Acute Vagus Nerve Stimulation Research Articles

Neuron-Microglia Interaction is Involved in Anti-inflammatory Response by Vagus Nerve Stimulation in the Prefrontal Cortex of Rats Injected with Polyinosinic:Polycytidylic Acid.

Injection of polyinosinic:polycytidylic acid (poly(I:C)) into experimental animals induces neuroimmunological responses and thus has been used for the study of neurological disorders such as anxiety, depression, and chronic fatigue. Here, we investigated the effects of vagus nerve stimulation (VNS) on poly(I:C)-induced neuroinflammation and associated behavioral consequences in rats. The microglia in the prefrontal cortex (PFC) displayed the activated form of morphology in poly(I:C)-injected rats and changed to a normal shape after acute VNS (aVNS). Production of phospho-NF-κB, phospho-IκB, IL-1β, and cleaved caspase 3 was elevated by poly(I:C) and downregulated by aVNS. In contrast, phospho-Akt levels were decreased by poly(I:C) and increased by aVNS. Neuronal production of fractalkine (CX3CL1) in the PFC was markedly reduced by poly(I:C), but recovered by aVNS. Fractalkine interaction with its receptor CX3CR1 was highly elevated by VNS. We further demonstrated that the pharmacological blockade of CX3CR1 activity counteracted the production of IL-1β, phospho-Akt, and cleaved form of caspase 3 that was modulated by VNS, suggesting the anti-inflammatory effects of fractalkine-CX3CR1 signaling as a mediator of neuron-microglia interaction. Behavioral assessments of pain and temperature sensations by von Frey and hot/cold plate tests showed significant improvement by chronic VNS (cVNS) and forced swimming and marble burying tests revealed that the depressive-like behaviors caused by poly(I:C) injection were rescued by cVNS. We also found that the recognition memory which was impaired by poly(I:C) administration was improved by cVNS. This study suggests that VNS may play a role in regulating neuroinflammation and somatosensory and cognitive functions in poly(I:C)-injected animals.

Personalized inference for neurostimulation with meta-learning: a case study of vagus nerve stimulation.

Objective. Neurostimulation is emerging as treatment for several diseases of the brain and peripheral organs. Due to variability arising from placement of stimulation devices, underlying neuroanatomy and physiological responses to stimulation, it is essential that neurostimulation protocols are personalized to maximize efficacy and safety. Building such personalized protocols would benefit from accumulated information in increasingly large datasets of other individuals' responses.Approach. To address that need, we propose a meta-learning family of algorithms to conduct few-shot optimization of key fitting parameters of physiological and neural responses in new individuals. While our method is agnostic to neurostimulation setting, here we demonstrate its effectiveness on the problem of physiological modeling of fiber recruitment during vagus nerve stimulation (VNS). Using data from acute VNS experiments, the mapping between amplitudes of stimulus-evoked compound action potentials (eCAPs) and physiological responses, such as heart rate and breathing interval modulation, is inferred.Main results. Using additional synthetic data sets to complement experimental results, we demonstrate that our meta-learning framework is capable of directly modeling the physiology-eCAP relationship for individual subjects with much fewer individually queried data points than standard methods.Significance. Our meta-learning framework is general and can be adapted to many input-response neurostimulation mapping problems. Moreover, this method leverages information from growing data sets of past patients, as a treatment is deployed. It can also be combined with several model types, including regression, Gaussian processes with Bayesian optimization, and beyond.

Identification of metabolic biomarkers of chronic vagus nerve stimulation (VNS) in subjects with drug-resistant epilepsy (DRE).

