Heart rate variability, the vagus and calm.
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826 to 850 of 1,007Norepinephrine and serotonin are required for vagus nerve stimulation directed cortical plasticity.
Vagus nerve stimulation (VNS) paired with forelimb training drives robust, specific reorganization of movement representations in the motor cortex. This effect is hypothesized to be mediated by VNS-dependent engagement of neuromodulatory networks. VNS influences activity in the locus coeruleus (LC) and dorsal raphe nucleus (DRN), but the involvement of these neuromodulatory networks in VNS-directed plasticity is unknown. We tested the hypothesis that cortical norepinephrine and serotonin are required for VNS-dependent enhancement of motor cortex plasticity. Rats were trained on a lever pressing task emphasizing proximal forelimb use. Once proficient, all rats received a surgically implanted vagus nerve cuff and cortical injections of either immunotoxins to deplete serotonin or norepinephrine, or vehicle control. Following surgical recovery, rats received half second bursts of 0.8 mA or s…
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Modulation of neuroinflammation and memory dysfunction using percutaneous vagus nerve stimulation in mice.
Background: The vagus nerve is involved in regulating immunity and resolving inflammation. Current strategies aimed at modulating neuroinflammation and cognitive decline, in many cases, are limited and ineffective.
Objective: We sought to develop a minimally invasive, targeted, vagus nerve stimulation approach (pVNS), and we tested its efficacy with respect to microglial activation and amelioration of cognitive dysfunction following lipopolysaccharide (LPS) endotoxemia in mice.
Methods: We stimulated the cervical vagus nerve in mice using an ultrasound-guided needle electrode under sevoflurane anesthesia. The concentric bipolar needle electrode was percutaneously placed adjacent to the carotid sheath and stimulation was verified in real-time using bradycardia as a biomarker. Activation of vagal fibers was confirmed with immunostaining in relevant brainstem structures, including the dorsa…
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Non-invasive vagus nerve stimulation reduces blood-brain barrier disruption in a rat model of ischemic stroke.
Background: Vagus nerve stimulation (VNS) significantly reduces infarct volume in rat models of cerebral ischemia, but the mechanism of this protective effect remains open.
Hypothesis: This study tested the hypothesis that non-invasive VNS (nVNS), during transient middle cerebral artery occlusion (MCAO), protects the blood-brain barrier (BBB), leading to reduced infarct size in ischemic brain.
Methods: Spontaneous hypertensive rats (SHRs) were subjected to a 90 min MCAO. nVNS treated rats received 5 stimulations (duration: 2 min; every 10 min) on the skin overlying the cervical vagus nerve in the neck beginning 30 min after MCAO onset. Control rats received the same stimulations on the quadriceps femoris muscle. Twenty-four hours after MCAO onset, MRI and immunohistochemistry (IHC) were performed for analyses of infarct size and BBB leakage.
Results: Compared with the control group, anat…
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Noble LJ, Gonzalez IJ, Meruva VB, Callahan KA, Belfort BD, Ramanathan KR, Meyers E, Kilgard MP, Rennaker RL, McIntyre CK (2017)MEDLINE-indexed journal, not yet read by usTranslational psychiatry90 citations Effects of vagus nerve stimulation on extinction of conditioned fear and post-traumatic stress disorder symptoms in rats.
Exposure-based therapies help patients with post-traumatic stress disorder (PTSD) to extinguish conditioned fear of trauma reminders. However, controlled laboratory studies indicate that PTSD patients do not extinguish conditioned fear as well as healthy controls, and exposure therapy has high failure and dropout rates. The present study examined whether vagus nerve stimulation (VNS) augments extinction of conditioned fear and attenuates PTSD-like symptoms in an animal model of PTSD. To model PTSD, rats were subjected to a single prolonged stress (SPS) protocol, which consisted of restraint, forced swim, loss of consciousness, and 1 week of social isolation. Like PTSD patients, rats subjected to SPS show impaired extinction of conditioned fear. The SPS procedure was followed, 1 week later, by auditory fear conditioning (AFC) and extinction. VNS or sham stimulation was administered during…
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Vagus nerve stimulation improves working memory performance.
