==== Front Front Neurosci Front Neurosci Front. Neurosci. Frontiers in Neuroscience 1662-4548 1662-453X Frontiers Media S.A. 10.3389/fnins.937.630.5798 Neuroscience Review "The Wandering Nerve Linking Heart and Mind" – The Complementary Role of Transcutaneous Vagus Nerve Stimulation in Modulating Neuro-Cardiovascular and Cognitive Performance Dolphin Helena 1 2 * Dukelow Tim 1 Finucane Ciaran 3 Commins Sean 4 McElwaine Paul 1 2 Kennelly Sean P. 1 2 1Department of Age-Related Healthcare, Tallaght University Hospital, Dublin, Ireland 2Department of Medical Gerontology, School of Medicine, Trinity College Dublin, Dublin, Ireland 3Department of Medical Physics, St James's Hospital, Dublin, Ireland 4Department of Psychology, Maynooth University, Maynooth, Ireland Edited by: Knut Asbjorn Hestad, Hedmark University of Applied Sciences, Norway Reviewed by: Lin Sørensen, University of Bergen, Norway; Guillaume T. Vallet, UMR 6024 Laboratoire de Psychologie Sociale et Cognitive (LAPSCO), France *Correspondence: Helena Dolphin, xyates@example.com This article was submitted to Autonomic Neuroscience, a section of the journal Frontiers in Neuroscience 16 6 2022 2384-27-31490317 3 2022 30 5 2022 Copyright © 2022 Dolphin, Dukelow, Finucane, Commins, McElwaine and Kennelly. 2022 Dolphin, Dukelow, Finucane, Commins, McElwaine and Kennelly https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. The vagus nerve is the longest nerve in the human body, providing afferent information about visceral sensation, integrity and somatic sensations to the CNS via brainstem nuclei to subcortical and cortical structures. Its efferent arm influences GI motility and secretion, cardiac ionotropy, chonotropy and heart rate variability, blood pressure responses, bronchoconstriction and modulates gag and cough responses via palatine and pharyngeal innervation. Vagus nerve stimulation has been utilized as a successful treatment for intractable epilepsy and treatment-resistant depression, and new non-invasive transcutaneous (t-VNS) devices offer equivalent therapeutic potential as invasive devices without the surgical risks. t-VNS offers exciting potential as a therapeutic intervention in cognitive decline and aging populations, classically affected by reduced cerebral perfusion by modulating both limbic and frontal cortical structures, regulating cerebral perfusion and improving parasympathetic modulation of the cardiovascular system. In this narrative review we summarize the research to date investigating the cognitive effects of VNS therapy, and its effects on neurocardiovascular stability. vagus nerve stimulation cognition neurocardiovascular control cerebral blood flow LC-NE system inhibitory control executive function Meath Foundation 10.13039/501100004162 ==== Body pmcIntroduction Vagus nerve stimulation (VNS) as a neurostimulation technique and has received renewed attention in recent years. Traditionally invasive VNS (iVNS) devices were sutured under the skin of the chest with a lateral left neck dissection undertaken to expose the left cervical vagus nerve and wrap a stimulating electrode around it. Each iVNS device is costly and up to 30% of patients have side effects post implantation (Morris and Mueller, 1999). Since the development in the early 2000s of peripheral stimulating devices that harness the vagus nerve's innervation of the skin of the external ear demonstrating efficacy in treating epilepsy, depression and headaches, interest in wider therapeutic potentials of this treatment have grown (Yap et al., 2020). Declining cognition associated with aging is a burgeoning global health crisis, with at least 152.8 million persons projected to have dementia worldwide by the year 2050 (Nichols et al., 2022). There are few effective treatments for cognitive decline and dementia, with no current cure (Cummings et al., 2021) and although the first disease modifying anti-amyloid agent has been licensed by the FDA (Steinbrook, 2021), more therapies are urgently needed to help alleviate the personal, societal and economic cost of increasing dementia diagnoses (Xu et al., 2017). Impaired cognition is associated with impaired autonomic function, specifically impaired parasympathetic measures of heart rate variability (HRV) (Forte et al., 2019; Cheng et al., 2022; Liu et al., 2022) likely reflective of the complex interplay between cognition and cardiac modulation, via the central autonomic network. Studies of patients with intractable epilepsy and treatment -resistant depression treated with iVNS devices showed signals indicating increased alertness and potentially cognitive improvements (Ghacibeh et al., 2006a; McGlone et al., 2008; Schevernels et al., 2016; Sun et al., 2017; van Bochove et al., 2018) and a small pilot study investigated iVNS devices in patients with Alzheimer's Disease with overall positive results (Sjögren et al., 2002; Merrill et al., 2006). Recent meta-analysis of t-VNS in young healthy adults has found an overall moderate effect especially for improved cognitive performance especially executive function (Ridgewell et al., 2021). However the neuroanatomical substrates of persons with treatment-resistant depression or epilepsy are likely both widely variable, and grossly different to both a young cognitively healthy adult and a person with mild cognitive impairment (MCI) or dementia and dedicated larger studies are required to investigate if t-VNS has therapeutic potential in this population. The purpose of this narrative review will be to outline the research to date investigating both cognitive outcomes of VNS in healthy and clinical populations, and the effect VNS has on HRV as a measure of autonomic tone. The mechanisms of action of VNS including neurotransmitter release, local increased cerebral blood flow and modulation of peripheral hemodynamics are discussed and future research recommendations outlined. Anatomy and Physiology of the Vagus Nerve The longest nerve in the body, the vagus nerve derives its name from the Latin for 'straying' or 'wandering.' Aptly named, the nerve has an extensive course, traveling from the medulla to the gut. The vagus nerve's function is to transmit information to and from the central nervous system (CNS) regarding control of the gastrointestinal, cardiovascular, and respiratory systems. It is comprised of approximately 80% afferent and 20% efferent fibers (Foley and Dubois, 1937; Agostini et al., 1957) including A, B and C fibers classified by conduction velocity (Erlanger and Gasser, 1937). Vagus neurons may involve visceral (cardiac, bronchopulmonary, gastrointestinal) or somatic (soft tissues, muscles of palate, pharynx) modulation. Afferent fibers are further sub classified