Transcutaneous Auricular Vagus Nerve Stimulation Attenuates Early Increases in Heart Rate Associated With the Cold Pressor Test.

INTRODUCTION: Transcutaneous auricular vagus nerve stimulation (taVNS) may be useful in treating disorders characterized by chronic parasympathetic disinhibition. Acute taVNS decreases resting heart rate in healthy individuals, but little is known regarding the effects of taVNS on the cardiac response to an acute stressor. To investigate effects on the acute stress response, we investigated how taVNS affected heart rate changes during a cold pressor test (CPT), a validated stress induction technique that reliably elicits a sympathetic stress response with marked increases in heart rate, anxiety, stress, and pain. MATERIALS AND METHODS: We recruited 24 healthy adults (ten women, mean age = 29 years) to participate in this randomized, crossover, exploratory trial. Each subject completed two taVNS treatments (one active, one sham) paired with CPTs in the same session. Order of active versus sham stimulation was randomized. Heart rate, along with ratings of anxiety, stress, and pain, was collected before, during, and after each round of taVNS/sham + CPT. RESULTS: In both stimulation conditions, heart rate was elevated from baseline in response to the CPT. Analyses also revealed a difference between active and sham taVNS during the first 40 seconds of the CPT (Δ heart rate [HR] = 12.75 ± 7.85 in the active condition; Δ HR = 16.09 ± 11.43 in the sham condition, p = 0.044). There were no significant differences in subjective ratings between active and sham taVNS. CONCLUSIONS: In this randomized, sham-controlled study, taVNS attenuated initial increases in HR in response to the CPT. Future studies are needed to investigate the effects of various taVNS doses and parameters on the CPT, in addition to other forms of stress induction. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT00113453.

A pilot randomized controlled trial of supervised, at-home, self-administered transcutaneous auricular vagus nerve stimulation (taVNS) to manage long COVID symptoms.

BACKGROUND: Although the coronavirus disease 19 (COVID-19) pandemic has now impacted the world for over two years, the persistent secondary neuropsychiatric effects are still not fully understood. These "long COVID" symptoms, also referred to as post-acute sequelae of SARS-CoV-2 infection (PASC), can persist for months after infection without any effective treatments. Long COVID involves a complex heterogenous symptomology and can lead to disability and limit work. Long COVID symptoms may be due to sustained inflammatory responses and prolonged immune response after infection. Interestingly, vagus nerve stimulation (VNS) may have anti-inflammatory effects, however, until recently, VNS could not be self-administered, at-home, noninvasively. METHODS: We created a double-blind, noninvasive transcutaneous auricular VNS (taVNS) system that can be self-administered at home with simultaneous remote monitoring of physiological biomarkers and video supervision by study staff. Subsequently, we carried out a pilot (n = 13) randomized, sham-controlled, trial with this system for four weeks to treat nine predefined long covid symptoms (anxiety, depression, vertigo, anosmia, ageusia, headaches, fatigue, irritability, brain fog). No in-person patient contact was needed, with informed consent, trainings, ratings, and all procedures being conducted remotely during the pandemic (2020-2021) and equipment being shipped to individuals' homes. This trial was registered on ClinicalTrials.gov under the identifier: NCT04638673 registered November 20, 2020. RESULTS: Four-weeks of at-home self-administered taVNS (two, one-hour sessions daily, delivered at suprathreshold intensities) was feasible and safe. Although our trial was not powered to determine efficacy as an intervention in a heterogenous population, the trends in the data suggest taVNS may have a mild to moderate effect in reducing mental fatigue symptoms in a subset of individuals. CONCLUSIONS: This innovative study demonstrates the safety and feasibility of supervised self-administered taVNS under a fully contactless protocol and suggests that future studies can safely investigate this novel form of brain stimulation at-home for a variety of neuropsychiatric and motor recovery applications.

Neurophysiologic Effects of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) via Electrical Stimulation of the Tragus: A Concurrent taVNS/fMRI Study and Review.

(Appeared originally in Brain Stimulation 2018; 11:492-500) Reprinted with permission from Elsevier.

The Future Is Noninvasive: A Brief Review of the Evolution and Clinical Utility of Vagus Nerve Stimulation.