Neuromodulation by means of vagus nerve stimulation (VNS) therapy, reduces seizure frequency and improves quality of life in subjects with drug-resistant epilepsy (DRE), yet its molecular mechanism remains unclear. This study investigates the impact of chronic VNS on lipid bioactive metabolites and fatty acids (FA) in the plasma and red blood cells of seven subjects with DRE. By measuring expression levels of peroxisome proliferator-activated receptor α (PPARα) and sirtuin1 (SIRT1) genes-key regulators in energy and lipid metabolism-and lipid profiles before and after various stages of VNS, this study identifies potential mechanisms by which VNS may reduce seizure frequency. Blood samples collected before VNS device implantation, after acute VNS stimulus, and following gradual intensity increments up to therapeutic levels revealed that VNS increases SIRT1 and PPARα expression and erythrocyte concentrations of PPARα ligands. Additionally, we observe reduced de novo lipogenesis biomarkers in erythrocytes, indicating that VNS may influence systemic lipid and energy metabolism. Our findings suggest that VNS could enhance neuronal function by modulating energy metabolism, thus potentially reducing seizure frequency in subjects with DRE. Future research targeting SIRT1 and PPARα may provide innovative therapeutic strategies for managing DRE. Plain Language Summary: The exact mechanism of VNS is still unknown. This study investigated the effects of VNS Therapy on energetic metabolism, suggesting possible novel biomarkers for DRE subjects and neuromodulation therapies.

Alteration of Excitation/Inhibition Imbalance in the Hippocampus and Amygdala of Drug-Resistant Epilepsy Patients Treated with Acute Vagus Nerve Stimulation.

An imbalance between excitation (E) and inhibition (I) in the brain has been identified as a key pathophysiology of epilepsy over the years. The hippocampus and amygdala in the limbic system play a crucial role in the initiation and conduction of epileptic seizures and are often referred to as the transfer station and amplifier of seizure activities. Existing animal and imaging studies reveal that the hippocampus and amygdala, which are significant parts of the vagal afferent network, can be modulated in order to generate an antiepileptic effect. Using stereo-electroencephalography (SEEG) data, we examined the E/I imbalance in the hippocampus and amygdala of ten drug-resistant epilepsy children treated with acute vagus nerve stimulation (VNS) by estimating the 1/f power slope of hippocampal and amygdala signals in the range of 1-80 Hz. While the change in the 1/f power slope from VNS-BASE varied between different stimulation amplitudes and brain regions, it was more prominent in the hippocampal region. In the hippocampal region, we found a flatter 1/f power slope during VNS-ON in patients with good responsiveness to VNS under the optimal stimulation amplitude, indicating that the E/I imbalance in the region was improved. There was no obvious change in 1/f power slope for VNS poor responders. For VNS non-responders, the 1/f power slope slightly increased when the stimulation was applied. Overall, this study implies that the regulation of E/I imbalance in the epileptic brain, especially in the hippocampal region, may be an acute intracranial effect of VNS.

Flexible IrOx neural electrode for mouse vagus nerve stimulation.

Vagus nerve stimulation (VNS) is being actively explored as a treatment for multiple conditions as part of bioelectronic medicine research. Reliable and safe VNS in mouse models is a critical need for understanding mechanisms of these. We report on the development and evaluation of a microfabricated cuff electrode (MouseFlex) constructed of polyimide (PI) and with iridium oxide (IrOx) electrodes that is thermoformed to 86 µm ± 12 µm radius to interface the mouse cervical vagus nerve (r ≈ 50 µm). Innovative bench-top methods were used to evaluate the stimulation stability and electrochemical properties of electrodes. Our aggressive stimulation stability (Stim-Stab) test utilized 1 billion pulses at a 1000 Hz with a current density of 6.28 A/cm2 (1.51 mC/cm2/phase) delivering 3023×103 C/cm2 to evaluate electrode lifetimes, and all electrodes remained functional. We also investigated the effects of thermoforming on their impedance, charge storage capacity (CSC), and charge injection capacity (CIC). The modest changes in electrochemical properties indicate that the thermoforming process was well tolerated. Thermoformed electrode safety and efficacy were evaluated in-vivo by performing acute VNS in mice and monitoring their heart and respiration rate as biomarkers. Their electrochemical properties were also measured before, during and after VNS. Bradycardia and bradypnea were reliably induced at stimulation currents of 100 to 200 µA, well below the in-vivo CIC of ∼1250 µA (∼0.5 mC/cm2), supporting their safety and efficacy. The electrode impedance increased and CIC decreased during in-vivo use, but largely reversed these changes in in-vitro testing after enzymatic cleaning, supporting their tolerance for surgical use. STATEMENT OF SIGNIFICANCE: Vagus nerve stimulation (VNS) is a rapidly growing aspect of healthcare and bioelectronic medicine research. Reliable and safe VNS in mice with small diameter (d ≈ 100 µm) nerves has been a challenge due to achieving intimate contact with the nerve, and the stimulation stability of commonly used electrodes. We demonstrate a microfabricated (MouseFlex) cuff electrode constructed of polyimide with IrOx electrodes that is thermoformed to contact the mouse cervical vagus. Bench studies highlight the stimulation stability exceeded 109 pulses at 6.28 A/cm2 and their electrochemical properties were measured before, during, and after bench and nerve stimulation. Nerve stimulation induced bradycardia and bradypnea at currents below the in-vivo charge injection capacity, supporting their safety, efficacy, and tolerance for surgical handling.