as general visceral afferent, general somatic afferent, or special visceral afferent. Two efferent fiber types are recognized, namely special visceral efferent and general visceral efferent (see Table 1). Fibers connect centrally to four vagal nuclei; the nucleus of the solitary tract (NTS) and spinal trigeminal nucleus which contain vagal afferent fibers and the nucleus ambiguous and dorsal motor nucleus of the vagus (DMN) from where vagal efferent fibers leave (Rutecki, 1990; Berthoud and Neuhuber, 2000). TABLE 1 The constituent fibers of the vagus nerve. FIBER Aα Aβ Aδ B C Fiber diameter 13–20 mm 6–12 mm 1–5 mm 1–5 mm 0.4–2 mm Gross anatomical structure Large Large Large Small Small Main function afferent Somatic touch pain temperature Somatic touch Visceral: pain stretch chemical, temperature Visceral Visceral: pain stretch chemical, temperature Main function efferent Muscle tone Muscle preganglionic preganglionic preganglionic preganglionic Myelin + + + + − Threshold mA 0.02–0.2 mA 0.02–0.2 mA 0.02–0.2 mA 0.04–0.6 mA 0.3–6 mA Conduction velocity ms 8–120 ms 35–75 ms 3–30 ms 3–15 ms 0.5–2 ms Purported effect of VNS on EEG Synchronization Synchronization Synchronization Synchronization Desynchronization Adapted from Groves et al. (2005). Afferent vagus fibers enter the medulla at the level of the olive, and terminate primarily in the NTS (Beckstead and Norgren, 1979; Kalia and Sullivan, 1982). Each vagus nerve (VN) synapses bilaterally in the NTS; so vagal afferent information is processed bilaterally in the CNS (Henry, 2002). Second order afferent fibers from the NTS project most densely to the parabrachial nucleus of the pons (PBN) with the NTS also projecting to noradrenergic (locus coeruleus) and serotonergic (raphe nuclei) neuromodulatory systems (Rutecki, 1990; Saper, 2000). From here vagal information is relayed to a number of mostly subcortical structures, including the hypothalamus, the central nucleus of the amygdala, the bed nucleus of the stria terminalis, and the intralaminar thalamic nucleus. Vagal afferent information is also sent to the anterior insular cortex which communicates with more rostral regions of the cortex (orbital and ventrolateral prefrontal cortex) and also indirectly with the medial prefrontal cortex (Öngür and Price, 2000; Saleem et al., 2008). These central structures are part of the central autonomic network (CAN) which is thought to be the origin of autonomic, behavioral, cognitive, and endocrine responses, capable of modulating the functioning of the autonomic nervous system (ANS) via descending pathways projecting onto sympathetic pre-ganglionic neurons in the spinal cord and onto the DMN at the origin of vagal efferents (Benarroch, 1993). The central connections of the DMN are considerable, with afferent projections arising from sites including the NST, magnocellular paraventricular nuclei and several medullary nuclei (Roges et al., 1980; Hansen, 2019). Whilst a minority of efferent fibers connect centrally, most DMN fibers project to GI organs via parasympathetic ganglia located close to or in the walls of viscera. Further efferent fibers originate from the nucleus ambiguous (NA), a motor nucleus located in the reticular formation of the medulla which gives rise to preganglionic neurons innervating the heart and lungs (Llewellyn-Smith and Verberne, 2011) which exert a cardio-inhibitory effect mediated via the sinoatrial and atrioventricular ganglia (Massari et al., 1995; Gatti et al., 1996). The right vagus nerve mostly innervates the sinoatrial node (involved in the pacemaker function of the heart) whereas the left vagus is mostly thought to innervate the atrioventricular node (regulating the force of contraction of the cardiac myocytes with less influence over heart rate) however comprehensive human studies confirming this precise delineation are needed (Coote, 2013). The dorsal branchiomotor division of the NA is the site of origin of efferent fibers innervating striated muscle of the palate, pharynx, larynx and upper esophagus. See Figure 1 for a schematic representation of the VN fibers and central projections. FIGURE 1 Schematic representation of afferent and efferent fibers of the vagus nerve and central projections. History of Vagus Nerve Stimulation Vagus nerve stimulation was initially proposed as a therapeutic intervention in 1871 (Neftel, 1871) and a device was designed to stimulate bilateral vagus nerves in the late 19th century (Lanska, 2002). Preclinical studies in the 1930–1950s demonstrated via EEG signaling that VNS had cortical stimulating activity (Bailey and Bremer, 1938; Zanchetti et al., 1952), and could terminate canine seizures (Zabara, 1985, 1992). Invasive VNS (iVNS) received United States regulatory approval for the adjunctive treatment of refractory seizures in 1997 and for use in treatment resistant depression in 2005 (O'Reardon et al., 2006). However, given the invasive nature of iVNS (requiring general anesthesia, thoracic implantation of a battery generator, and neck dissection to attach stimulating electrodes to the left cervical vagus nerve), the concept of non-invasive VNS was proposed in 2000 whereby, drawing on evidence from studies of auricular acupuncture, it was postulated that transcutaneous vagal stimulation could represent a valuable tool in epilepsy treatment (Ventureyra, 2000). Non-invasive VNS involves using stimulating electrodes on the skin to excite afferent vagal fibers and can be performed via the ear (transcutaneous auricular VNS: t-VNS) or the neck (transcutaneous cervical VNS: tcVNS). For the purposes of this narrative review non-invasive VNS will refer to auricular t-VNS. The technique of t-VNS exploits the peripheral anatomy of the vagus nerve, activating vagal afferent projections through stimulation of the auricular branch of vagus nerve (ABVN) at the ear (Peuker and Filler, 2002; Mercante et al., 2018) see Figure 2 for a schematic representation of the anatomy of the ABVN and central structures it modulates. Anti-seizure efficacy equivalent to iVNS was demonstrated in preclinical studies before the feasibility and therapeutic significance of this technique in humans were demonstrated (Stefan et al., 2012) and evidence from multiple functional brain imaging studies confirms significant activation of central vagal projections via this non-invasive method (Kraus et al., 2013; Frangos et al., 2015; Yakunina et al., 2017; Badran et al., 2018a). FIGURE 2 Schematic diagram of innervation of ABVN and central projections, adapted with permission from Kaniusas et al. (2019). Transcutaneous auricular vagus nerve stimulation waveforms can be delivered at a variety of different parameter settings which vary frequency (Hz), amplitude (mA), pulse width (μs-msec) and duration of stimulation. It is currently being investigated as a therapeutic intervention for a variety of medical disorders including epilepsy, migraine and cluster headaches, tinnitus, atrial fibrillation, Parkinson's disease, schizophrenia, impaired glucose tolerance, obesity, and pain (Goadsby et al., 2014; Huang et al., 2014; Laqua et al., 2014; Hasan et al., 2015; Hyvarinen et al., 2015; Nesbitt et al., 2015; Stavrakis et al., 2015; Cakmak et al., 2017; Obst et al., 2020). There is particular interest in the evolving literature reporting the use of t-VNS in cognitive disorders (Broncel et al., 2020; Lam et al., 2021). Potential mechanisms of action include modulation of HRV, impacts on cerebral perfusion, and noradrenergic neuromodulation. The complementary role of vagus nerve stimulation in modulating neuro-cardiovascular and cognitive performance is explored in detail below. See Figure 2 for a schematic diagram of the area of innervation of the ABVN and its central projections. Cognitive Performance and Vagus Nerve Stimulation Brain imaging during t-VNS demonstrates strong activation of vagal projections to subcortical nuclei and frontal brain regions, i.e., superior frontal gyrus and medial frontal gyrus during stimulation (Kraus et al., 2013) (See below in "Mechanisms of Action" for further detailed discussion regarding the neuroanatomical structures modulated during VNS). Cognitive effects of both iVNS and t-VNS in both clinical populations and healthy volunteers will be examined under the following themes: Cognitive control, i.e., the non-automatic regulation of behavior to achieve a goal (Gonthier, 2014) a primarily executive function that involves suppression of goal-irrelevant stimuli via response and attention-inhibition (Tiego et al., 2018) and it primarily involves the lateral prefrontal cortex (Dixon, 2015); Language, both assessing categorical fluency a semantic memory language task involving the temporal lobe, and word recognition and retrieval which mostly involves episodic working memory, involving prefrontal cortex and medial temporal structures (Squire and Zola, 1998; Camina and Güell, 2017); Associative memory, a subcategory of declarative episodic memory and involves the ability to link disparate novel stimuli (Naveh-Benjamin, 2000); Emotion recognition as a subtype of cognition involves areas of the brain involved in perceiving social information including the medial prefrontal cortex and the orbitofrontal cortex (Bachmann et al., 2018) and regions implicated in emotional processing, including the cortical orbitofrontal cortex and the anterior cingulate cortex but also subcortical structures including the amygdala, hypothalamus, basal ganglia and the periaqueductal gray matter (van den Stock et al., 2011). Interest in the potential role of VNS as a cognitive enhancer started following a preclinical rodent study of an inhibitory-avoidance task. Subjects received a single exposure to a foot shock followed immediately by VNS or sham. Those undergoing true VNS stimulation had longer step times demonstrating enhanced avoidance and this effect was modulated by the intensity of the stimulus, with 0.4 mA being an effective level of stimulation and 0.2 and 0.8 mA having no significant effect (Clark et al., 1995). Subsequent in-human trials tested word recognition in patients with intractable epilepsy who had iVNS devices implanted 2–24 weeks prior to testing. The stimulation parameters were 30Hz, 0.5 xyates@example.com ms pulse width compared to an amplitude of 0.75–1 mA, and improved word recognition was only found in the group stimulated at the lower amplitude (Clark et al., 1999). These results paved the way for further investigation in this area as detailed below. Vagus Nerve Stimulation and Cognitive Control, i.e., Executive Function in Healthy Volunteers Inhibitory control is commonly measured using performance on tasks such as the Stroop, Eriksen Flanker (Flanker), and Simon tasks, i.e., forced-choice reaction time tasks that require participants to selectively attend and respond to target stimuli whilst ignoring goal-irrelevant distracting stimuli (Kornblum et al., 1990; MacLeod, 1991; Eriksen, 1995). Enhanced response times, as reflected by participants' ability to stop a process and change to another response simultaneously and sequentially, and increased post error slowing were demonstrated during t-VNS (Sellaro et al., 2015; Steenbergen et al., 2015). Post error slowing refers to appropriate slowing after negative feedback or unforeseen errors and is linked to the activity of the locus coeruleus–norepinephrine (LC–NE) system and therefore postulated to be enhanced by VNS. As with the above trials, there were fewer false alarms during a more challenging paradigm with t-VNS when working memory processes were simultaneously engaged (Beste et al., 2016) and improved response selection and control performance was demonstrated with t-VNS in a serial reaction time test in young volunteers (Jongkees et al., 2018). In a sequence learning paradigm, the presentation of so-called reversal trials is associated with longer response latencies as compared to non-reversal trials, a result attributable to the 'inhibition of return' type phenomenon. Inhibition of return refers to an inhibitory after-effect of attention whereby, following exogenous orientation of attention to a stimulus, processing of stimuli at this location is first facilitated and then inhibited (Wang et al., 2018). Jongkees et al. (2018) demonstrated that active t-VNS, as compared to sham stimulation in the context of a serial reaction time test, reduced reaction time for reversal trials, eliminating the inhibition of return like effect described above. In a similar experimental set up, increased attention, globally enhanced accuracy and reduced performance costs were demonstrated in a Stop-Change paradigm with t-VNS (Keute et al., 2020). Results in this area have not been uniformly positive. In a testing paradigm in healthy volunteers using higher than average amplitude settings (see Table 2) there were no improvements in a Stroop test, Modified Flanker test or a number/letter working memory task with t-VNS. Improved accuracy in a dimensional change card sorting task was however noted (Borges et al., 2020). Similar previous studies failed to show improved behavioral performance with t-VNS (Fischer et al., 2018; Ventura-Bort et al., 2018) however non-performance parameters, namely a frontal EEG signal (P3 amplitude) thought to change with response inhibition and higher salivary amylase levels, were noted in the intervention group (Ventura-Bort et al., 2018). Further studies