      • et al.
      Increase in 20-50 Hz (gamma frequencies) power spectrum and synchronization after chronic vagal nerve stimulation.
      investigated the chronic effect of VNS on EEG rhythms. These authors compared the power spectrum before and one year after VNS implant and found no significant changes for the delta, theta, alpha, and beta bands but an increase in power in the gamma band. They also observed a significant decrease in synchronization in theta frequencies and an increase in gamma band and interhemispheric synchronization.
      Ernst et al

      Ernst LD, Steffan PJ, Srikanth P, et al. Electrocorticography analysis in patients with dual neurostimulators supports desynchronization as a mechanism of action for acute vagal nerve stimulator stimulation. J Clin Neurophysiol. Published online April 7, 2021. https://dx.doi.org/10.1097/WNP.0000000000000847.

      also reported that acute VNS stimulation resulted in desynchronization in theta bands in ECoGs recorded in patients with dual (VNS and responsive neurostimulation) neurostimulators.
      Brádzil et al
      • Brázdil M.
      • Doležalová I.
      • Koritáková E.
      • et al.
      EEG reactivity predicts individual efficacy of vagal nerve stimulation in intractable epileptics.
      studied EEG reactivity to standard stimuli (photic, hyperpnea) to predict individual response to VNS. Power spectral analysis revealed significant differences in EEG reactivity between responders and nonresponders; in particular, the dynamics of alpha and gamma activity was shown to be strongly associated with VNS efficacy.

      Spikes and Interictal Epileptiform Activity

      Irrespective of spectral analysis, a decrease in spike frequency could be shown with VNS in several studies. Hallböök et al
      • Hallböök T.
      • Lundgren J.
      • Blennow G.
      • Strömblad L.G.
      • Rosén I.
      Long term effects on epileptiform activity with vagus nerve stimulation in children.
      reported that VNS reduced interictal epileptiform discharges (IEDs), especially during sleep (rapid eye movement, delta-sleep) and the number of recorded EEG seizures. In addition, Zanchetti et al
      • Zanchetti A.
      • Wang S.C.
      • Moruzzi G.
      The effect of vagal afferent stimulation on the EEG pattern of the cat.
      observed a reduction of spindles and suppression of spiking activity after afferent vagal stimulation on the EEG of a cat. Koo
      • Koo B.
      EEG changes with vagus nerve stimulation.
      investigated EEG changes in patients at baseline and three, six, and 12 months postoperatively. VNS was shown to induce EEG changes in the form of clustering of epileptiform activity followed by progressively increased periods of spike-free intervals. Kuba et al
      • Kuba R.
      • Guzaninová M.
      • Brázdil M.
      • Novák Z.
      • Chrastina J.
      • Rektor I.
      Effect of vagal nerve stimulation on interictal epileptiform discharges: a scalp EEG study.
      ,
      • Kuba R.
      • Nesvadba D.
      • Brázdil M.
      • Oslejsková H.
      • Ryzí M.
      • Rektor I.
      Effect of chronic vagal nerve stimulation on interictal epileptiform discharges.
      studied the effect of both acute and chronic vagal nerve stimulation on IEDs. The authors compared the rate and duration of IEDs on EEG at baseline and at five-year follow-up visit in 32 patients and found both the rate and duration to decrease significantly over time, especially in responders. Wang et al
      • Wang H.
      • Chen X.
      • Lin Z.
      • et al.
      Long-term effect of vagus nerve stimulation on interictal epileptiform discharges in refractory epilepsy.
      showed on serial EEGs a progressive decrease in the number of IEDs with time.
      The effect of VNS on interictal epileptiform activity also was recorded with intracranial recordings using one hippocampal depth electrode in a patient with intractable seizures. Spike frequencies and the occurrence of epileptiform sharp waves were compared before and during VNS using a 5- and a 30-Hz stimulus. Stimulation at 30 Hz produced a significant decrease in the occurrence of epileptiform sharp waves, whereas 5-Hz stimulation was associated with a significant increase in epileptiform sharp waves, providing additional evidence as to the decisive role of the stimulating frequency.
      • Olejniczak P.W.
      • Fisch B.J.
      • Carey M.
      • Butterbaugh G.
      • Happel L.
      • Tardo C.
      The effect of vagus nerve stimulation on epileptiform activity recorded from hippocampal depth electrodes.

