04343nas a2200433 4500008004100000022001400041245015100055210006900206260001600275490000700291520297600298653001003274653000903284653001903293653002403312653001103336653001503347653001103362653000903373653001603382653002803398653004603426653002803472100001803500700002303518700002103541700002203562700001803584700001403602700001903616700001703635700002603652700002403678700002103702700002303723700001903746700002303765856012103788 2025 eng d a2050-084X00aThe effect of transcutaneous auricular vagus nerve stimulation on cardiovascular function in subarachnoid hemorrhage patients: A randomized trial.0 aeffect of transcutaneous auricular vagus nerve stimulation on ca c2025 Jan 090 v133 a

BACKGROUND: Subarachnoid hemorrhage (SAH) is characterized by intense central inflammation, leading to substantial post-hemorrhagic complications such as vasospasm and delayed cerebral ischemia. Given the anti-inflammatory effect of transcutaneous auricular vagus nerve stimulation (taVNS) and its ability to promote brain plasticity, taVNS has emerged as a promising therapeutic option for SAH patients. However, the effects of taVNS on cardiovascular dynamics in critically ill patients, like those with SAH, have not yet been investigated. Given the association between cardiac complications and elevated risk of poor clinical outcomes after SAH, it is essential to characterize the cardiovascular effects of taVNS to ensure this approach is safe in this fragile population. Therefore, this study assessed the impact of both acute and repetitive taVNS on cardiovascular function.

METHODS: In this randomized clinical trial, 24 SAH patients were assigned to either a taVNS treatment or a sham treatment group. During their stay in the intensive care unit, we monitored patient electrocardiogram readings and vital signs. We compared long-term changes in heart rate, heart rate variability (HRV), QT interval, and blood pressure between the two groups. Additionally, we assessed the effects of acute taVNS by comparing cardiovascular metrics before, during, and after the intervention. We also explored acute cardiovascular biomarkers in patients exhibiting clinical improvement.

RESULTS: We found that repetitive taVNS did not significantly alter heart rate, QT interval, blood pressure, or intracranial pressure (ICP). However, repetitive taVNS increased overall HRV and parasympathetic activity compared to the sham treatment. The increase in parasympathetic activity was most pronounced from 2 to 4 days after initial treatment (Cohen's = 0.50). Acutely, taVNS increased heart rate, blood pressure, and peripheral perfusion index without affecting the corrected QT interval, ICP, or HRV. The acute post-treatment elevation in heart rate was more pronounced in patients who experienced a decrease of more than one point in their modified Rankin Score at the time of discharge.

CONCLUSIONS: Our study found that taVNS treatment did not induce adverse cardiovascular effects, such as bradycardia or QT prolongation, supporting its development as a safe immunomodulatory treatment approach for SAH patients. The observed acute increase in heart rate after taVNS treatment may serve as a biomarker for SAH patients who could derive greater benefit from this treatment.

FUNDING: The American Association of Neurological Surgeons (ALH), The Aneurysm and AVM Foundation (ALH), The National Institutes of Health R01-EB026439, P41-EB018783, U24-NS109103, R21-NS128307 (ECL, PB), McDonnell Center for Systems Neuroscience (ECL, PB), and Fondazione Neurone (PB).

CLINICAL TRIAL NUMBER: NCT04557618.

10aAdult10aAged10aBlood Pressure10aElectrocardiography10aFemale10aHeart Rate10aHumans10aMale10aMiddle Aged10aSubarachnoid Hemorrhage10aTranscutaneous Electric Nerve Stimulation10aVagus Nerve Stimulation1 aTan, Gansheng1 aHuguenard, Anna, L1 aDonovan, Kara, M1 aDemarest, Phillip1 aLiu, Xiaoxuan1 aLi, Ziwei1 aAdamek, Markus1 aLavine, Kory1 aVellimana, Ananthv, K1 aKummer, Terrance, T1 aOsbun, Joshua, W1 aZipfel, Gregory, J1 aBrunner, Peter1 aLeuthardt, Eric, C uhttps://neurotechcenter.org/publications/2025/effect-transcutaneous-auricular-vagus-nerve-stimulation-cardiovascular04492nas a2200409 4500008004100000022001400041245016200055210006900217260000900286300001300295490000700308520319000315653001003505653001103515653001103526653001703537653000903554653001603563653002403579653004203603653002803645653002203673653002803695100002003723700001803743700002303761700001903784700001803803700002103821700001803842700002203860700002003882700002003902700001903922700002003941856012103961 2024 eng d a1932-620300aNon-invasive Auricular Vagus nerve stimulation for Subarachnoid Hemorrhage (NAVSaH): Protocol for a prospective, triple-blinded, randomized controlled trial.0 aNoninvasive Auricular Vagus nerve stimulation for Subarachnoid H c2024 ae03011540 v193 a

BACKGROUND: Inflammation has been implicated in driving the morbidity associated with subarachnoid hemorrhage (SAH). Despite understanding the important role of inflammation in morbidity following SAH, there is no current effective way to modulate this deleterious response. There is a critical need for a novel approach to immunomodulation that can be safely, rapidly, and effectively deployed in SAH patients. Vagus nerve stimulation (VNS) provides a non-pharmacologic approach to immunomodulation, with prior studies demonstrating VNS can reduce systemic inflammatory markers, and VNS has had early success treating inflammatory conditions such as arthritis, sepsis, and inflammatory bowel diseases. The aim of the Non-invasive Auricular Vagus nerve stimulation for Subarachnoid Hemorrhage (NAVSaH) trial is to translate the use of non-invasive transcutaneous auricular VNS (taVNS) to spontaneous SAH, with our central hypothesis being that implementing taVNS in the acute period following spontaneous SAH attenuates the expected inflammatory response to hemorrhage and curtails morbidity associated with inflammatory-mediated clinical endpoints.