investigating EEG amplitudes affected by t-VNS and cognitive control paradigms included one involving an acoustic rather than visual oddball paradigm. In this context, t-VNS augmented the P3 amplitude, and with random noise stimulation with t-VNS reaction times were reduced (Rufener et al., 2018). There are myriad potential reasons for replication challenges in this newly expanding area of research and may include stimulation parameter differences including lack of pre-testing active stimulation. TABLE 2 Cognition and VNS in healthy volunteer populations. COGNITION AND VNS: Healthy volunteers Stimulation Parameters Study iVNS/tVNS Hz mA Pulse width Time Population Task Outcome Steenbergen et al., 2015 tVNS 25Hz 0.5mA 200–300 μs 30 s blocks Healthy young adult volunteers n = 30 Stop change paradigm Enhanced response selection and faster response times when two actions executed in succession Sellaro et al., 2015 tVNS left outer auditory canal 25Hz 0.5 mA 200–300 μs 30 s blocks Healthy young adult volunteers n = 40 Modified Flanker test Increased post error slowing during active tVNS Jacobs et al., 2015 tVNS left external acoustic meatus 8Hz 5.0 mA 200 μs 17 min Healthy older adults avg age 60.5 n = 30 -Face name recognition task −15 word learning test -Digit span forward/backward -Verbal fluency test -Concept shifting task -Letter digit subtraction -Stroop color word test Higher number of accurate "hits" during tVNS for face name recognition Beste et al., 2016 tVNS left inner ear 25Hz 0.5 mA 200–300 μs 30 s on/30 s off Healthy young volunteers n = 51 Inhibitory control (go-no-go task) Fewer false alarms in the more challenging paradigm, i.e., when working memory processes also engaged Colzato et al., 2017 tVNS Left outer auditory canal 25Hz 0.5 mA 200–300 μs 30 s on/30 s off Healthy young volunteers n = 38 Emotion recognition Reading the mind in the Eyes test Enhanced emotion recognition for easy (not challenging) items suggesting it promoted the ability to decode salient social cues Fischer et al., 2018 tVNS 25Hz Avg 1.3 mA (0.4–3.3) 200–300 μs Continuous Healthy adult volunteers n = 21 -Adapted response conflict Simon task -Novelty oddball task No behavioral change noted Down-regulated N2 potential EEG reading Ventura-Bort et al., 2018 tVNS Left cymba conchae 25 Hz −1.3 mA (0.4–3.3) active −1.49 mA (0.6–4.8) sham 200–300 μs 28 min task 1 7 min task 2 Healthy young volunteers n = 21 -Novelty oddball task -number version of the Simon task -No difference with tVNS with difficult targets or novel stimuli -Difference between tVNS and sham stimulation (P3 amplitude) in EEG parameters for easy targets associated with larger increase in sAA levels after tVNS Rufener et al., 2018 tVNS Left cymba conchae 25Hz 0.5 mA 250 μs 30 s on/30 s off Started 90 min prior to task Healthy young volunteers n = 20 avg age 24.8 -Acoustic oddball paradigm (respond as quickly as possible whenever a target tone was detected) - tVNS increased EEG parameter P3 amplitude - Random noise stimulation reduced the reaction time Maharjan et al., 2018 tVNS at left ear both anterior (cymba conchae) and posterior of ear −80Hz −10Hz -No stim 10–15 mA 180 μs in square waveform 25–35 min lead in time Healthy adult males n = 18 Two olfactory tests (odor threshold test (OTT) and supra-threshold test (STT) High frequency (80Hz) VNS positively modulated olfactory performance in healthy participants and showed significant increase in NIRS recordings of the right hemispheric orbitofrontal cortex Colzato et al., 2018 tVNS left concha n = 40 sham left earlobe n = 40 25Hz 0.5 mA 200–300 μs 15 min lead in time Healthy young volunteers n = 80 (50 females, 30 males, mean age 20.96) Convergent and divergent thinking tasks -Fluency scores were significantly higher in the active tVNS group (able to generate more answers) -tVNS affected cognitive flexibility, i.e., participants could think of more different categories than sham Jongkees et al., 2018 tVNS left medial acoustic meatus 25Hz 0.5 mA 200–300 μs 30 s blocks 15 min lead in time Healthy young adult volunteers n = 40 Serial reaction time test Enhanced response selection process and action control performance Burger et al., 2019 tVNS Left cymba conchae 25Hz 0.5 mA 250 μs 30 s on/30 s off 10 min lead in time Healthy young volunteers n = 61 Computerized fear conditioning, fear generalization, and fear extinction paradigm No difference in physiological and declarative indices of fear between tVNS and sham conditions Mertens et al., 2020 tVNS cymba conchae 25Hz 0.5 mA for 16 0.54–0.57 mA for rest 250 μs 30 s during consolidation Healthy volunteers −n = 41 age avg 22.2 −n = 24 age avg 55.1 Word recognition task No effect on verbal word memory Giraudier et al., 2020 tVNS left cymba conchae (active) or left earlobe (sham) 25Hz Active 1.48 mA ± 0.59 sham 1.31 mA ± 0.5 200–300 μs 30 s on/30 s off Stimulated for 23 min 5 min before 13 min during and 5 in after lexical decision task Healthy volunteers −n = 60 −46 = female -avg age 23.45 Lexical decision task and recognition memory task of selected German words (either emotionally charged or neutral) Also – BP, HR and sAA Overall no effect of tVNS on task performance or word recognition memory – however higher recollection based memory performance was observed during tVNS than sham Borges et al., 2020 tVNS 25Hz 2.19 mA (±0.93) 200–300 μs 30 s on/30 s off 4 min lead in time Healthy adult volunteers n = 35 -Modified Flanker test -Spatial Stroop task -Number/Letter task -Dimensional change card sorting task Only the DCCS shows improvement with tVNS Keute et al., 2020 tVNS left cymba conchae 25Hz 2.37 mA (±0.16) 200 μs 30 s on/30 s off 30 min lead in time Healthy adult volunteers n = 22 Stop Change paradigm (go-no-go task) Globally enhanced accuracy across conditions -Reduced the performance costs of go/change response conflicts -increased attention Sun et al., 2021 Study 1 tVNS Left cymba conchae Sham: no stimulation 25Hz Online 0.7 ± 0.36 mA Offline 0.69 ± 0.38 mA Sham 0.73 ± 0.27 mA 500 μs 30 s on and 30 s off 25 min pre task (offline) or 15 min during task (online) Healthy young volunteer n = 46 (25 female, average age 20.39 ± 1.96) Spatial stimuli task Four blocks with 72 experiment trials in each block Offline (pre-task stim for 25 min) tVNS significantly increased hits in spatial 3-back task but not rejections or reaction times Sun et al., 2021 Study 2 tVNS left cymba conchae sham; active stimulation of earlobe 25 Hz Active: 0.74 mA ± 0.37 Sham: 0.84 mA ± 0.39 500 μs 30 s on and 30 s off Both 25 min stimulation Healthy young volunteers n = 58 (24 female, average age 19.9 ± 1.49) Spatial stimuli task Four blocks with 72 experiment trials in each block Offline (pre- task stimulation for 25 min) tVNS improved hits but not correct rejections or reaction time of accurate trials in spatial WM performance Kaan et al., 2021 tVNS Left tragus 25Hz 1–6 mA 250 μs Healthy young volunteers n = 33 control n = 29 experiment -Word retention: – non-rhyming, easily separable words -rhyming words tVNS was associated with higher accuracy but only when the items are phonologically similar McIntire et al., 2021 Cervical VNS via gammaCore device cVNS vs. sham (n = 20 both groups) 25Hz Not available Not available 2 min cycles Healthy young military recruits n = 40 (M:F 33:7) avg age 28 ± 6 years 34 h of continuous sleep deprivation Air Force–Multi-Attribute Task Battery (AF-MATB); simultaneously monitor and respond to four separate cognitive process tasks: a visual system alert monitoring task, a visual–motor tracking task, an auditory communication monitoring task and a management task cVNS significantly improved objective arousal and multitasking for as long as 24-h post-stimulation Subjective ratings of fatigue also improved The most recent studies in this area have involved a spatial stimulation and response inhibition multitask, with notable improved results in accuracy with 25 min pre-assessment t-VNS stimulation (Sun et al., 2021) and improved objective attention, arousal and multitasking ability in sleep deprived military personnel (McIntire et al., 2021). Vagus Nerve Stimulation and Language in Healthy Volunteers Fluency scores in healthy volunteers during a convergent and divergent thinking task were significantly higher during active t-VNS at the left conchae, and categorical flexibility (i.e., participants' ability to think of more and varied categories of nouns) was also significantly improved (Colzato et al., 2018). However, an experimental design investigating the difference in effect of t-VNS on word recognition memory in young compared to older volunteers (average age 22.2 and 55.1) whereby t-VNS was delivered for 30 s during the consolidation phase of a word recognition memory task showed no improvement in accuracy scores for immediate recall or delayed recognition in both age groups (Mertens et al., 2020). Possible reasons for this may be that 30 s of t-VNS may be insufficient for a non-invasive device to effectively stimulate the vagal afferent pathway, that longer and more repetitive stimulation of the vagus nerve might be required to effectively modulate hippocampal processes via synaptic plasticity. A recent investigation of word retention, stimulating the left tragus with t-VNS at again similar parameters but wider amplitude found improved accuracy in word retention but only in items that rhymed, i.e., were phonologically similar (Kaan et al., 2021). Vagus Nerve Stimulation and Associative Memory in Healthy Volunteers Transcutaneous auricular vagus nerve stimulation has been tested in a group of healthy older adults to determine the technique's impact on performance in a face-name association task (Jacobs et al., 2015). VNS was employed in the encoding and consolidation phases of the task with active and sham stimulation compared in a randomized crossover design. Active t-VNS was demonstrated to increase the number of 'hits' on the memory task. Stimulation parameters employed differed somewhat from those seen in the broader literature concerning the impact of VNS on cognitive function. A stimulation intensity of 5.0 mA, a pulse width of 0.2 ms, and a frequency of 8Hz were utilized, citing previous functional and electrophysiological studies (Kraus et al., 2007; Polak et al., 2009). A stimulation lead in time of 17 min was also utilized, which has been theorized to be beneficial for targeted neuronal plasticity (Hays et al., 2013). Vagus Nerve Stimulation and Emotion Recognition in Healthy Volunteers This ability to recognize different emotions in others was investigated and found to be enhanced by t-VNS at the left outer auditory canal in young healthy adults but only for objectively easy, not challenging, items via the Reading the Mind in the Eyes test (Colzato et al., 2017). Subsequent investigations of fear conditioning and extinction in young volunteers, after previous positive studies, found that t-VNS at the left cymba conchae did not infer any difference in physiological or declarative indices of fear or improve fear extinction (Burger et al., 2019). Further studies are needed in this area to elucidate if t-VNS has a specific beneficial effect, given its ability to modulate both cortical and subcortical structures. See Table 2 for parameters settings and outcomes in trials of VNS in healthy volunteers. Vagus Nerve Stimulation and Cognition in Clinical Populations In this section we highlight the studies to date investigating the cognitive effects of VNS on clinical populations, mostly with treatment-resistant depression or epilepsy. Many studies investigating the role of VNS in clinical populations has involved invasive VNS (iVNS). A further potential confounder is the impact some of these underlying pathologies have on cognition, the altered medial temporal anatomy especially in cases of epilepsy and the medications used to manage these conditions can also have deleterious effects on cognition. Vagus Nerve Stimulation and Cognitive Control, i.e., Executive Function in Clinical Populations Vagus nerve stimulation has been shown experimentally to have mixed results when examining the subdomain of decision making, specifically on the Iowa Gambling Task (IGT). In one paradigm eleven patients with refractory epilepsy and iVNS devices completed a gambling task involving control and experimental trials with active VNS synchronized to stimulate in the latter. Whilst improved performance was demonstrated in the earlier part of the task, this trend was reversed later in the experimental trial with active stimulation trending toward being detrimental to performance (Martin et al., 2004). Technical failure and a cumulative stimulation-dose effect were amongst the potential explanations proposed by the authors to explain this phenomenon. Decision-making may depend on intact working memory (Bechara and Martin, 2004) and several studies have demonstrated working memory involvement in the IGT (Bagneux et al., 2013) which may have affected results in this study. Working memory refers to a cognitive process that provides temporary storage and manipulation of the information necessary for complex cognitive tasks (Baddeley, 2010). Literature concerning the impact of acutely administered VNS on working memory is promising but limited to a small number of studies. In one experimental paradigm, twenty participants with poorly controlled epilepsy were required to perform a