      Cortical Excitability

      In addition, VNS was shown to modulate cortical excitability in a rat model of motor cortex excitability. De Herdt et al
      • De Herdt V.
      • De Waele J.
      • Raedt R.
      • et al.
      Modulation of seizure threshold by vagus nerve stimulation in an animal model for motor seizures.
      observed an overall significant increase of the motor seizure threshold after one hour of VNS compared with baseline. Another study
      • Mollet L.
      • Grimonprez A.
      • Raedt R.
      • et al.
      Intensity-dependent modulatory effects of vagus nerve stimulation on cortical excitability.
      from the same group showed that output current intensities as low as 0.25 mA were sufficient to decrease cortical excitability in a protocol of stimulation of five one-hour periods for four days. Higher output intensities (0.5–1 mA) did not result in further increase of cortical excitability thresholds. These data are of great interest because they clearly show the effect of VNS upon cortical excitability and highlight the absence of a linear correlation between the amplitude of the output current and the decrease in excitability. These results are consistent with our own findings (described later).
      The question of the effect of output current was addressed by Bunch et al
      • Bunch S.
      • DeGiorgio C.M.
      • Krahl S.
      • et al.
      Vagus nerve stimulation for epilepsy: is output current correlated with acute response?.
      on the basis of the retrospective analysis of a multicenter randomized trial of three unique paradigms of VNS. It was shown that in 61 patients, the output current, ranging from 0.25 to 1.5 mA, was not a major determinant of the acute response to VNS. As found by other studies, many patients acutely respond to low current (<1 mA), and only a few showed further improvement through a higher output current.
      • Bunch S.
      • DeGiorgio C.M.
      • Krahl S.
      • et al.
      Vagus nerve stimulation for epilepsy: is output current correlated with acute response?.
      ,
      • Jaseja H.
      EEG-desynchronization as the major mechanism of anti-epileptic action of vagal nerve stimulation in patients with intractable seizures: clinical neurophysiological evidence.

      Resting State MEG Connectivity Analysis

      On the basis of a resting state magnetoencephalography (MEG) connectivity analysis, Babajani-Feremi et al
      • Babajani-Feremi A.
      • Noorizadeh N.
      • Mudigoudar B.
      • Wheless J.W.
      Predicting seizure outcome of vagus nerve stimulation using MEG-based network topology.
      found differences between VNS responders and nonresponders. They observed that the modularity and transitivity in VNS responders were significantly larger and smaller, respectively, than those observed in VNS nonresponders. Despite the impressive ability of their model to properly classify the patients between controls (prediction accuracy of 87%), VNS responders, and nonresponders, identification of the characteristics of the network of patients likely to respond to VNS does not provide clear insights into how VNS affects the involved networks in responders.