Vagus nerve stimulation (VNS) is used for treating refractory epilepsy and major depression. While the impact of this treatment on seizures has been established, its impact on human cognition remains equivocal. The goal of this study is to elucidate the immediate effects of vagus nerve stimulation on attention, cognition, and emotional reactivity in patients with epilepsy. Twenty patients (12 male and 8 female; 45 ± 13 years old) treated with VNS due to refractory epilepsy participated in the study. Subjects performed a computer-based test of executive functions embedded with emotional distractors while their brain activity was recorded with electroencephalography. Subjects' cognitive performance, early visual event-related potential N1, and frontal alpha asymmetry were studied when cyclic vagus nerve stimulation was on and when it was off. We found that vagus nerve stimulation improved …
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The genesis and presentation of anxiety in disorders of autonomic overexcitation.
Introduction: We investigated the genesis and presentation of previously-reported anxiety in disorders of autonomic overexcitation in relation to interoception, body vigilance and trauma to test our hypothesis that patients with the postural tachycardia syndrome (PoTS), vasovagal syncope (VVS) and essential hyperhidrosis (EH) represent atypical anxiety phenotypes in whom affective symptoms are more related to apprehension and vigilance of physiological (interoceptive) feedback than neurotic or trauma-related factors.
Methods: The Anxiety Sensitivity Index, Body Vigilance Scale, Self-consciousness Scale, Childhood Traumatic Events Scale and heartbeat tracking tasks were completed by 23 healthy controls, 21 PoTS, 20 EH and 20 VVS patients. Interoceptive accuracy (IA) was assessed during supine rest (9min), isometric exercise (3min), cold pressor (90s) and head up tilt (HUT) (9min).
Results…
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Reorganization of Motor Cortex by Vagus Nerve Stimulation Requires Cholinergic Innervation.
Background: Vagus nerve stimulation (VNS) paired with forelimb training drives robust, specific reorganization of movement representations in the motor cortex. The mechanisms that underlie VNS-dependent enhancement of map plasticity are largely unknown. The cholinergic nucleus basalis (NB) is a critical substrate in cortical plasticity, and several studies suggest that VNS activates cholinergic circuitry.
Objective: We examined whether the NB is required for VNS-dependent enhancement of map plasticity in the motor cortex.
Methods: Rats were trained to perform a lever pressing task and then received injections of the immunotoxin 192-IgG-saporin to selectively lesion cholinergic neurons of the NB. After lesion, rats underwent five days of motor training during which VNS was paired with successful trials. At the conclusion of behavioral training, intracortical microstimulation was used to d…
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Cortical Map Plasticity as a Function of Vagus Nerve Stimulation Intensity.
Background: Pairing sensory or motor events with vagus nerve stimulation (VNS) can reorganize sensory or motor cortex. Repeatedly pairing a tone with a brief period of VNS increases the proportion of primary auditory cortex (A1) responding to the frequency of the paired tone. However, the relationship between VNS intensity and cortical map plasticity is not known.
Objective/hypothesis: The primary goal of this study was to determine the range of VNS intensities that can be used to direct cortical map plasticity.
Methods: The rats were exposed to a 9 kHz tone paired with VNS at intensities of 0.4, 0.8, 1.2, or 1.6 mA.
Results: In rats that received moderate (0.4-0.8 mA) intensity VNS, 75% more cortical neurons were tuned to frequencies near the paired tone frequency. A two-fold effective range is broader than expected based on previous VNS studies. Rats that received high (1.2-1.6 mA) int…
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Chen SP, Ay I, Lopes de Morais A, Qin T, Zheng Y, Sadeghian H, Oka F, Simon B, Eikermann-Haerter K, Ayata C (2016)MEDLINE-indexed journal, not yet read by usPain115 citations Vagus nerve stimulation inhibits cortical spreading depression.