computer-based Executive-Reaction Time (Executive RT) Test, wherein ability to memorize and store the orientation of a triangle and indicate its position in response to a go signal were assessed whilst VNS was delivered in a cyclic fashion. Active iVNS stimulation was associated with fewer errors in the subtask relying on working memory (Sun et al., 2017). The effect of active iVNS on response inhibition was also assessed by employing a classic stop-signal task in participants with refractory epilepsy (Schevernels et al., 2016). Quicker response inhibition has been demonstrated during active stimulation in patients who had previously shown a larger therapeutic effect of VNS. The beneficial effects of VNS on cognitive control may be maximally demonstrated in so-called 'VNS responders' (for the primary clinical indication) as demonstrated by patients with iVNS devices who undertook the Eriksen Flanker task during both VNS 'on' and 'off' stimulation. Only those deemed VNS responders (i.e., those whose seizure frequency had decreased by >50% post-device implantation) had demonstrable improved reaction times and reduced distractor interference during active stimulation (van Bochove et al., 2018). There is a subcategory of patients with refractory epilepsy who do not respond to iVNS therapy, i.e., do not have seizure reduction of 50%, and deemed "non-responders." It is notable that a current output of 2.28 mA was utilized in the VNS "responder" group and it's possible that, in keeping with previous studies examining optimal amplitude for stimulation, that the higher amplitudes employed exceeded that at which cognitive control is optimized for the iVNS "non-responders." Further research is needed in this area in particular regarding stimulation parameters and iVNS responders. Vagus Nerve Stimulation and Language in Clinical Populations In the first study of its kind, building on previous preclinical research, the impact of iVNS on word retrieval memory was assessed via an experimental protocol whereby participants with iVNS devices inserted for epilepsy control, were required to read a series of paragraphs, and subsequently identify words that were highlighted in the text. The study population comprised two groups of patients who were administered active (0.5–1.5 mA) or sham VNS, delivered 2-min after learning in the memory consolidation phase. An inverted U-shaped relationship was demonstrated regarding stimulus intensity and modulation of cognitive performance, with memory enhancing effects demonstrated only at moderate intensities, namely 0.5 mA (Clark et al., 1999). These results were in part corroborated by a subsequent study which employed higher stimulation intensities (>1.0 mA) and failed to demonstrate enhancement of verbal recognition memory, in fact demonstrating a reversible deterioration in figural memory (Helmstaedter et al., 2001). However, study design may have impacted cognitive outcomes here as delivery of stimulation was not restricted to the consolidation period. The propensity for iVNS to positively impact word retrieval memory in a population of patients being treated with iVNS for intractable epilepsy was highlighted again in 2006 whereby the impact of iVNS on performance in the Hopkins Verbal Learning Test was assessed, demonstrating a significant improvement in word retention when active (amplitude 0.5 mA) as opposed to sham stimulation was applied during memory consolidation (Ghacibeh et al., 2006b). Vagus Nerve Stimulation and Emotional Recognition in Clinical Populations The effect of t-VNS on participants' ability to recognize facial emotions in three experimental paradigms (graded presentation, static images and in a go-no-go task) was assessed in a group of adolescents diagnosed with major depressive disorder (MDD). In non-depressed controls t-VNS delivered at 1Hz, 0.5 mA 30 s block with 15 min lead in time, demonstrated enhanced recognition of emotions but notably led to a significant decrease in the ability of those with MDD to recognize sad emotions (Koenig et al., 2021). See Table 3 for parameters settings and outcomes in trials of VNS in clinical populations and please see below "VNS, cognition and HRV" for a discussion of VNS in Alzheimer's disease. TABLE 3 VNS and cognition in clinical populations. COGNITION AND VNS: Clinical Populations Stimulation Parameters Study iVNS/tVNS Hz mA Pulse width Time Population Task Outcome Clark et al., 1999 iVNS 2–24/52 post implantation 30Hz −0.5 mA −0.75–1.5 mA 0.5 ms 30 s Intractable epilepsy n = 10 Word recognition task Improved word recognition memory only when 0.5 mA delivered post reading Sjögren et al., 2002 iVNS Assessed at 3 and 6 months 20Hz 0.25 mA, increased 0.25 mA increments over 2 weeks then fixed 500 μs 30 s followed by 5 min pause Probable Alzheimer's n = 10 age 67 ± 7.6 8 women 2 men Median change in ADAS-cog Median change in MMSE after 3 and 6/12 Depression, behavior and QOL variables After 6/12 8 of 10 patients showed improvement from 3/12 ADAS-cog scores After 6/12 7 of 10 patients improved MMSE score by average 2.5 points No change in other variables Martin et al., 2004 iVNS 30Hz 0.5 mA 500 μs 60 s Intractable epilepsy n = 11 Iowa Gambling Task Conflicting results, deleterious at higher doses Merrill et al., 2006 iVNS At least 1 year of VNS treatment 20Hz 0.25 mA, increased in 0.25 mA increments over 2 weeks then fixed 500 μs 30 s followed by 5 min pause Probable Alzheimer's n = 17 (age 63 range 57–81) 11 women 6 men Median change in ADAS-cog Median change in MMSE after 1 year Depression, behavior and QOL variables At 1 year, 41% had improvement or no decline from baseline on ADAS-cog 70% had improvement or no decline on MMSE No change in other variables Helmstaedter et al., 2001 iVNS 5–7/12 post implantation 30Hz Mean 1.75 mA (range 1–2.5) 500 μs 30 s–4.5 min Intractable Epilepsy n = 11 Word recognition task Design recognition task Deterioration in figural recognition memory Dodrill and Morris, 2001 iVNS 12–16/52 after implantation 30 Hz in high stim group 1 Hz in low stim group Avg 1.3 mA in high simulation group Avg 1.2 mA in low stimulation group 500 μs 130 μs 30 s on every 5 min 30 s on every 3 h Intractable Epilepsy n = 160 Wonderlic personell test, Stroop test, Digit cancelation, Symbol Digit Modalities No significant changes were noted in the cognitive tests in low or high stimulation Ghacibeh et al., 2006b iVNS >3/12 post implantation X 0.5 mA x 30 s Intractable Epilepsy n = 10 Hopkins verbal learning test Improved retention index McGlone et al., 2008 iVNS 12/12 post implantation 30 Hz 0.5–3 mA avg 1.72 ± 0.53 500 μs 30 s every 5 min Intractable epilepsy n = 16 Memory Observation Questionnaire Improved subjective