      Brain Functional Connectivity Studies

      Functional connectivity refers to the statistical link that can exist between the activities recorded from distinct brain structures, reflecting links between underlying neuronal populations. Functional connectivity at the macroscopic scale can be measured by EEG (scalp or intracranial), MEG, and fMRI (the latter being an indirect marker of neural activity through the hemodynamic response).
      • Bastos A.M.
      • Schoffelen J.M.
      A tutorial review of functional connectivity analysis methods and their interpretational pitfalls.
      Connectivity measures across several channels lead to potentially very complex matrices (that can, in addition, evolve with time). It is thus interesting to summarize these data using methods derived from graph theory to describe the general organization of brain networks and their efficiency in transmitting information.
      • Fornito A.
      • Zalesky A.
      • Bullmore E.
      Fundamentals of Brain Network Analysis.
      Fraschini et al
      • Fraschini M.
      • Puligheddu M.
      • Demuru M.
      • et al.
      VNS induced desynchronization in gamma bands correlates with positive clinical outcome in temporal lobe pharmacoresistant epilepsy.
      showed that VNS-induced global decrease of functional connectivity in the gamma band was significantly higher in responders than in patients who failed to show improvement after VNS. The analysis was based on the phase lag index (PLI),
      • Stam C.J.
      • Nolte G.
      • Daffertshofer A.
      Phase lag index: assessment of functional connectivity from multi channel EEG and MEG with diminished bias from common sources.
      which allows the study of the global functional connectivity among the EEG sensors and reduces the effect of volume conduction. Subsequent studies have extensively investigated the effect of chronic VNS on EEG functional connectivity, including the one by Bodin et al
      • Bodin C.
      • Aubert S.
      • Daquin G.
      • et al.
      Responders to vagus nerve stimulation (VNS) in refractory epilepsy have reduced interictal cortical synchronicity on scalp EEG.
      from our group looking at the alterations of connectivity between ON and OFF stimulation periods. In 19 patients with chronic VNS, responders to VNS (R) had reduced interictal functional connectivity on scalp EEG. R had a lower global level of functional connectivity (EEG broadband) than nonresponders (p < 0.0001). In addition, ON periods of stimulation were characterized by lower values of Fc than OFF periods.
      • Bodin C.
      • Aubert S.
      • Daquin G.
      • et al.
      Responders to vagus nerve stimulation (VNS) in refractory epilepsy have reduced interictal cortical synchronicity on scalp EEG.
      We replicated this study with intracerebral recordings (depth electrodes) on five adult patients who simultaneously had stereoelectroencephalography (SEEG) and a VNS implant.
      • Bartolomei F.
      • Bonini F.
      • Vidal E.
      • et al.
      How does vagal nerve stimulation (VNS) change EEG brain functional connectivity?.
      Interdependencies between bipolar SEEG channels were estimated by nonlinear regression analysis (h2 index) and compared between ON and OFF periods of stimulation. All these patients but one had no benefit from VNS. The only responder had >50% reduction of seizure on VNS but was still very disabled by his seizures. Fc analysis revealed an increase of functional connectivity values during ON periods for four patients and decreased values for the R patient. These results were consistent with the hypothesis that the therapeutic effect may be related to the VNS-induced decrease in functional connectivity. Furthermore, and most importantly, this study analyzed several combinations of stimulation parameters. Surprisingly, Fc tended to vary in a nonlinear fashion with different settings of stimulation. This implies that setting the parameters of stimulation is complex and merely increasing the intensity or frequency of stimulation may prove irrelevant to decrease the synchrony and optimize the therapeutic effect.
      More recently, Sangare et al
      • Sangare A.
      • Marchi A.
      • Pruvost-Robieux E.
      • et al.
      The effectiveness of vagus nerve stimulation in drug-resistant epilepsy correlates with vagus nerve stimulation-induced electroencephalography desynchronization.
      replicated these results in 35 patients with epilepsy. The synchronization in scalp-EEG time series was compared between ON and OFF periods of stimulation, using average PLI in sensor space and phase-locking value between ten sources. For responder patients, PLI during ON periods was significantly lower than that during OFF periods in several EEG subband frequencies (delta, theta, and beta). For nonresponders, there were no significant differences. The correlation between VNS-induced interictal EEG time-series decrease in functional connectivity and decrease in seizure frequency suggested that the therapeutic effect of VNS may be related to changes in interictal functional connectivity. A recent study
      • Vespa S.
      • Heyse J.
      • Stumpp L.
      • et al.
      Vagus nerve stimulation elicits sleep EEG desynchronization and network changes in responder patients in epilepsy.
      investigated the effect of VNS on Fc during two states of vigilance (wakefulness vs stage-N2 sleep). Weighted PLI was computed as a connectivity measure of synchronization for VNS OFF and ON conditions in 24 patients. In responders, stronger VNS-induced theta desynchronization (p < 0.05) was found in sleep but not during wakefulness. There also is some evidence showing that chronic VNS influences network measures. Fraschini et al
      • Fraschini M.
      • Puligheddu M.
      • Demuru M.
      • et al.
      VNS induced desynchronization in gamma bands correlates with positive clinical outcome in temporal lobe pharmacoresistant epilepsy.
      reported significant effects of long-term VNS on Minimum Spanning Tree in responders with a more integrated/efficient global network, results that were, however, not replicated by Sangare et al,
      • Sangare A.
      • Marchi A.
      • Pruvost-Robieux E.
      • et al.
      The effectiveness of vagus nerve stimulation in drug-resistant epilepsy correlates with vagus nerve stimulation-induced electroencephalography desynchronization.
      and Vespa et al
      • Vespa S.
      • Heyse J.
      • Stumpp L.
      • et al.
      Vagus nerve stimulation elicits sleep EEG desynchronization and network changes in responder patients in epilepsy.
      showed a stronger decrease of global efficiency during sleep in responders than in nonresponders.
      Interictal connectivity is profoundly modified in patients with epilepsy.
      • Bartolomei F.
      • Lagarde S.
      • Wendling F.
      • et al.
      Defining epileptogenic networks: contribution of SEEG and signal analysis.
      SEEG and EEG/MEG connectivity studies revealed an increased connectivity within the epileptogenic zone (EZ), whereas the other zones tended to show decreased connectivity.
      • Lagarde S.
      • Roehri N.
      • Lambert I.
      • et al.
      Interictal stereotactic-EEG functional connectivity in refractory focal epilepsies.
      Reducing the hyperconnectivity in the EZ could be a pivotal mechanisms of VNS therapy in focal epilepsies. In generalized epilepsy, a more widespread effect on Fc is probably at work along with modulation of the noradrenergic drive.
      In addition, the effect of VNS stimulation on functional connectivity during seizure has been investigated. Focal seizures are associated with an increase in functional connectivity affecting the EZ network and also distant regions (propagation networks) (Bartolomei et al
      • Bartolomei F.
      • Lagarde S.
      • Wendling F.
      • et al.
      Defining epileptogenic networks: contribution of SEEG and signal analysis.
      ). Ravan et al
      • Ravan M.
      • Sabesan S.
      • D’Cruz O.
      On quantitative biomarkers of VNS therapy using EEG and ECG signals.
      evaluated whether the automated delivery of VNS at seizure onset could reduce the severity of seizures as reflected by EEG spatial synchronization—a measure of seizure propagation. Acutely stimulated seizures displayed reduced ictal spread, indicating that when delivered within the appropriate time frame, VNS may decrease spatial synchronization (extent of hypersynchrony) in addition to temporal synchronization.
      In another study by the same authors,
      • Ravan M.
      Investigating the correlation between short-term effectiveness of VNS Therapy in reducing the severity of seizures and long-term responsiveness.
      it is reported that automatic delivery of VNS therapy acutely reduces ictal spatial synchronization (EEG-based quantitative feature) in patients who later responded to VNS in long-term follow-up, indicating a susceptibility of the same network to VNS to be responsible for both acute seizure termination and also long-term seizure prevention. These findings show that the timing of stimulation also is pivotal in the equation.