Vagus nerve stimulation (VNS) is a form of neuromodulation that stimulates the vagus nerve. VNS had been suggested as an intervention in the late 1800s and was rediscovered in the late 1980s as a promising treatment for refractory epilepsy. Since then, VNS has been approved by the U.S. Food and Drug Administration (FDA) for treatment of epilepsy, morbid obesity, and treatment-resistant depression. Unfortunately, VNS is underutilized, as it is costly to implant and often only suggested when all other treatment options have been exhausted. Discovery of a noninvasive method of VNS known as transcutaneous auricular VNS (taVNS), which activates the vagus through stimulation of the auricular branch of the vagus nerve, has reignited excitement around VNS. taVNS has immense potential as a safe, at-home, wearable treatment for various neuropsychiatric disorders. Major strides are being made in both invasive and noninvasive VNS that aim to make this technology more accessible to patients who would find benefit, including the ongoing RECOVER trial, a randomized controlled trial in up to 1,000 individuals to further evaluate the efficacy of VNS for treatment-resistant depression. In this brief review, we first discuss the early history of VNS; then its clinical utility in FDA-approved indications; and, finally, noninvasive VNS.

Sonication of the Anterior Thalamus With MRI-Guided Transcranial Focused Ultrasound (tFUS) Alters Pain Thresholds in Healthy Adults: A Double-Blind, Sham-Controlled Study.

(Appeared originally in Brain Stimulation 2020; 13:1805-1812) Reprinted with permission from Elsevier.

A pilot randomized controlled trial of supervised, at-home, self-administered transcutaneous auricular vagus nerve stimulation (taVNS) to manage long COVID symptoms.

Background Although the coronavirus disease 19 (COVID-19) pandemic has now impacted the world for over two years, the persistent secondary neuropsychiatric effects are still not fully understood. These "long COVID" symptoms, also referred to as post-acute sequelae of SARS-CoV-2 infection (PASC), can persist for months after infection without any effective treatments. Long COVID involves a complex heterogenous symptomology and can lead to disability and limit work. Long COVID symptoms may be due to sustained inflammatory responses and prolonged immune response after infection. Interestingly, vagus nerve stimulation (VNS) may have anti-inflammatory effects, however, until recently, VNS could not be self-administered, at-home, noninvasively. Methods We created a double-blind, noninvasive transcutaneous auricular VNS (taVNS) system that can be self-administered at home with simultaneous remote monitoring of physiological biomarkers and video supervision by study staff. Subsequently, we carried out a pilot (n = 13) randomized, sham-controlled, trial with this system for four weeks to treat nine predefined long covid symptoms (anxiety, depression, vertigo, anosmia, ageusia, headaches, fatigue, irritability, brain fog). No in-person patient contact was needed, with informed consent, trainings, ratings, and all procedures being conducted remotely during the pandemic (2020-2021) and equipment being shipped to individuals' homes. This trial was registered onClinicalTrials.gov under the identifier: NCT04638673. Results Four-weeks of at-home self-administered taVNS (two, one-hour sessions daily, delivered at suprathreshold intensities) was feasible and safe. Although our trial was not powered to determine efficacy as an intervention in a heterogenous population, the trends in the data suggest taVNS may have a mild to moderate effect in reducing mental fatigue symptoms in a subset of individuals. This innovative study demonstrates the safety and feasibility of supervised self-administered taVNS under a fully contactless protocol and suggests that future studies can safely investigate this novel form of brain stimulation at-home for a variety of neuropsychiatric and motor recovery applications.

A Comprehensive Review of Vagus Nerve Stimulation for Depression.

OBJECTIVES: Vagus nerve stimulation (VNS) is reemerging as an exciting form of brain stimulation, due in part to the development of its noninvasive counterpart transcutaneous auricular VNS. As the field grows, it is important to understand where VNS emerged from, including its history and the studies that were conducted over the past four decades. Here, we offer a comprehensive review of the history of VNS in the treatment of major depression. MATERIALS AND METHODS: Using PubMed, we reviewed the history of VNS and aggregated the literature into a narrative review of four key VNS epochs: 1) early invention and development of VNS, 2) path to Food and Drug Administration (FDA) approval for depression, 3) refinement of VNS treatment parameters, and 4) neuroimaging of VNS. RESULTS: VNS was described in the literature in the early 1900s; however, gained traction in the 1980s as Zabara and colleagues developed an implantable neurocybernetic prosthesis to treat epilepsy. As epilepsy trials proceed in the 1990s, promising mood effects emerged and were studied, ultimately leading to the approval of VNS for depression in 2005. Since then, there have been advances in understanding the mechanism of action. Imaging techniques like functional magnetic resonance imaging and positron emission tomography further aid in understanding direct brain effects of VNS. CONCLUSIONS: The mood effects of VNS were discovered from clinical trials investigating the use of VNS for reducing seizures in epileptic patients. Since then, VNS has gone on to be FDA approved for depression. The field of VNS is growing, and as noninvasive VNS quickly advances, it is important to consider a historical perspective to develop future brain stimulation therapies.