Vagus nerve stimulation has recently been reported to improve symptoms of migraine. Cortical spreading depression is the electrophysiological event underlying migraine aura and is a trigger for headache. We tested whether vagus nerve stimulation inhibits cortical spreading depression to explain its antimigraine effect. Unilateral vagus nerve stimulation was delivered either noninvasively through the skin or directly by electrodes placed around the nerve. Systemic physiology was monitored throughout the study. Both noninvasive transcutaneous and invasive direct vagus nerve stimulations significantly suppressed spreading depression susceptibility in the occipital cortex in rats. The electrical stimulation threshold to evoke a spreading depression was elevated by more than 2-fold, the frequency of spreading depressions during continuous topical 1 M KCl was reduced by ∼40%, and propagation s…
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Inoue T, Abe C, Sung SS, Moscalu S, Jankowski J, Huang L, Ye H, Rosin DL, Guyenet PG, Okusa MD (2016)MEDLINE-indexed journal, not yet read by usThe Journal of clinical investigation247 citations Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through α7nAChR+ splenocytes.
The nervous and immune systems interact in complex ways to maintain homeostasis and respond to stress or injury, and rapid nerve conduction can provide instantaneous input for modulating inflammation. The inflammatory reflex referred to as the cholinergic antiinflammatory pathway regulates innate and adaptive immunity, and modulation of this reflex by vagus nerve stimulation (VNS) is effective in various inflammatory disease models, such as rheumatoid arthritis and inflammatory bowel disease. Effectiveness of VNS in these models necessitates the integration of neural signals and α7 nicotinic acetylcholine receptors (α7nAChRs) on splenic macrophages. Here, we sought to determine whether electrical stimulation of the vagus nerve attenuates kidney ischemia-reperfusion injury (IRI), which promotes the release of proinflammatory molecules. Stimulation of vagal afferents or efferents in mice 2…
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Vagus Nerve Stimulation Delivered with Motor Training Enhances Recovery of Function after Traumatic Brain Injury.
Traumatic Brain Injury (TBI) is one of the largest health problems in the United States, and affects nearly 2 million people every year. The effects of TBI, including weakness and loss of coordination, can be debilitating and last years after the initial injury. Recovery of motor function is often incomplete. We have developed a method using electrical stimulation of the vagus nerve paired with forelimb use by which we have demonstrated enhanced recovery from ischemic and hemorrhagic stroke. Here we have tested the hypothesis that vagus nerve stimulation (VNS) paired with physical rehabilitation could enhance functional recovery after TBI. We trained rats to pull on a handle to receive a food reward. Following training, they received a controlled-cortical impact (CCI) in the forelimb area of motor cortex opposite the trained forelimb, and were then randomized into two treatment groups. O…
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Complications and safety of vagus nerve stimulation: 25 years of experience at a single center.
OBJECTIVE The goal of this paper was to investigate surgical and hardware complications in a longitudinal retrospective study. METHODS The authors of this registry study analyzed the surgical and hardware complications in 247 patients who underwent the implantation of a vagus nerve stimulation (VNS) device between 1990 and 2014. The mean follow-up time was 12 years. RESULTS In total, 497 procedures were performed for 247 primary VNS implantations. Complications related to surgery occurred in 8.6% of all implantation procedures that were performed. The respective rate for hardware complications was 3.7%. Surgical complications included postoperative hematoma in 1.9%, infection in 2.6%, vocal cord palsy in 1.4%, lower facial weakness in 0.2%, pain and sensory-related complications in 1.4%, aseptic reaction in 0.2%, cable discomfort in 0.2%, surgical cable break in 0.2%, oversized stimulato…
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Making sense of what you sense: Disentangling interoceptive awareness, sensibility and accuracy.