Acute Vagus Nerve Stimulation Facilitates Short Term Memory and Cognitive Flexibility in Rats.

Vagus nerve stimulation (VNS) causes the release of several neuromodulators, leading to cortical activation and deactivation. The resulting preparatory cortical plasticity can be used to increase learning and memory in both rats and humans. The effects of VNS on cognition have mostly been studied either in animal models of different pathologies, and/or after extended VNS. Considerably less is known about the effects of acute VNS. Here, we examined the effects of acute VNS on short-term memory and cognitive flexibility in naïve rats, using three cognitive tasks that require comparatively brief (single session) training periods. In all tasks, VNS was delivered immediately before or during the testing phase. We used a rule-shifting task to test cognitive flexibility, a novel object recognition task to measure short-term object memory, and a delayed spontaneous alternation task to measure spatial short-term memory. We also analyzed exploratory behavior in an elevated plus maze to determine the effects of acute VNS on anxiety. Our results indicate that acute VNS can improve memory and cognitive flexibility relative to Sham-stimulation, and these effects are independent of unspecific VNS-induced changes in locomotion or anxiety.

Vagus Nerve Stimulation Modulates Phase-Amplitude Coupling in Thalamic Local Field Potentials

ObjectiveThe antiseizure effects of vagus nerve stimulation (VNS) are thought to be mediated by the modulation of afferent thalamocortical circuitry. Cross-frequency phase-amplitude coupling (PAC) is a mechanism of hierarchical network coordination across multiple spatiotemporal scales. In this study, we leverage local field potential (LFP) recordings from the centromedian (CM) (n = 3) and anterior (ATN) (n = 2) nuclei in five patients with tandem thalamic deep brain stimulation and VNS to study neurophysiological changes in the thalamus in response to VNS. Materials and MethodsBipolar LFP data were recorded from contact pairs spanning target nuclei in VNS “on” and “off” states. ResultsActive VNS was associated with increased PAC between theta, alpha, and beta phase and gamma amplitude in CM (q < 0.05). Within the ATN, PAC changes also were observed, although these were less robust. In both nuclei, active VNS also modulated interhemispheric bithalamic functional connectivity. ConclusionsWe report that VNS is associated with enhanced PAC and coordinated interhemispheric interactions within and between thalamic nuclei, respectively. These findings advance understanding of putative neurophysiological effects of acute VNS and contextualize previous animal and human studies showing distributed cortical synchronization after VNS.