      Discussion

      Despite the large number of studies, crucial puzzle pieces are missing to fully understand the antiseizure effect of VNS. The means by which the information is processed, filtered, and relayed from one input nucleus to the successive output structures within the so-called vagal afferent network
      • Hachem L.D.
      • Wong S.M.
      • Ibrahim G.M.
      The vagus afferent network: emerging role in translational connectomics.
      is obviously highly complex. A linear model of successive bottom-up transmission of information (excitation/inhibition) may be too crude to reflect the complexity of the effect of stimulation delivered at 20 to 30 Hz and may turn out to be a misconception of the dynamic modulation induced by stimulation.
      The effect on the cortex itself viewed as a final target can be studied regardless of the preceding steps occurring within the “black box.” A clear understanding of the correlation between the parameters of stimulation and functional connectivity and spatial and temporal synchronization still needs to be established.
      As shown with the nonlinear relationship between parameters and functional connectivity, there is probably no such thing as one single mechanism but several, depending on parameters of stimulation and duty cycle, which significantly vary across studies (Table 1), and certainly depending on the dynamic state of the brain when the stimulation reaches the target neurons.
      Table 1Main VNS Studies in Epilepsy With Special Attention to the Stimulation Parameters.
      StudyParameters
      Hammond et al
      • Hammond E.J.
      • Uthman B.M.
      • Wilder B.J.
      • et al.
      Neurochemical effects of vagus nerve stimulation in humans.
      1.25–3 mA, 10–30 Hz (1 patient at 2 Hz), 500 μs
      Evans et al
      • Evans M.S.
      • Verma-Ahuja S.
      • Naritoku D.K.
      • Espinosa J.A.
      Intraoperative human vagus nerve compound action potentials.
      0.25–3 mA, 1–5 Hz, 16 stimuli during surgery
      Usami et al
      • Usami K.
      • Kawai K.
      • Sonoo M.
      • Saito N.
      Scalp-recorded evoked potentials as a marker for afferent nerve impulse in clinical vagus nerve stimulation.
      0.25–1 mA, 30 Hz, 130–500 μs
      Vespa et al
      • Vespa S.
      • Stumpp L.
      • Bouckaert C.
      • et al.
      Vagus nerve stimulation-induced laryngeal motor evoked potentials: a possible biomarker of effective nerve activation.
      0.25–1 mA, 20 Hz, 250 μs
      Bouckaert et al
      • Bouckaert C.
      • Raedt R.
      • Larsen L.E.
      • et al.
      Laryngeal muscle-evoked potential recording as an indicator of vagal nerve fiber activation.
      >0.25 up to tolerability, 30 Hz, 130–500 μs, 7 s ON–18 s OFF
      De Taeye et al
      • De Taeye L.
      • Vonck K.
      • van Bochove M.
      • et al.
      The P3 event-related potential is a biomarker for the efficacy of vagus nerve stimulation in patients with epilepsy.
      0.75–3 mA, 25–30 Hz, 250–500 μs
      Ben-Menachem et al, 1995
      • Ben-Menachem E.
      • Hamberger A.
      • Hedner T.
      • et al.
      Effects of vagus nerve stimulation on amino acids and other metabolites in the CSF of patients with partial seizures.
      High stim = 1.25–3 mA, 30 s ON–5 min OFF