A Review of Parameter Settings for Invasive and Non-invasive Vagus Nerve Stimulation (VNS) Applied in Neurological and Psychiatric Disorders.

Vagus nerve stimulation (VNS) is an established form of neuromodulation with a long history of promising applications. Earliest reports of VNS in the literature date to the late 1800's in experiments conducted by Dr. James Corning. Over the past century, both invasive and non-invasive VNS have demonstrated promise in treating a variety of disorders, including epilepsy, depression, and post-stroke motor rehabilitation. As VNS continues to rapidly grow in popularity and application, the field generally lacks a consensus on optimum stimulation parameters. Stimulation parameters have a significant impact on the efficacy of neuromodulation, and here we will describe the longitudinal evolution of VNS parameters in the following categorical progression: (1) animal models, (2) epilepsy, (3) treatment resistant depression, (4) neuroplasticity and rehabilitation, and (5) transcutaneous auricular VNS (taVNS). We additionally offer a historical perspective of the various applications and summarize the range and most commonly used parameters in over 130 implanted and non-invasive VNS studies over five applications.

Sonication of the anterior thalamus with MRI-Guided transcranial focused ultrasound (tFUS) alters pain thresholds in healthy adults: A double-blind, sham-controlled study.

BACKGROUND: Transcranial focused ultrasound (tFUS) is a noninvasive brain stimulation method that may modulate deep brain structures. This study investigates whether sonication of the right anterior thalamus would modulate thermal pain thresholds in healthy individuals. METHODS: We enrolled 19 healthy individuals in this three-visit, double-blind, sham-controlled, crossover trial. Participants first underwent a structural MRI scan used solely for tFUS targeting. They then attended two identical experimental tFUS visits (counterbalanced by condition) at least one week apart. Within the MRI scanner, participants received two, 10-min sessions of either active or sham tFUS spread 10 min apart targeting the right anterior thalamus [fundamental frequency: 650 kHz, Pulse repetition frequency: 10 Hz, Pulse Width: 5 ms, Duty Cycle: 5%, Sonication Duration: 30s, Inter-Sonication Interval: 30 s, Number of Sonications: 10, ISPTA.0 995 mW/cm2, ISPTA.3 719 mW/cm2, Peak rarefactional pressure 0.72 MPa]. The primary outcome measure was quantitative sensory thresholding (QST), measuring sensory, pain, and tolerance thresholds to a thermal stimulus applied to the left forearm before and after right anterior thalamic tFUS. RESULTS: The right anterior thalamus was accurately sonicated in 17 of the 19 subjects. Thermal pain sensitivity was significantly attenuated after active tFUS. The pre-post x active-sham interaction was significant (F(1,245.95) = 4.03, p = .046). This interaction indicates that in the sham stimulation condition, thermal pain thresholds decreased 1.08 °C (SE = 0.28) pre-post session, but only decreased .51 °C (SE = 0.30) pre-post session in the active stimulation group. CONCLUSIONS: Two 10-min sessions of anterior thalamic tFUS induces antinociceptive effects in healthy individuals. Future studies should optimize the parameter space, dose and duration of this effect which may lead to multi-session tFUS interventions for pain disorders.

Short trains of transcutaneous auricular vagus nerve stimulation (taVNS) have parameter-specific effects on heart rate.

