Vagus Nerve Stimulation for Alzheimer's Disease
(WALLe Trial)
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Academic
Recruiting
Sponsor: Massachusetts General Hospital
Must not be taking: Investigational drugs
Disqualifiers: MCI, Dementia, Schizophrenia, Substance abuse, others
No Placebo Group
Trial Summary
What is the purpose of this trial?
In this research study the investigators want to find out if a non-invasive electrical brain stimulation method called RAVANS (also called tVNS) can have a beneficial effect on cognition in older individuals. The investigators also want to understand whether certain individual factors contribute to the effect of RAVANS on cognition. RAVANS is only used in research studies.
Will I have to stop taking my current medications?
The trial requires that your medications be stable for at least 30 days before participating, so you may need to continue your current medications without changes.
What data supports the effectiveness of the treatment Vagus Nerve Stimulation for Alzheimer's Disease?
Transcutaneous vagus nerve stimulation (tVNS) has been shown to modulate brain activity and has been used successfully for conditions like epilepsy and depression, suggesting potential benefits for Alzheimer's Disease. It is a non-invasive method that stimulates the vagus nerve through the skin, which may help in managing symptoms by affecting brain function.12345
Is transcutaneous auricular vagus nerve stimulation (taVNS) safe for humans?
How does the treatment of transcutaneous vagus nerve stimulation for Alzheimer's disease differ from other treatments?
This treatment is unique because it uses non-invasive electrical stimulation of the ear to activate the vagus nerve, which may enhance cognitive function without the need for surgery or medication. Unlike traditional treatments, it offers a novel approach by potentially improving brain function through the modulation of neural pathways and cardiovascular stability.910111213
Eligibility Criteria
This trial is for individuals aged 60-85 with mild Alzheimer's or aging-related cognitive decline, fluent in English, and have stable health conditions like controlled hypertension. They must score within certain limits on cognitive tests and be right-handed. Exclusions include metal implants incompatible with MRI, severe psychiatric disorders, active cancer or heart disease, major head trauma history, substance abuse within the past two years.Inclusion Criteria
Fluent in English
Right-handed
Willingness and ability to comply with scheduled visits, magnetic resonance imaging (MRI) scanning, laboratory tests, and other study procedures
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Exclusion Criteria
I have an active blood, kidney, lung, hormone, or liver disorder.
I have a serious heart condition or have had a stroke.
Substance abuse within the past 2 years
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Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Cross-over Intervention
Participants undergo a cross-over design of sham versus RAVANS stimulation during a functional magnetic resonance imaging (fMRI) task
4 weeks
2 sessions
Treatment
Participants receive daily tVNS or sham sessions during 10 visits
2 weeks
10 visits (in-person)
Follow-up
Participants undergo two follow-up cognitive assessments to monitor changes in cognition and inflammatory responses
4 months
2 visits (in-person)
Treatment Details
Interventions
- Active transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions (Behavioural Intervention)
- Sham transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions (Behavioural Intervention)
Trial OverviewThe study examines if RAVANS (non-invasive electrical brain stimulation) can improve cognition in older adults. Participants will receive either the actual tVNS treatment or a sham (fake) version during ten-minute sessions to compare effects on brain function.
Participant Groups
6Treatment groups
Experimental Treatment
Placebo Group
Group I: cross-over Stimulation-ShamExperimental Treatment2 Interventions
Cross-over: experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) followed by sham One time RAVANS versus one time Sham Two weeks wash-out
Group II: cross-over Sham-StimulationExperimental Treatment2 Interventions
Cross-over: Sham followed by experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) One time RAVANS versus one time Sham Two weeks wash-out
Group III: Stimulation preceded by cross-over Stimulation-ShamExperimental Treatment1 Intervention
Cross-over: experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) followed by sham Wash-out period of four weeks Ten daily sessions of RAVANS during 2 weeks
Group IV: Stimulation preceded by cross-over Sham-StimulationExperimental Treatment1 Intervention
Cross-over: Sham followed by experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) Wash-out period of four weeks Ten daily sessions of RAVANS during 2 weeks
Group V: Sham preceded by cross-over Sham-StimulationPlacebo Group1 Intervention
Cross-over: Sham followed by experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) Wash-out period of four weeks Ten daily sessions of sham during 2 weeks
Group VI: Sham preceded by cross-over Stimulation-ShamPlacebo Group1 Intervention
Cross-over: experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) followed by Sham Wash-out period of four weeks Ten daily sessions of sham during 2 weeks
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Massachusetts General HospitalCharlestown, MA
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Who Is Running the Clinical Trial?