      Low stim = 1.25–3 mA, 3 s ON–90 min OFF
      Aalbers et al
      • Aalbers M.W.
      • Klinkenberg S.
      • Rijkers K.
      • et al.
      The effects of vagus nerve stimulation on pro- and anti-inflammatory cytokines in children with refractory epilepsy: an exploratory study.
      High stim = 0.25 mA, 30 Hz, 500 μs, 30 s ON–5 min OFF

      Low stim = 0.25 mA, 1 Hz, 100 μs, 14 s ON–1 min OFF
      Klinkenberg et al
      • Klinkenberg S.
      • van den Borne C.J.H.
      • Aalbers M.W.
      • et al.
      The effects of vagus nerve stimulation on tryptophan metabolites in children with intractable epilepsy.
      High stim = <2.75 mA, 30 Hz, 500 μs, 30 s ON–5 min OFF

      Low stim = <2.75 mA, 1 Hz, 100 μs, 14 s ON–60 min OFF
      Ko et al
      • Ko D.
      • Heck C.
      • Grafton S.
      • et al.
      Vagus nerve stimulation activates central nervous system structures in epileptic patients during PET H2(15)O blood flow imaging.
      2 mA, 30 Hz, 60 s during PET scan
      Henry et al
      • Henry T.R.
      • Bakay R.A.E.
      • Pennell P.B.
      • Epstein C.M.
      • Votaw J.R.
      Brain blood-flow alterations induced by therapeutic vagus nerve stimulation in partial epilepsy: II. Prolonged effects at high and low levels of stimulation.
      High stim = 0.25–2.5 mA, 30 Hz, 500 μs, 30 s ON–5 min OFF