The potential of invasive and non-invasive vagus nerve stimulation to improve verbal memory performance in epilepsy patients

It has been demonstrated that acute vagus nerve stimulation (VNS) improves word recognition memory in epilepsy patients. Transcutaneous auricular vagus nerve stimulation (taVNS) has gained interest as a non-invasive alternative to improve cognition. In this prospective randomized cross-over study, we investigated the effect of both invasive VNS and taVNS on verbal memory performance in 15 patients with drug-resistant epilepsy. All patients conducted a word recognition memory paradigm in 3 conditions: VNS ON, VNS OFF and taVNS (3-period 3-treatment cross-over study design). For each condition, patients memorized 21 highlighted words from text paragraphs. Afterwards, the intervention was delivered for 30 s. Immediate recall and delayed recognition scores were obtained for each condition. This memory paradigm was repeated after 6 weeks of VNS therapy in 2 conditions: VNS ON and VNS OFF (2-period 2-treatment cross-over study design). Acute VNS and taVNS did not improve verbal memory performance. Immediate recall and delayed recognition scores were significantly improved after 6 weeks of VNS treatment irrespective of the acute intervention. We can conclude that the previously described positive effects of invasive VNS on verbal memory performance could not be replicated with invasive VNS and taVNS. An improved verbal memory performance was seen after 6 weeks of VNS treatment, suggesting that longer and more repetitive stimulation of the vagal pathway is required to modulate verbal memory performance.Clinical trial registration number: NCT05031208.

Vagus nerve stimulation modulates hippocampal inflammation caused by continuous stress in rats

BackgroundPrevious studies have shown that vagus nerve stimulation (VNS) can attenuate inflammatory responses in peripheral tissues and also improve some neurological disorders and cognitive function in the brain. However, it is not clear how VNS is involved in neuropathological processes in brain tissues. Here, we investigated the regulatory effects of VNS on the production of proinflammatory cytokines in the hippocampus of an animal model of continuous stress (CS).MethodsCS was induced by placing rats in cages immersed with water, and acute or chronic electrical stimulation was applied to the cervical vagus nerve of CS animals. Protein levels in the gastric and hippocampal tissues were measured by western blotting and protein signals analyzed by immunofluorescence staining. von Frey test and forced swimming test were performed to assess pain sensitivity and depressive-like behavior in rats, respectively.ResultsLevels of TNF-α, IL-1β, and IL-6 in the gastric and hippocampal tissues were significantly increased in CS animals compared to the untreated control and downregulated by acute VNS (aVNS). Iba-1-labeled microglial cells in the hippocampus of CS animals revealed morphological features of activated inflammatory cells and then changed to a normal shape by VNS. VNS elevated hippocampal expression of α7 nicotinic acetylcholine receptors (α7 nAChR) in CS animals, and pharmacological blockade of α7 nAChR increased the production of TNF-α, IL-1β, and IL-6, thus suppressing cholinergic anti-inflammatory activity that was mediated by VNS. Chronic VNS (cVNS) down-regulated the hippocampal production of active form of caspase 3 and 5-HT1A receptors and also decreased levels of TNF-α, IL-1β, and IL-6 in the gastric and hippocampal tissues of CS animals. Pain sensitivity and depressive-like behavior, which were increased by CS, were improved by cVNS.ConclusionsOur data suggest that VNS may be involved in modulating pathophysiological processes caused by CS in the brain.

Acute vagus nerve stimulation does not affect liking or wanting ratings of food in healthy participants

The vagus nerve plays a vital role in the regulation of food intake and vagal afferent signals may help regulate food cue reactivity by providing negative homeostatic feedback. Despite strong evidence from preclinical studies on vagal afferent “satiety” signals in guiding food intake, evidence from human studies is largely inconclusive to date. Here, we investigated the acute effects of left or right transcutaneous auricular vagus nerve stimulation (taVNS) on subjective ratings of wanting and liking of various food and non-food items in 82 healthy participants (46 women, MBMI = 23.1 kg/m2). In contrast to previous reports in patients with depression, we found moderate to anecdotal evidence supporting the absence of taVNS-induced changes in food ratings. To test whether the absence of taVNS effects on food ratings is due to heterogeneity in the sample, we conducted post hoc subgroup analyses by splitting the data according to stimulation side and sex (between-subject factors) as well as caloric density, perceived healthiness, and flavor (sweet vs. savory) of the food (within-subject factors). This multiverse analysis largely supported the absence of taVNS-induced changes since the strongest subgroup effects provided only anecdotal evidence in favor of taVNS-induced changes. We conclude that acute taVNS only has a marginal effect on subjective ratings of food, suggesting that it is an unlikely mechanism for the reported long-term effects of VNS on body weight. In light of an absence of acute taVNS effects on conscious food liking and wanting, our results call for future research on the correspondence between acute and chronic effects of vagal afferent stimulation.