Garfinkel and Critchley (2013) recently proposed a three level model of interoception. Only few studies, however, have empirically tested this theoretical model thus far. The present study aimed at investigating (1) the central assumptions of this model, i.e. that Accuracy, Sensibility and Awareness are distinguishable facets of interoception and that Interoceptive Accuracy is the basic level of interoception, and (2) whether cardiovascular activation (as indexed by heart rate) is differentially related to the three facets of interoception. Analyses were conducted on a total sample of N=159 healthy participants (118 female [74.2%]; mean age=23.9years, SD=3.3, range=19-45) who performed either the heartbeat tracking task, the heartbeat discrimination task or both. The results suggest that Accuracy, Sensibility and Awareness are empirically distinct facets of interoception, showing no corr…
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miR-210 mediates vagus nerve stimulation-induced antioxidant stress and anti-apoptosis reactions following cerebral ischemia/reperfusion injury in rats.
Vagus nerve stimulation (VNS) exerts neuroprotective effects against cerebral ischemia/reperfusion (I/R) injury and modulates redox status, potentially through the activity of miR-210, an important microRNA that is regulated by hypoxia-inducible factor and Akt-dependent pathways. The aim of this study was to determine the mechanisms of VNS- and miR-210-mediated hypoxic tolerance. Male Sprague-Dawley rats were preconditioned with a miR-210 antagomir (A) or with an antagomir control (AC), followed by middle cerebral artery occlusion and VNS treatment. The animals were divided into eight groups: sham I/R, I/R, I/R+AC, I/R+A, sham I/R+VNS, I/R+VNS, I/R+VNS+AC, and I/R+VNS+A. Activation of the endogenous cholinergic a7 nicotinic acetylcholine receptor (a7nAchR) pathway was identified using double immunofluorescence staining. miR-210 expression was measured by PCR. Behavioral outcomes, infarct…
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Harrison BJ, Fullana MA, Soriano-Mas C, Via E, Pujol J, Martínez-Zalacaín I, Tinoco-Gonzalez D, Davey CG, López-Solà M, Pérez Sola V, Menchón JM, Cardoner N (2015)MEDLINE-indexed journal, not yet read by usHuman brain mapping31 citations A neural mediator of human anxiety sensitivity.
Advances in the neuroscientific understanding of bodily autonomic awareness, or interoception, have led to the hypothesis that human trait anxiety sensitivity (AS)-the fear of bodily autonomic arousal-is primarily mediated by the anterior insular cortex. Despite broad appeal, few experimental studies have comprehensively addressed this hypothesis. We recruited 55 individuals exhibiting a range of AS and assessed them with functional magnetic resonance imaging (fMRI) during aversive fear conditioning. For each participant, three primary measures of interest were derived: a trait Anxiety Sensitivity Index score; an in-scanner rating of elevated bodily anxiety sensations during fear conditioning; and a corresponding estimate of whole-brain functional activation to the conditioned versus nonconditioned stimuli. Using a voxel-wise mediation analysis framework, we formally tested for 'neural m…
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Skoluda N, Strahler J, Schlotz W, Niederberger L, Marques S, Fischer S, Thoma MV, Spoerri C, Ehlert U, Nater UM (2015)MEDLINE-indexed journal, not yet read by usPsychoneuroendocrinology159 citations Intra-individual psychological and physiological responses to acute laboratory stressors of different intensity.
Objectives: The phenomenon of stress is understood as a multidimensional concept which can be captured by psychological and physiological measures. There are various laboratory stress protocols which enable stress to be investigated under controlled conditions. However, little is known about whether these protocols differ with regard to the induced psycho-physiological stress response pattern.
Methods: In a within-subjects design, 20 healthy young men underwent four of the most common stress protocols (Stroop test [Stroop], cold pressor test [CPT], Trier Social Stress Test [TSST], and bicycle ergometer test [Ergometer]) and a no-stress control condition (rest) in a randomized order. For the multidimensional assessment of the stress response, perceived stress, endocrine and autonomic biomarkers (salivary cortisol, salivary alpha-amylase, and heart rate) were obtained during the experiment…
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Vagus nerve stimulation delivered during motor rehabilitation improves recovery in a rat model of stroke.