      Low stim = 0.25–1.25 mA, 1 Hz, 130 μs, 30 s ON–180 min OFF
      Narayanan et al
      • Narayanan J.T.
      • Watts R.
      • Haddad N.
      • Labar D.R.
      • Li P.M.
      • Filippi C.G.
      Cerebral activation during vagus nerve stimulation: a functional MR study.
      0.5–2.0 mA, 30 Hz, 30 s ON and 30 s OFF
      Marrosu et al, 2013
      • Marrosu F.
      • Serra A.
      • Maleci A.
      • Puligheddu M.
      • Biggio G.
      • Piga M.
      Correlation between GABA(A) receptor density and vagus nerve stimulation in individuals with drug-resistant partial epilepsy.
      1.75–2 mA, 30 Hz, 500 μs, 30 s ON–5 min OFF
      Zhu et al
      • Zhu J.
      • Wang J.
      • Xu C.
      • et al.
      The functional connectivity study on the brainstem-cortical/subcortical structures in responders following cervical vagus nerve stimulation.
      1.5 mA, 30 Hz, 250 μs, 30 s ON–5 min OFF
      Yu et al
      • Yu R.
      • Park H.J.
      • Cho H.
      • et al.
      Interregional metabolic connectivity of 2-deoxy-2[18 F]fluoro-D-glucose positron emission tomography in vagus nerve stimulation for pediatric patients with epilepsy: a retrospective cross-sectional study.
      2–2.5 mA, 30 s ON–5 min OFF
      Hallböök et al
      • Hallböök T.
      • Lundgren J.
      • Blennow G.
      • Strömblad L.G.
      • Rosén I.
      Long term effects on epileptiform activity with vagus nerve stimulation in children.
      1.5 mA, 30 Hz, 500 μs, 30 s ON–5 min OFF
      Koo et al
      • Koo B.
      • Ham S.D.
      • Sood S.
      • Tarver B.
      Human vagus nerve electrophysiology: a guide to vagus nerve stimulation parameters.
      Increase of 0.25 mA every 2 wk up to patient tolerance, 20–30 Hz, 500 μs, 30 s ON–5 min OFF
      Kuba et al
      • Kuba R.
      • Guzaninová M.
      • Brázdil M.
      • Novák Z.
      • Chrastina J.
      • Rektor I.
      Effect of vagal nerve stimulation on interictal epileptiform discharges: a scalp EEG study.
      20–30 Hz, 500 μs, 30 s ON–5 min OFF or 21 s ON–3 min OFF
      Kuba et al
      • Kuba R.
      • Nesvadba D.
      • Brázdil M.
      • Oslejsková H.
      • Ryzí M.
      • Rektor I.
      Effect of chronic vagal nerve stimulation on interictal epileptiform discharges.
      20–30 Hz, 500 μs, 21 s ON–3 min OFF or 21 s ON–1.8 min OFF
      Wang et al
      • Wang H.
      • Chen X.
      • Lin Z.
      • et al.
      Long-term effect of vagus nerve stimulation on interictal epileptiform discharges in refractory epilepsy.
      0.75–1.75 mA, 20–30 Hz, 250–500 μs, 30 s ON–5 min OFF
      Olejniczak et al
      • Olejniczak P.W.
      • Fisch B.J.
      • Carey M.
      • Butterbaugh G.
      • Happel L.
      • Tardo C.
      The effect of vagus nerve stimulation on epileptiform activity recorded from hippocampal depth electrodes.
      (case report)
      2.75 mA, 30 Hz, 500 μs, 30 s ON–1.1 min OFF
      Bunch et al
      • Bunch S.
      • DeGiorgio C.M.
      • Krahl S.
      • et al.
      Vagus nerve stimulation for epilepsy: is output current correlated with acute response?.
      Group A: <1.5 mA, 20 Hz, 500 μs, 7 s ON–18 s OFF