Vagus nerve stimulation activates nucleus of solitary tract neurons via supramedullary pathways.

Vagus nerve stimulation (VNS) treats patients with drug-resistant epilepsy, depression and heart failure, but the mechanisms responsible are uncertain. The mild stimulus intensities used in chronic VNS suggest activation of myelinated primary visceral afferents projecting to the nucleus of the solitary tract (NTS). Here, we monitored the activity of second and higher order NTS neurons in response to peripheral vagal activation using therapeutic VNS criteria. A bipolar stimulating electrode activated the left cervical vagus nerve, and stereotaxically placed single tungsten electrodes recorded unit activity from the left caudomedial NTS of chloralose-anaesthetized rats. High-intensity single electrical stimuli established vagal afferent conduction velocity (myelinated A-type or unmyelinated C-type) as well as synaptic order (second vs. higher order using paired electrical stimuli) for inputs to single NTS neurons. Then, VNS treatment was applied. A mid-collicular knife cut (KC) divided the brainstem from all supramedullary regions to determine their contribution to NTS activity. Our chief findings indicate that the KC reduced basal spontaneous activity of second-order NTS neurons receiving myelinated vagal input by 85%. In these neurons, acute VNS increased activity similarly in Control and KC animals. Interestingly, the KC interrupted VNS activation of higher order NTS neurons and second-order NTS neurons receiving unmyelinated vagal input, indicating that supramedullary descending projections to NTS are needed to amplify the peripheral neuronal signal from VNS. The present study begins to define the pathways activated during VNS and will help to better identify the central nervous system contributions to the therapeutic benefits of VNS therapy. KEY POINTS: Vagus nerve stimulation is routinely used in the clinic to treat epilepsy and depression, despite our uncertainty about how this treatment works. For this study, the connections between the nucleus of the solitary tract (NTS) and the higher brain regions were severed to learn more about their contribution to activity of these neurons during stimulation. Severing these brain connections reduced baseline activity as well as reducing stimulation-induced activation for NTS neurons receiving myelinated vagal input. Higher brain regions play a significant role in maintaining both normal activity in NTS and indirect mechanisms of enhancing NTS neuronal activity during vagus nerve stimulation.

A rodent model of acute vagus nerve stimulation for modulation of gastric function characterized by a gastric balloon

A rodent model of acute vagus nerve stimulation for modulation of gastric function characterized by a gastric balloon

Vagus Nerve Stimulation Elicits Sleep EEG Desynchronization and Network Changes in Responder Patients in Epilepsy.

Neural desynchronization was shown as a key mechanism of vagus nerve stimulation (VNS) action in epilepsy, and EEG synchronization measures are explored as possible response biomarkers. Since brain functional organization in sleep shows different synchrony and network properties compared to wakefulness, we aimed to explore the effects of acute VNS on EEG-derived measures in the two different states of vigilance. EEG epochs were retrospectively analyzed from twenty-four VNS-treated epileptic patients (11 responders, 13 non-responders) in calm wakefulness and stage N2 sleep. Weighted Phase Lag Index (wPLI) was computed as connectivity measure of synchronization, for VNS OFF and VNS ON conditions. Global efficiency (GE) was computed as a network measure of integration. Ratios OFF/ON were obtained as desynchronization/de-integration index. Values were compared between responders and non-responders, and between EEG states. ROC curve and area-under-the-curve (AUC) analysis was performed for response classification. In responders, stronger VNS-induced theta desynchronization (p < 0.05) and decreased GE (p < 0.05) were found in sleep, but not in wakefulness. Theta sleep wPLI Ratio OFF/ON yielded an AUC of 0.825, and 79% accuracy as a response biomarker if a cut-off value is set at 1.05. Considering all patients, the VNS-induced GE decrease was significantly more important in sleep compared to awake EEGstate (p < 0.01). In conclusion, stronger sleep EEG desynchronization in theta band distinguishes responders to VNS therapy from non-responders. VNS-induced reduction of network integration occurs significantly more in sleep than in wakefulness.