Massachusetts General HospitalLead Sponsor
National Institute on Aging (NIA)Collaborator
References
Transcutaneous vagus nerve stimulation: retrospective assessment of cardiac safety in a pilot study. [2022]Vagus nerve stimulation has been successfully used as a treatment strategy for epilepsy and affective disorders for years. Transcutaneous vagus nerve stimulation (tVNS) is a new non-invasive method to stimulate the vagus nerve, which has been shown to modulate neuronal activity in distinct brain areas.
Laboratory Administration of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS): Technique, Targeting, and Considerations. [2020]Non-invasive vagus nerve stimulation (VNS) may be administered via a novel, emerging neuromodulatory technique known as transcutaneous auricular vagus nerve stimulation (taVNS). Unlike cervically-implanted VNS, taVNS is an inexpensive and non-surgical method used to modulate the vagus system. taVNS is appealing as it allows for rapid translation of basic VNS research and serves as a safe, inexpensive, and portable neurostimulation system for the future treatment of central and peripheral disease. The background and rationale for taVNS is described, along with electrical and parametric considerations, proper ear targeting and attachment of stimulation electrodes, individual dosing via determination of perception threshold (PT), and safe administration of taVNS.
Evoked pain analgesia in chronic pelvic pain patients using respiratory-gated auricular vagal afferent nerve stimulation. [2022]Previous vagus nerve stimulation (VNS) studies have demonstrated antinociceptive effects, and recent noninvasive approaches, termed transcutaneous-vagus nerve stimulation (t-VNS), have utilized stimulation of the auricular branch of the vagus nerve in the ear. The dorsal medullary vagal system operates in tune with respiration, and we propose that supplying vagal afferent stimulation gated to the exhalation phase of respiration can optimize t-VNS.
Transcutaneous auricular vagus nerve stimulation therapy in patients with cognitively preserved structural focal epilepsy: A case series report. [2023]Transcutaneous auricular vagus nerve stimulation (taVNS) was performed in two patients suffering structural focal epilepsy with preserved intellectual ability to show the feasibility of taVNS for specific patient groups.
[Clinical Application of Transcutaneous Auricular Vagus Nerve Stimulation]. [2022]Transcutaneous auricular vagus nerve stimulation (taVNS) refers to stimulation of the vagus nerve through the skin of the left cymba conchae and is a unique strategy that is investigated as a useful therapeutic approach for a variety of conditions including epilepsy, depression, cardiac diseases, tinnitus, and migraine. A randomized double-blind clinical trial was performed in patients with drug-resistant epilepsy. Although several pilot studies were performed before this trial and showed that taVNS was safe, well tolerated, and feasible for long-term treatment, no statistically significant difference was observed between the high- and low-stimulation groups, and further studies are warranted to gain a deeper understanding of this subject. A tingling sensation or pain at the site of stimulation is the most common adverse effect associated with taVNS. Therefore, intermittent stimulation, ranging from 30 minutes to several hours, is provided during each session several times a day. Currently, taVNS is not approved for insurance coverage by the Japan Ministry of Health, Labour, and Welfare. Further studies and investigations are necessary in the near future.
Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis. [2023]Transcutaneous auricular vagus nerve stimulation (taVNS) has been investigated as a novel neuromodulation tool. Although taVNS is generally considered safe with only mild and transient adverse effects (AEs), those specifically caused by taVNS have not yet been investigated. This systematic review and meta-analysis on taVNS aimed to (1) systematically analyze study characteristics and AE assessment, (2) characterize and analyze possible AEs and their incidence, (3) search for predictable risk factors, (4) analyze the severity of AE, and (5) suggest an evidence-based taVNS adverse events questionnaire for safety monitoring. The articles searched were published through April 7, 2022, in Medline, Embase, Web of Science, Cochrane, and Lilacs databases. In general, we evaluated 177 studies that assessed 6322 subjects. From these, 55.37% of studies did not mention the presence or absence of any AEs; only 24.86% of the studies described that at least one adverse event occurred. In the 35 studies reporting the number of subjects with at least one adverse event, a meta-analytic approach to calculate the risk differences of developing an adverse event between active taVNS and controls was used. The meta-analytic overall adverse events incidence rate was calculated for the total number of adverse events reported on a 100,000 person-minutes-days scale. There were no differences in risk of developing an adverse event between active taVNS and controls. The incidence of AE, in general, was 12.84/100,000 person-minutes-days of stimulation, and the most frequently reported were ear pain, headache, and tingling. Almost half of the studies did not report the presence or absence of any AEs. We attribute this to the absence of AE in those studies. There was no causal relationship between taVNS and severe adverse events. This is the first systematic review and meta-analysis of transcutaneous auricular stimulation safety. Overall, taVNS is a safe and feasible option for clinical intervention.