      Group B: <1.5 mA, 20 Hz, 250 μs, 30 s ON–30 s OFF

      Group C: <1.5 mA, 30 Hz, 500 μs, 30 s ON–3 min OFF
      Fraschini et al
      • Fraschini M.
      • Puligheddu M.
      • Demuru M.
      • et al.
      VNS induced desynchronization in gamma bands correlates with positive clinical outcome in temporal lobe pharmacoresistant epilepsy.
      30 Hz, 30 s ON–5 min OFF
      Bodin et al
      • Bodin C.
      • Aubert S.
      • Daquin G.
      • et al.
      Responders to vagus nerve stimulation (VNS) in refractory epilepsy have reduced interictal cortical synchronicity on scalp EEG.
      0.5–2.5 mA, 30 Hz, 500 μs
      Bartolomei et al
      • Bartolomei F.
      • Bonini F.
      • Vidal E.
      • et al.
      How does vagal nerve stimulation (VNS) change EEG brain functional connectivity?.
      1.5–2 mA, 30 Hz, 30 s ON–500 s OFF
      Ravan et al
      • Ravan M.
      • Sabesan S.
      • D’Cruz O.
      On quantitative biomarkers of VNS therapy using EEG and ECG signals.
      >0.5 mA
      Stim, stimulation.
      Individual variability plays a role as well. The variability of the vagus nerve itself determines the activation profile of fibers throughout the nerve.
      • Helmers S.L.
      • Begnaud J.
      • Cowley A.
      • et al.
      Application of a computational model of vagus nerve stimulation.
      As for duty cycle, it was shown in freely moving rats that VNS applied with a rapid cycle (7 seconds on, 18 seconds off) was more robust and had a greater effect on hippocampal EEG than the standard cycle (30 seconds on, 300 seconds off).
      • Larsen L.E.
      • Wadman W.J.
      • Marinazzo D.
      • et al.
      Vagus nerve stimulation applied with a rapid cycle has more profound influence on hippocampal electrophysiology than a standard cycle.
      Other parameters, such as the pattern of stimulation itself
      • Szabó C.Á.
      • Salinas F.S.
      • Papanastassiou A.M.
      • et al.
      High-frequency burst vagal nerve simulation therapy in a natural primate model of genetic generalized epilepsy.
      and the timing of stimulation in relation to seizure onset, also play a key role. As shown by Contreras et al,
      • Contreras D.
      • Llinas R.
      Voltage-sensitive dye imaging of neocortical spatiotemporal dynamics to afferent activation frequency.
      neocortical activation is determined not only by the dynamic character of the input but also by the intrinsic dynamics of the cortical circuitry. The epileptic brain may not require the same stimulation all the time. Switching parameters gives rise to different and even opposite effects, as shown by the early EEG studies with frequency. Merely increasing the output current may not always be the right way to optimize the effect. Increasing from 0.25 to 1 mA gives rise to an increase in Fc, whereas a further increase from 1 to 1.5 mA leads to its decrease (Fig. 1). Indeed, excessive output current may prove deleterious. One hypothesis could be that response to VNS obeys an inverted U shape curve. This was reported in some studies on VNS and central plasticity
      • Morrison R.A.
      • Danaphongse T.T.
      • Abe S.T.
      • et al.
      High intensity VNS disrupts VNS-mediated plasticity in motor cortex.
      and hippocampal progenitor proliferation
      • Filipescu C.
      • Lagarde S.
      • Lambert I.
      • et al.
      The effect of medial pulvinar stimulation on temporal lobe seizures.
      and in a more recent study on parameters associated with clinical response in epilepsy.
      • Fahoum F.
      • Boffini M.
      • Kann L.
      • et al.
      VNS parameters for clinical response in epilepsy.
      Figure thumbnail gr1
      Figure 1Alterations in functional connectivity (h2) under different VNS parameter settings. The figure shows the nonlinear relationship between functional connectivity index (here h2 derived from intracerebral recordings) and VNS parameters. Increasing the stimulation amplitude from 0.25 to 1 mA gives rise to an increase in Fc, whereas a further increase from 1 to 1.5 mA leads to its decrease. Changing the frequency from 30 to 20 Hz or the pulse width from 250 to 500 ms decreases the Fc. Data derived from Bartolomei et al
      • Bartolomei F.
      • Bonini F.
      • Vidal E.
      • et al.
      How does vagal nerve stimulation (VNS) change EEG brain functional connectivity?.
      globally show a high variability across patients and plead for an individualized analysis of connectivity indexes to optimize VNS parameters in each patient.
      The nonlinear relationship between the alteration of parameters and functional connectivity not only highlights the tremendous complexity of the issue but also should prompt an analysis of the effect of each parameter individually and in a controlled way. An ongoing multicentric randomized controlled study called OPSTIMVAG is under way in France (study registration number: ISD RCB: 2020-A02657-32/SI: 20.10.26.53022). In the treatment group, the settings of parameters are determined on the basis of the PLI-based functional connectivity values. Furthermore, the effect may vary among patients and epilepsy type. With the advent of personalized medicine, a biomarker of functional connectivity would be very useful to set up the parameters on the basis of an objective and reproducible factor. It would be a smart way to shorten the trial-and-error period and may allow us to quickly identify nonresponders and provide guidance for these patients toward other strategies, such as DBS with innovative targets. Even though many studies clearly show that VNS reduces both functional connectivity (global interictal synchronization) and spatial synchronization, it is still unclear how this effect is obtained. It is likely that the desynchronizing effect of VNS derives from the alteration of the activity of brainstem nuclei such as the NTS that in relay strongly modifies the activity of the left thalamus, which then has widespread connections to many cortical areas (Fig. 2). Bilateral VNS, although still unexplored, could amplify the effect of VNS on functional connectivity by bringing into play the right-sided vagal network, in addition to the left.
      Figure thumbnail gr2
      Figure 2Main structures involved in the afferent vagal network.

      Conclusions

      The modulation of the vagal afferent network through stimulation by an implanted VNS device triggers a cascade of neurochemical and electrophysiological events that arise at the brainstem, then reach the limbic system and eventually the cortex. Increasing evidence obtained from surface EEG and depth recordings has shown that in responders, VNS is associated with a reduction in functional connectivity. Thus, it can be concluded that VNS can counteract specific epileptic networks, reducing their abnormally high connectivity through modulation of the vagal afferent network. The dismantlement of the individual role of each of the different parameters of VNS on functional connectivity metrics will undoubtedly be of the utmost importance to advance further.

      Authorship Statements

      Romain Carron wrote the original draft of the manuscript and edited its different versions. Paolo Roncon edited the document and designed Figure 2. Stanislas Lagarde, Maxine Dibue, Marc Zanello, and Fabrice Bartolomei reviewed and edited the different versions of the manuscript.

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