Acute vagus nerve stimulation enhances reversal learning in rats

Cognitive flexibility is a prefrontal cortex-dependent neurocognitive process that enables behavioral adaptation in response to changes in environmental contingencies. Electrical vagus nerve stimulation (VNS) enhances several forms of learning and neuroplasticity, but its effects on cognitive flexibility have not been evaluated. In the current study, a within-subjects design was used to assess the effects of VNS on performance in a novel visual discrimination reversal learning task conducted in touchscreen operant chambers. The task design enabled simultaneous assessment of acute VNS both on reversal learning and on recall of a well-learned discrimination problem. Acute VNS delivered in conjunction with stimuli presentation during reversal learning reliably enhanced learning of new reward contingencies. Enhancement was not observed, however, if VNS was delivered during the session but was not coincident with presentation of to-be-learned stimuli. In addition, whereas VNS delivered at 30 HZ enhanced performance, the same enhancement was not observed using 10 or 50 Hz. Together, these data show that acute VNS facilitates reversal learning and indicate that the timing and frequency of the VNS are critical for these enhancing effects. In separate rats, administration of the norepinephrine reuptake inhibitor atomoxetine also enhanced reversal learning in the same task, consistent with a noradrenergic mechanism through which VNS enhances cognitive flexibility.

Implant- and anesthesia-related factors affecting cardiopulmonary threshold intensities for vagus nerve stimulation

Objective. Vagus nerve stimulation (VNS) is typically delivered at increasing stimulus intensity until a neurological or physiological response is observed (‘threshold’) for dose calibration, preclinically and therapeutically. Factors affecting VNS thresholds have not been studied systematically. In a rodent model of VNS we measured neural and physiological responses to increasing VNS intensity, determined neurological and physiological thresholds and examined the effect of implant- and anesthesia-related factors on thresholds. Approach. In acute and chronic vagus implants (45 and 20 rats, respectively) VNS was delivered under isoflurane, ketamine-xylazine, or awake conditions. Evoked compound action potentials (CAPs) were recorded and activation of different fiber types was extracted. Elicited physiological responses were registered, including changes in heart rate (HR), breathing rate (BR), and blood pressure (BP). CAP and physiological thresholds were determined. Main results. The threshold for evoking discernable CAPs (>10 µV) (CAP threshold) is significantly lower than what elicits 5%–10% drop in heart rate (heart rate threshold, HRT) (25 µA ± 1.8 vs. 80 µA ± 5.1, respectively; mean ± SEM). Changes in BP and small changes in BR (bradypnea) occur at lowest intensities (70 µA ± 8.3), followed by HR changes (80 µA ± 5.1) and finally significant changes in BR (apnea) (310 μA ± 32.5). HRT and electrode impedance are correlated in chronic (Pearson correlation r= 0.47; p< 0.001) but not in acute implants (r = −0.34; p NS); HRT and impedance both increase with implant age (r= 0.44; p< 0.001 and r = 0.64; p < 0.001, respectively). HRT is lowest when animals are awake (200 µA ± 35.5), followed by ketamine-xylazine (640 µA ± 151.5), and isoflurane (1000 µA ± 139.5). The sequence of physiological responses with increasing VNS intensity is the same in anesthetized and awake animals. Pulsing frequency affects physiological responses but not CAPs. Significance. Implant age, electrode impedance, and type of anesthesia affect VNS thresholds and should be accounted for when calibrating stimulation dose.