and objective memory scores compared to baseline, but similar to medical management Schevernels et al., 2016 iVNS >18/12 post implantation Avg 25 (20–30) Avg 2.3 mA (0.75–3.0) Avg 431 μs (130–500 μs) 7 s on/ 18 s off Intractable epilepsy n = 20 Stop signal task VNS responders demonstrated quicker response inhibition Sun et al., 2017 iVNS 2–130 months post implantation 30Hz 1.5–1.75 mA 250 μs 30 s on/48 s off Intractable epilepsy n = 20 Executive reaction time test (go-no-go task) Improved working memory (only when 3 participants with cognitive impairment removed) van Bochove et al., 2018 iVNS 20 or 30 Hz Avg 2.28 mA (0.75–3.0) 250 μs or 500 μs 7 s on/ 18 s off Intractable epilepsy n = 17 Eriksen Flanker task VNS responders demonstrated improved reaction times and decreased distraction interference Koenig et al., 2021 tVNS Left conchae 1Hz 0.5 mA 250 μs 30 s on/30 s off 15 min lead in time -Adolescents with major depressive disorder n = 33 control group: adolescents with headache n = 30 Facial emotional recognition in three tests 1. As a graded presentation 2. As static images 3. in a go – no -go task -In non-depressed controls tVNS enhances the general ability to recognize emotions -tVNS specifically led to a decrease in the recognition of sad emotions in patients with MDD Linking Brain and Heart: Potential Mechanisms of Action of Vagus Nerve Stimulation-Mediated Cognitive Enhancement There are many potential mechanisms through which VNS may exert its cognitive enhancing effects, including direct neurotransmitter release, increased cerebral perfusion to discreet neuroanatomical structures, reduced neuro-inflammation and via modulation of peripheral hemodynamics. For the purposes of this narrative review, we will analyze the link between cerebral blood flow, cerebral autoregulation and cardiac modulation. Beyond the scope of this review is how t-VNS may therapeutically affect the inflammatory cascade via activating the cholinergic anti-inflammatory pathway and the beneficial effects this may have in aging populations. Mechanism of Action: Vagus Nerve Stimulation and Local Neurotransmitter Release The main neurotransmitters centrally released via the afferent projections of the vagus nerve are thought to be GABA and Norepinephrine (NE). For a comprehensive review of the preclinical and clinical studies detailing the evidence supporting the modulation of these neurotransmitters during iVNS and t-VNS see (Colzato and Beste, 2020). As the primary inhibitory neurotransmitter in the brain, higher levels of GABA decrease cortical excitability, and is the accepted proposed method for VNS' anti-seizure efficacy. It has been suggested that increased cortical inhibition due to high GABA levels can sharpen task-relevant representations in the cortex and inhibit competing responses, thereby facilitating response selection and inhibition processes (Munakata et al., 2011; de la Vega et al., 2014). Norepinephrine is a crucial neurotransmitter modulating arousal and attention, and is primarily released via the locus coeruleus (LC). There are two distinct modes of LC firing that are associated with equally distinct modes of attentional strategy. Connections with the orbitofrontal cortex and anterior cingulate cortex are thought to drive the LC-NE system into one of these two stable states of activity, a high tonic (sustained) mode or a phasic (bursting) mode accompanied by moderate tonic activity (Aston-Jones and Cohen, 2005). This switching of attentional state via tonic LC activity is thought to result in a flexible attentional system that allows cycling between behaviors to find and meet task demands in one's environment, i.e., the adaptive gain theory (Aston-Jones and Cohen, 2005). Interestingly, and similar to the effects noted with iVNS stimulation levels and responses by Clark et al. (1995), moderate levels of NE augment prefrontal cortex function, whereas high and low concentrations of NE impair function, i.e., NE exhibits an inverted-U relationship between LC-NE activity and optimal performance on attention tasks (Berridge and Waterhouse, 2003). However, in general as NE levels rise executive function improves, likely via enhanced activation of the prefrontal cortex and frontoparietal control network (Xing et al., 2016; Unsworth and Robison, 2017). Inhibitory control for action cancelation is specifically enhanced with noradrenergic modulation, likely via this prefrontal cortical network (Chambers et al., 2009; Duann et al., 2009). Older adults with more dense LC innervation (i.e., higher neuromelanin MRI contrast) had overall better performance on a reversal memory tasks (Hämmerer et al., 2018) and had improved cognitive reserve (Clewett et al., 2016). Similarly in a post-mortem study of patients with Alzheimer's disease, lower LC cell integrity and greater cortical tangle density was associated with greater tau burden beyond the medial temporal lobes and worsening memory decline, identifying LC integrity as a promising indicator of initial AD-related processes (Jacobs et al., 2021). Studies have also demonstrated a decline in GABA concentration in frontal and parietal regions in aging populations, areas crucial for cognitive control (Gao et al., 2013; Porges et al., 2017). NE and GABA may in fact work synergistically to facilitate executive functioning; GABA by encouraging response inhibition of task irrelevant stimuli and NE via the LC-NE system increasing frontal NE release and thus executive functioning (Ridgewell et al., 2021). Mechanism of Action: Vagus Nerve Stimulation Increases Cerebral Perfusion Cerebral autoregulation is the phenomenon by which the brain receives the same cerebral blood flow (CBF) despite variations in perfusion pressure. The aim of autoregulation is to protect the brain against hypoxia and edema as a result of decreased or critically high arterial blood pressures respectively. Multiple factors physiologically modify autoregulation including blood CO2 levels, hypoxia etc. While still controversial, the ANS may play a prominent role in cerebral autoregulation in response to such stimuli, inducing vasodilation or constriction, and parasympathetic and sympathetic nerves are anatomically located in the same perineural sheath innervating cerebral arteries (Tamayo and Siepmann, 2021). The means by which VNS exerts its cognitive enhancing effect is probably multimodal, however modulating CBF is likely a crucial factor. Multiple modalities have been utilized to assess for CBF changes due to vagus nerve stimulation, including position emission tomography (PET), functional magnetic resonance imaging (fMRI) and single photon emission computed tomography (SPECT) studies and trials of patients with