MATERIALS AND METHODS: The overall objectives for the NAHSaH trial are to 1) Define the impact that taVNS has on SAH-induced inflammatory markers in the plasma and cerebrospinal fluid (CSF), 2) Determine whether taVNS following SAH reduces radiographic vasospasm, and 3) Determine whether taVNS following SAH reduces chronic hydrocephalus. Following presentation to a single enrollment site, enrolled SAH patients are randomly assigned twice daily treatment with either taVNS or sham stimulation for the duration of their intensive care unit stay. Blood and CSF are drawn before initiation of treatment sessions, and then every three days during a patient's hospital stay. Primary endpoints include change in the inflammatory cytokine TNF-α in plasma and cerebrospinal fluid between day 1 and day 13, rate of radiographic vasospasm, and rate of requirement for long-term CSF diversion via a ventricular shunt. Secondary outcomes include exploratory analyses of a panel of additional cytokines, number and type of hospitalized acquired infections, duration of external ventricular drain in days, interventions required for vasospasm, continuous physiology data before, during, and after treatment sessions, hospital length of stay, intensive care unit length of stay, and modified Rankin Scale score (mRS) at admission, discharge, and each at follow-up appointment for up to two years following SAH.

DISCUSSION: Inflammation plays a central role in morbidity following SAH. This NAVSaH trial is innovative because it diverges from the pharmacologic status quo by harnessing a novel non-invasive neuromodulatory approach and its known anti-inflammatory effects to alter the pathophysiology of SAH. The investigation of a new, effective, and rapidly deployable intervention in SAH offers a new route to improve outcomes following SAH.

TRIAL REGISTRATION: Clinical Trials Registered, NCT04557618. Registered on September 21, 2020, and the first patient was enrolled on January 4, 2021.

10aAdult10aFemale10aHumans10aInflammation10aMale10aMiddle Aged10aProspective Studies10aRandomized Controlled Trials as Topic10aSubarachnoid Hemorrhage10aTreatment Outcome10aVagus Nerve Stimulation1 aHuguenard, Anna1 aTan, Gansheng1 aJohnson, Gabrielle1 aAdamek, Markus1 aCoxon, Andrew1 aKummer, Terrance1 aOsbun, Joshua1 aVellimana, Ananth1 aLimbrick, David1 aZipfel, Gregory1 aBrunner, Peter1 aLeuthardt, Eric uhttps://neurotechcenter.org/publications/2024/non-invasive-auricular-vagus-nerve-stimulation-subarachnoid-hemorrhage02268nas a2200337 4500008004100000022001400041245011100055210006900166260001200235300001100247490000800258520124200266653002501508653001001533653000901543653001701552653002001569653001801589653002601607653002501633653001101658653001101669653000901680653001601689100002301705700003201728700001901760700001901779700001901798856011301817 2021 eng d a1095-957200aModulation in cortical excitability disrupts information transfer in perceptual-level stimulus processing.0 aModulation in cortical excitability disrupts information transfe c11/2021 a1184980 v2433 a

Despite significant interest in the neural underpinnings of behavioral variability, little light has been shed on the cortical mechanism underlying the failure to respond to perceptual-level stimuli. We hypothesized that cortical activity resulting from perceptual-level stimuli is sensitive to the moment-to-moment fluctuations in cortical excitability, and thus may not suffice to produce a behavioral response. We tested this hypothesis using electrocorticographic recordings to follow the propagation of cortical activity in six human subjects that responded to perceptual-level auditory stimuli. Here we show that for presentations that did not result in a behavioral response, the likelihood of cortical activity decreased from auditory cortex to motor cortex, and was related to reduced local cortical excitability. Cortical excitability was quantified using instantaneous voltage during a short window prior to cortical activity onset. Therefore, when humans are presented with an auditory stimulus close to perceptual-level threshold, moment-by-moment fluctuations in cortical excitability determine whether cortical responses to sensory stimulation successfully connect auditory input to a resultant behavioral response.

10aAcoustic Stimulation10aAdult10aAged10aAlpha Rhythm10aAuditory Cortex10aBrain Mapping10aCortical Excitability10aElectrocorticography10aFemale10aHumans10aMale10aMiddle Aged1 aMoheimanian, Ladan1 aParaskevopoulou, Sivylla, E1 aAdamek, Markus1 aSchalk, Gerwin1 aBrunner, Peter uhttps://neurotechcenter.org/publications/2021/modulation-cortical-excitability-disrupts-information-transfer