Short-Term Effects of Vagus Nerve Stimulation on Learning and Evoked Activity in Auditory Cortex

Chronic vagus nerve stimulation (VNS) has been shown to facilitate learning, but effects of acute VNS on neural coding and behavior remain less well understood. Ferrets implanted with cuff electrodes on the vagus nerve were trained by classical conditioning on an auditory tone frequency-reward association. One tone was associated with reward while another tone was not. Tone frequencies and reward associations were changed every 2 d, requiring learning of a new relationship. When tones were paired with VNS, animals consistently learned the new association within 2 d. When VNS occurred randomly between trials, learning within 2 d was unreliable. In passively listening animals, neural activity in primary auditory cortex (A1) and pupil size were recorded before and after acute VNS-tone pairing. After pairing with a neuron’s best-frequency (BF) tone, responses by a subpopulation of neurons were reduced. VNS paired with an off-BF tone or during intertrial intervals had no effect. The BF-specific reduction in neural responses after VNS remained, even after regressing out changes explained by pupil-indexed arousal. VNS induced brief dilation in the pupil, and the size of this change predicted the magnitude of persistent changes in the neural response. This interaction suggests that fluctuations in neuromodulation associated with arousal gate the long-term VNS effects on neural activity.

Treatment of Super-Refractory Status Epilepticus: A Review.

Purpose:Super-refractory status epilepticus (SRSE) presents management challenges due to the absence of randomized controlled trials and a plethora of potential medical therapies. The literature on treatment options for SRSE reports variable success and quality of evidence. This review is a sequel to the 2020 American Epilepsy Society (AES) comprehensive review of the treatment of convulsive refractory status epilepticus (RSE).Methods:We sought to determine the effectiveness of treatment options for SRSE. We performed a structured literature search (MEDLINE, Embase, CENTRAL, CINAHL) for studies on reported treatments of SRSE. We excluded antiseizure medications (ASMs) covered in the 2016 AES guideline on the treatment of established SE and the convulsive RSE comprehensive review of the 2020 AES. Literature was reviewed on the effectiveness of vagus nerve stimulation, ketogenic diet (KD), lidocaine, inhalation anesthetics, brain surgery, therapeutic hypothermia, perampanel, pregabalin (PGB), and topiramate in the treatment of SRSE. Two authors reviewed each therapeutic intervention. We graded the level of the evidence according to the 2017 classification scheme of the American Academy of Neurology.Results:For SRSE (level U; 39 class IV studies total), insufficient evidence exists to support that perampanel, PGB, lidocaine, or acute vagus nerve stimulation (VNS) is effective. For children and adults with SRSE, insufficient evidence exists to support that the KD is effective (level U; 5 class IV studies). For adults with SRSE, insufficient evidence exists that brain surgery is effective (level U, 7 class IV studies). For adults with SRSE insufficient, evidence exists that therapeutic hypothermia is effective (level C, 1 class II and 4 class IV studies). For neonates with hypoxic-ischemic encephalopathy, insufficient evidence exists that therapeutic hypothermia reduces seizure burden (level U; 1 class IV study). For adults with SRSE, insufficient evidence exists that inhalation anesthetics are effective (level U, 1 class IV study) and that there is a potential risk of neurotoxicity.Conclusion:For patients with SRSE insufficient, evidence exists that any of the ASMs reviewed, inhalational anesthetics, ketogenic diet, acute VNS, brain surgery, and therapeutic hypothermia are effective treatments. Data supporting the use of these treatments for SRSE are scarce and limited mainly to small case series and case reports and are confounded by differences in patients’ population, and comedications, among other factors.

Acute Cardiovascular Responses to Vagus Nerve Stimulation after Experimental Spinal Cord Injury.