iVNS treatment for epilepsy and depression have demonstrated a variety of CBF modulatory effects at specific cortical and subcortical areas. Increased CBF at the orbitofrontal cortex (Henry et al., 1998; Bohning et al., 2001; Lomarev et al., 2002; Mu et al., 2004; Vonck et al., 2008), temporal lobe (Ko et al., 1996; Lomarev et al., 2002; Liu et al., 2003; Vonck et al., 2008; Conway et al., 2012), insular cortex (Liu and Hu, 1988; Henry et al., 1998, 2004), bilateral frontal lobes (Sucholeiki et al., 2002), left dorsolateral prefrontal cortex (Kosel et al., 2011) and subcortical structures including thalamus, hypothalamus, basal ganglia and other nuclei (Narayanan et al., 2002; Sucholeiki et al., 2002; Conway et al., 2012) has been observed. For a comprehensive review see Chae et al. (2003). Notably analysis undertaken during acute iVNS has noted bilateral decreased hippocampal CBF (Henry et al., 1998; Mu et al., 2004; Vonck et al., 2008). This has been replicated in t-VNS functional imaging studies which have confirmed stimulation and increased CBF at vagally innervated brain regions during auricular t-VNS and notably decreased perfusion at hippocampal regions (Kraus et al., 2007, 2013; Frangos and Komisaruk, 2017). T-VNS has also demonstrated efficacy in increasing arousal in comatose patients who respond to auditory signaling and again the brain regions noted on fMRI to be activated were similar to previous iVNS studies, including left superior temporal gyrus, left prefrontal cortex, left insular cortex, left middle frontal gyrus among other cortical and subcortical structures (Yu et al., 2021). It is worth considering that intermittently stimulating neurons at different frequencies produces drastically different changes in neuronal behavior with low frequency stimulation inducing long term depression (LTD) and less connectivity while intermittent high frequency stimulation produces long term potentiation (LTP) and increased signaling (Lomarev et al., 2002; Kealy and Commins, 2010). Therefore acute VNS stimulates brain regions mostly involved in alertness and frontal processing, whereas chronic stimulation may improve LTP in classic memory-associated regions, including the hippocampus. Evidence for this can be seen in preclinical studies (Zuo et al., 2007) but also significant increases in hippocampal gray matter volume over time has been observed in patients with iVNS devices inserted for treatment-resistant depression (Perini et al., 2017). More recently, Near Infrared Spectroscopy (NIRS) has been utilized to monitor cerebral blood flow and increased frontal perfusion in patients with epilepsy was noted during iVNS when paired with a cognitive task (Kunii et al., 2021). Both dementia and even its prodromal stage, MCI, are characterized by a reduction in cerebral blood flow (Mazza et al., 2011; Sierra-Marcos, 2017). A meta-analysis of twenty-six studies investigating CBF in MCI found overall reduced tissue oxygenation, CBF and velocity in MCI compared to healthy controls (Beishon et al., 2017) and studies are underway investigating the CBF changes that may occur with cognitive stimulation in MCI and dementia (Beishon et al., 2019). Similar findings have been noted in patients with Alzheimer's disease, with reduced CBF in many cortical regions including temporal (Sandson et al., 1996; Alsop et al., 2000; Asllani et al., 2008; Yoshiura et al., 2009; Ding et al., 2014) parietal (Alsop et al., 2000; Johnson et al., 2005) and other regions including precuneus, frontal and posterior cingulate cortex (Alsop et al., 2008; Yoshiura et al., 2009). Mechanism of Action: Vagus Nerve Stimulation Modulates Peripheral Hemodynamics As well as modulating central neurotransmitter release and cerebral blood flow, VNS has been shown to have positive peripheral modulatory effects in pathological states characterized by impaired autonomic regulation including postural orthostatic tachycardia syndrome (POTS) (Petelin Gadze et al., 2018) specifically patients with POTS and impaired vagal cardiac control, as defined by reduced HRV (Jacob et al., 2019). T-VNS has also shown benefits in modulating blood pressure in induced orthostatic hypotension (Tobaldini et al., 2019). These studies suggest VNS may have a role in positively manipulating the peripheral baroreceptor-reflex and thus cerebral autoregulation, and potentially may improve cortical perfusion via this route, however further dedicated studies are required to precisely delineate this relationship. Vagus Nerve Stimulation and Heart Rate Variability Heart rate variability analysis can be performed via a variety of approaches and is based on the extrapolation of time intervals between each R wave peak (Shaffer and Ginsberg, 2017), discounting any ectopic beats or arrhythmias, e.g., atrial fibrillation. The most commonly applied methods to determine HRV are time-domain analysis and frequency/spectral analysis. Indices deriving from the time domain analysis quantify the amount of variance in the selected inter-beat interval employing statistical measures, such as the standard deviation of the normal beat intervals (SDNN) and the root mean square of successive differences between normal beats (RMSSD) (Shaffer et al., 2014). The spectral analysis of HRV identifies oscillatory rhythms that occur in specific frequency ranges. Three main components of the spectrums can be identified as: the very low frequency band (VLF), below 0.04 Hz, likely influenced by thermoregulatory mechanisms and circadian rhythms; the low-frequency band (LF) between 0.04 and 0.15 Hz in humans, a marker influenced by baroreflex (Furlan et al., 2019) sympathetic and parasympathetic modulation; the high-frequency band (HF) in the range from 0.15 to 0.4 Hz, a marker of vagal modulation that is influenced by respiratory activity (Montano et al., 2009; Shaffer et al., 2014). One of the limitations of HRV analysis is high within and between individual variability, which may be reduced by longer measurement intervals, i.e., 24 h but which is resultantly harder to process. For a comprehensive review on the various indices please see Merrick et al. (2017). The ANS influences cardiac beat-to-beat interval length in response to several factors. The sympathetic and parasympathetic systems are the principal rapidly reacting systems that control heart rate. The two systems have different latency periods with sympathetic effects on heart rate slower than parasympathetic (Warner and Cox, 1962; Pickering and Davies, 1973; Koizumi et al., 1983) i.e., the parasympathetic system has the ability to alter heart rate within 1–2 beats, while sympathetic effects take up to 10
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