Transcutaneous auricular vagus nerve stimulators: a review of past, present, and future devices. [2022]As an emerging neuromodulation therapy, transcutaneous auricular vagus nerve stimulation (taVNS) has been proven to be safe and effective for epilepsy, major depressive disorders, insomnia, glucose metabolic disorders, pain, stroke, post stroke rehabilitation, anxiety, fear, cognitive impairment, cardiovascular disorders, tinnitus, Prader-Willi Syndrome, and COVID-19.
Transcutaneous Auricular Vagus Nerve Stimulation Normalizes Induced Gastric Myoelectrical Dysrhythmias in Controls Assessed by Body-Surface Gastric Mapping. [2023]Transcutaneous auricular vagus nerve stimulation (TaVNS) is a supplementary treatment for gastric symptoms resulting from dysrhythmias. The main objective of this study was to quantify the effects of 10, 40, and 80 Hz TaVNS and sham in healthy individuals in response to a 5-minute water-load (WL5) test.
Transcutaneous vagus nerve stimulation - A brief introduction and overview. [2022]Invasive cervical vagus nerve stimulation (VNS) is approved for the treatment of epilepsies, depression, obesity, and for stroke-rehabilitation. The procedure requires surgery, has side-effects, is expensive and not readily available. Consequently, transcutaneous VNS (tVNS) has been developed 20 years ago as non-invasive, less expensive, and easily applicable alternative. Since the vagus nerve reaches the skin at the outer acoustic canal and ear, and reflex-responses such as the ear-cough-reflex or the auriculo-cardiac reflex have been observed upon auricular stimulation, the ear seems well suited for tVNS. However, several sensory nerves with variable fiber-density and significant overlap innervate the outer ear: the auricular branch of the vagus nerve (ABVN), the auriculotemporal nerve, greater auricular nerve, and to some extent the lesser occipital nerve. VNS requires activation of Aβ-fibers which are far less present in the ABVN than the cervical vagus nerve. Thus, optimal stimulation sites and parameters, and tVNS-algorithms need to be further explored. Unravelling central pathways and structures that mediate tVNS-effects is another challenge. tVNS impulses reach the nucleus of the solitary tract and activate the locus-coeruleus-norepinephrine system. However, many more brain areas are activated or deactivated upon VNS, including structures of the central autonomic network and the limbic system. Still, the realm of therapeutic tVNS applications grows rapidly and includes medication-refractory epilepsies, depressive mood disorders, headaches including migraine, pain, heart failure, gastrointestinal inflammatory diseases and many more. tVNS might become a standard tool to enhance autonomic balance and function in various autonomic, neurological, psychiatric, rheumatologic, as well as other diseases.
Neurophysiologic effects of transcutaneous auricular vagus nerve stimulation (taVNS) via electrical stimulation of the tragus: A concurrent taVNS/fMRI study and review. [2020]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.
Cognition-enhancing effect of vagus nerve stimulation in patients with Alzheimer's disease: a pilot study. [2022]Vagus nerve stimulation (VNS) is an established treatment method for therapy-refractory epilepsy and, in Europe, for treatment-resistant depression also. Clinical and experimental investigations have also shown positive effects of VNS on cognition in epilepsy and depression. The purpose of the present pilot study was to investigate the effect of VNS on cognition in patients with Alzheimer's disease.
Vagus nerve stimulation in patients with Alzheimer's disease: Additional follow-up results of a pilot study through 1 year. [2022]Cognitive-enhancing effects of vagus nerve stimulation (VNS) have been reported during 6 months of treatment in a pilot study of patients with Alzheimer's disease (AD). Data through 1 year of VNS (collected from June 2000 to September 2003) are now reported.
"The Wandering Nerve Linking Heart and Mind" - The Complementary Role of Transcutaneous Vagus Nerve Stimulation in Modulating Neuro-Cardiovascular and Cognitive Performance. [2022]The vagus nerve is the longest nerve in the human body, providing afferent information about visceral sensation, integrity and somatic sensations to the CNS via brainstem nuclei to subcortical and cortical structures. Its efferent arm influences GI motility and secretion, cardiac ionotropy, chonotropy and heart rate variability, blood pressure responses, bronchoconstriction and modulates gag and cough responses via palatine and pharyngeal innervation. Vagus nerve stimulation has been utilized as a successful treatment for intractable epilepsy and treatment-resistant depression, and new non-invasive transcutaneous (t-VNS) devices offer equivalent therapeutic potential as invasive devices without the surgical risks. t-VNS offers exciting potential as a therapeutic intervention in cognitive decline and aging populations, classically affected by reduced cerebral perfusion by modulating both limbic and frontal cortical structures, regulating cerebral perfusion and improving parasympathetic modulation of the cardiovascular system. In this narrative review we summarize the research to date investigating the cognitive effects of VNS therapy, and its effects on neurocardiovascular stability.