Pairing vagus nerve stimulation (VNS) with rehabilitation has emerged as a potential strategy to enhance plasticity and improve recovery in a range of neurological disorders. A recent study highlights the therapeutic promise of VNS in promoting motor recovery after spinal cord injury (SCI). We investigated the safety of acute VNS in a rat model of chronic SCI. We measured the cardiovascular response to various VNS paradigms following chronic high-thoracic SCI that is known to deleteriously impact cardiovascular control. Dose-response experiments with continuous VNS revealed an SCI-dependent increase in sensitivity for heart rate (HR) and blood pressure (BP) compared with controls. A clinically relevant intermittent VNS resulted in transient reduction in HR in rats with SCI; however, BP remained unaltered. In all experiments, the effect lasted only while the VNS stimulus train was present, as HR and BP restored to baseline values as soon as VNS ended. No prolonged episodes of persisting hypotension were seen in either group. Further, VNS did not trigger autonomic dysreflexia or exacerbate the severity of autonomic dysreflexia when induced during or after stimulation sessions. Overall, these findings provide initial evidence that intermittent VNS at parameters used for targeted plasticity therapy (30 Hz, 0.8 mA) appears safe and supports further investigation of this potential therapy for use following SCI.

PEDOT:PSS electrodes for acute experimental evaluation of vagus nerve stimulation on rodents.

The vagus nerve (VN) is involved in the autonomic regulation of many physiological systems (cardiovascular, respiratory, gastrointestinal, etc.) and its stimulation is already an approved therapy for refractory epilepsy and depression. Other pathologies are thought to be treatable through vagus nerve stimulation (VNS), such as heart failure, cardiac arrhythmia, inflammation or auto-immune diseases. However, the efficacy of the stimulation is not always optimal, partly due to the materials and the architecture of currently available electrodes. Standard electrodes, composed of metallic rings that stimulate the whole diameter of the nerve, are not adapted to experimentations involving spatial selectivity. Efficient and selective charge injection is usually difficult to achieve simultaneously, especially in experimental setups using rodents, due to the thin diameter of their VN. In this paper, we show that we can take advantage of the high charge injection property of conducting polymers to acutely stimulate the vagus nerve in rodents, using individual active electrodes with dimensions $725\,\,\mu \mathrm{m}\times \,450\,\,\mu\mathrm{m}$. A particular PEDOT:PSS architecture integrating 12 active electrodes is developed and applied to the VN of one rat. A closed-loop VNS system developed in our previous works is used to stimulate the VN while analyzing the heart rate response. Results show the feasibility of this kind of electrodes for acute VNS on rodents and open the path towards new experimentations focused on selective stimulation and recording.

Vagal Nerve Stimulation for Treatment-Resistant Depression.

Major depressive disorder (MDD) is prevalent. Although standards antidepressants are more effective than placebo, up to 35% of patients do not respond to 4 or more conventional treatments and are considered to have treatment-resistant depression (TRD). Considerable effort has been devoted to trying to find effective treatments for TRD. This review focuses on vagus nerve stimulation (VNS), approved for TRD in 2005 by the Food and Drugs Administration. Stimulation is carried by bipolar electrodes on the left cervical vagus nerve, which are attached to an implanted stimulator generator. The vagus bundle contains about 80% of afferent fibers terminating in the medulla, from which there are projections to many areas of brain, including the limbic forebrain. Various types of brain imaging studies reveal widespread functional effects in brain after either acute or chronic VNS. Although more randomized control trials of VNS need to be carried out before a definitive conclusion can be reached about its efficacy, the results of open studies, carried out over period of 1 to 2 years, show much more efficacy when compared with results from treatment as usual studies. There is an increase in clinical response to VNS between 3 and 12 months, which is quite different from that seen with standard antidepressant treatment of MDD. Preclinically, VNS affects many of the same brain areas, neurotransmitters (serotonin, norepinephrine) and signal transduction mechanisms (brain-derived neurotrophic factor-tropomyosin receptor kinase B) as those found with traditional antidepressants. Nevertheless, the mechanisms by which VNS benefits patients nonresponsive to conventional antidepressants is unclear, with further research needed to clarify this.