Neural plasticity is widely believed to support functional recovery following brain damage. Vagus nerve stimulation paired with different forelimb movements causes long-lasting map plasticity in rat primary motor cortex that is specific to the paired movement. We tested the hypothesis that repeatedly pairing vagus nerve stimulation with upper forelimb movements would improve recovery of motor function in a rat model of stroke. Rats were separated into 3 groups: vagus nerve stimulation during rehabilitation (rehab), vagus nerve stimulation after rehab, and rehab alone. Animals underwent 4 training stages: shaping (motor skill learning), prelesion training, postlesion training, and therapeutic training. Rats were given a unilateral ischemic lesion within motor cortex and implanted with a left vagus nerve cuff. Animals were allowed 1 week of recovery before postlesion baseline training. Dur…
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A role for primate subgenual cingulate cortex in sustaining autonomic arousal.
The subgenual anterior cingulate cortex (subgenual ACC) plays an important role in regulating emotion, and degeneration in this area correlates with depressed mood and anhedonia. Despite this understanding, it remains unknown how this part of the prefrontal cortex causally contributes to emotion, especially positive emotions. Using Pavlovian conditioning procedures in macaque monkeys, we examined the contribution of the subgenual ACC to autonomic arousal associated with positive emotional events. After such conditioning, autonomic arousal increases in response to cues that predict rewards, and monkeys maintain this heightened state of arousal during an interval before reward delivery. Here we show that although monkeys with lesions of the subgenual ACC show the initial, cue-evoked arousal, they fail to sustain a high level of arousal until the anticipated reward is delivered. Control pro…
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The timing and amount of vagus nerve stimulation during rehabilitative training affect poststroke recovery of forelimb strength.
Loss of upper arm strength after stroke is a leading cause of disability. Strategies that can enhance the benefits of rehabilitative training could improve motor function after stroke. Recent studies in a rat model of ischemic stroke have demonstrated that vagus nerve stimulation (VNS) paired with rehabilitative training substantially improves recovery of forelimb strength compared with extensive rehabilitative training without VNS. Here we report that the timing and amount of stimulation affect the degree of forelimb strength recovery. Similar amounts of Delayed VNS delivered 2 h after daily rehabilitative training sessions resulted in significantly less improvement compared with that on delivery of VNS that is paired with identical rehabilitative training. Significantly less recovery also occurred when several-fold more VNS was delivered during rehabilitative training. Both delayed and…
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Psychophysiological arousal at encoding leads to reduced reactivity but enhanced emotional memory following sleep.
While sleep's role in emotional memory processing is gaining increasing support, its effect on emotion regulation remains equivocal. Moreover, little is known about the link between emotional reactivity at the time of encoding and subsequent sleep-based emotional memory consolidation. This study examined whether sleep would potentiate, protect, or depotentiate measures of heart rate and skin conductance in response to scenes containing emotional and neutral objects, and assessed how these measures of reactivity would predict subsequent memory for the objects across delays of sleep and wake. Heart rate deceleration (HRD) and skin conductance response (SCR) data were collected at encoding and recognition. Although HRD and SCR reactivity to objects were depotentiated after a sleep-filled delay, they remained unchanged after a delay containing wakefulness. Moreover, increased arousal respons…
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Rapid remission of conditioned fear expression with extinction training paired with vagus nerve stimulation.
Background: Fearful experiences can produce long-lasting and debilitating memories. Extinction of conditioned fear requires consolidation of new memories that compete with fearful associations. In human subjects, as well as rats, posttraining stimulation of the vagus nerve enhances memory consolidation. Subjects with posttraumatic stress disorder show impaired extinction of conditioned fear. The objective of this study was to determine whether vagus nerve stimulation (VNS) can enhance the consolidation of extinction of conditioned fear.
Methods: Male Sprague-Dawley rats were trained on an auditory fear conditioning task followed by 1 to 10 days of extinction training. Treatment with vagus nerve or sham stimulation was administered concurrently with exposure to the fear conditioned stimulus. Another group was given VNS and extinction training but the VNS was not paired with exposure to co…
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Vagus nerve stimulation during rehabilitative training improves forelimb strength following ischemic stroke.