BACKGROUND: Optimal parameters of transcutaneous auricular vagus nerve stimulation (taVNS) are still undetermined. Given the vagus nerve's role in regulating heart rate (HR), it is important to determine safety and HR effects of various taVNS parameters. OBJECTIVE: We conducted two sequential trials to systematically test the effects of various taVNS parameters on HR. METHODS: 15 healthy individuals participated in the initial two-visit, crossover exploratory trial, receiving either tragus (active) or earlobe (control) stimulation each visit. Nine stimulation blocks of varying parameters (pulse width: 100 µs, 200 µs, 500 µs; frequency: 1 Hz, 10 Hz, 25 Hz) were administered each visit. HR was recorded and analyzed for stimulation-induced changes. Using similar methods and the two best parameters from trial 1 (500µs 10 Hz and 500µs 25 Hz), 20 healthy individuals then participated in a follow-up confirmatory study. RESULTS: Trial 1- There was no overall effect of the nine conditions on HR during stimulation. However multivariate analysis revealed two parameters that significantly decreased HR during active stimulation compared to control (500µs 10 Hz and 500µs 25 Hz; p < 0.01). Additionally, active taVNS significantly attenuated overall sympathetic HR rebound (post-stimulation) compared to control (p < 0.001). Trial 2-For these two conditions, active taVNS significantly decreased HR compared to control (p = 0.02), with the strongest effects at 500µs 10 Hz (p = 0.032). CONCLUSION: These studies suggest that 60s blocks of tragus stimulation are safe, and some specific parameters modulate HR. Of the nine parameters studied, 500µs 10 Hz induced the greatest HR effects.

Neurophysiologic effects of transcutaneous auricular vagus nerve stimulation (taVNS) via electrical stimulation of the tragus: A concurrent taVNS/fMRI study and review.

BACKGROUND: Electrical stimulation of the auricular branch of the vagus nerve (ABVN) via transcutaneous auricular vagus nerve stimulation (taVNS) may influence afferent vagal networks. There have been 5 prior taVNS/fMRI studies, with inconsistent findings due to variability in stimulation targets and parameters. OBJECTIVE: We developed a taVNS/fMRI system to enable concurrent electrical stimulation and fMRI acquisition to compare the effects of taVNS in relation to control stimulation. METHODS: We enrolled 17 healthy adults in this single-blind, crossover taVNS/fMRI trial. Based on parameters shown to affect heart rate in healthy volunteers, participants received either left tragus (active) or earlobe (control) stimulation at 500 µs 25 HZ for 60 s (repeated 3 times over 6 min). Whole brain fMRI analysis was performed exploring the effect of: active stimulation, control stimulation, and the comparison. Region of interest analysis of the midbrain and brainstem was also conducted. RESULTS: Active stimulation produced significant increased BOLD signal in the contralateral postcentral gyrus, bilateral insula, frontal cortex, right operculum, and left cerebellum. Control stimulation produced BOLD signal activation in the contralateral postcentral gyrus. In the active vs. control contrast, tragus stimulation produced significantly greater BOLD increases in the right caudate, bilateral anterior cingulate, cerebellum, left prefrontal cortex, and mid-cingulate. CONCLUSION: Stimulation of the tragus activates the cerebral afferents of the vagal pathway and combined with our review of the literature suggest that taVNS is a promising form of VNS. Future taVNS/fMRI studies should systematically explore various parameters and alternative stimulation targets aimed to optimize this novel form of neuromodulation.

What goes up, can come down: Novel brain stimulation paradigms may attenuate craving and craving-related neural circuitry in substance dependent individuals.

Vulnerability to drug related cues is one of the leading causes for continued use and relapse among substance dependent individuals. Using drugs in the face of cues may be associated with dysfunction in at least two frontal-striatal neural circuits: (1) elevated activity in medial and ventral areas that govern limbic arousal (including the medial prefrontal cortex (MPFC) and ventral striatum) or (2) depressed activity in dorsal and lateral areas that govern cognitive control (including the dorsolateral prefrontal cortex (DLPFC) and dorsal striatum). Transcranial magnetic stimulation (TMS) is emerging as a promising new tool for the attenuation of craving among multiple substance dependent populations. To date however, nearly all repetitive TMS studies in addiction have focused on amplifying activity in frontal-striatal circuits that govern cognitive control. This manuscript reviews recent work using TMS as a tool to decrease craving for multiple substances and provides a theoretical model for how clinical researchers might approach target and frequency selection for TMS of addiction. To buttress this model, preliminary data from a single-blind, sham-controlled, crossover study of 11 cocaine-dependent individuals is also presented. These results suggest that attenuating MPFC activity through theta burst stimulation decreases activity in the striatum and anterior insula. It is also more likely to attenuate craving than sham TMS. Hence, while many TMS studies are focused on applying LTP-like stimulation to the DLPFC, the MPFC might be a new, efficacious, and treatable target for craving in cocaine dependent individuals.