Upper limb impairment is a common debilitating consequence of ischemic stroke. Physical rehabilitation after stroke enhances neuroplasticity and improves limb function, but does not typically restore normal movement. We have recently developed a novel method that uses vagus nerve stimulation (VNS) paired with forelimb movements to drive specific, long-lasting map plasticity in rat primary motor cortex. Here we report that VNS paired with rehabilitative training can enhance recovery of forelimb force generation following infarction of primary motor cortex in rats. Quantitative measures of forelimb function returned to pre-lesion levels when VNS was delivered during rehab training. Intensive rehab training without VNS failed to restore function back to pre-lesion levels. Animals that received VNS during rehab improved twice as much as rats that received the same rehabilitation without VNS.…
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Electrophysiological and neurochemical effects of long-term vagus nerve stimulation on the rat monoaminergic systems.
Vagus nerve stimulation (VNS) is an adjunctive treatment for resistant epilepsy and depression. Electrophysiological recordings in the rat brain have already shown that chronic VNS increases norepinephrine (NE) neuronal firing activity and, subsequently, that of serotonin (5-HT) neurons through an activation of their excitatory α1-adrenoceptors. Long-term VNS was shown to increase the tonic activation of post-synaptic 5-HT1A receptors in the hippocampus. This study was aimed at examining the effect of VNS on extracellular 5-HT, NE and dopamine (DA) levels in different brain areas using in vivo microdialysis, on NE transmission in the hippocampus, and DA neuronal firing activity using electrophysiology. Rats were implanted with a VNS device and stimulated for 14 d with standard parameters used in treatment-resistant depression (0.25 mA, 20 Hz, 500 μs, 30 s on-5 min off). The results of th…
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Efficacy of vagus nerve stimulation over time: review of 65 consecutive patients with treatment-resistant epilepsy treated with VNS > 10 years.
Objective: Studies have reported improved seizure control with increased duration of vagus nerve stimulation (VNS) but are prone to methodological biases. We analyzed the efficacy of VNS over time in patients with treatment-resistant epilepsy (TRE) who underwent VNS therapy 10 or more years.
Methods: We retrospectively reviewed 65 consecutive patients (29 females) who underwent VNS therapy ≥ 10 years. The mean age at VNS insertion was 30.0 years. Forty-four adults (≥ 18 years; 67.7%) and 21 children (32.3%) were included. Seizure frequency and antiepileptic drug (AED) regimens were recorded prior to VNS and, following VNS insertion, at 6 months, 1 year, 2 years, and every 2 years thereafter.
Results: The mean duration of VNS therapy for this group was 10.4 years, and the mean decrease in seizure frequency at last follow-up was 76.3%. The mean reduction in seizures at 6 months and years 1…
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Raedt R, Clinckers R, Mollet L, Vonck K, El Tahry R, Wyckhuys T, De Herdt V, Carrette E, Wadman W, Michotte Y, Smolders I, Boon P, Meurs A (2011)MEDLINE-indexed journal, not yet read by usJournal of neurochemistry189 citations Increased hippocampal noradrenaline is a biomarker for efficacy of vagus nerve stimulation in a limbic seizure model.
Vagus nerve stimulation (VNS) is an effective adjunctive treatment for medically refractory epilepsy. In this study, we measured VNS-induced changes in hippocampal neurotransmitter levels and determined their potential involvement in the anticonvulsive action of VNS, to elucidate the mechanism of action responsible for the seizure suppressing effect of VNS in an animal model for limbic seizures. We used in vivo intracerebral microdialysis to measure VNS-induced changes in hippocampal extracellular concentrations of noradrenaline, dopamine, serotonin and GABA in freely moving, male Wistar rats. During the same experiment, the effect of VNS on pilocarpine-induced limbic seizures was assessed using video-EEG monitoring. The involvement of VNS-induced increases in hippocampal noradrenaline in the mechanims of action of VNS was evaluated by blocking hippocampal α(2)-receptors. VNS produced a …
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