Diminishing Accelerated Long-term Forgetting in Mild Cognitive Impairment

NCT05289804 | Completed Phase 1

• 2 other identifiers: SPREC102021-23AARG-21-848486
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

This study is designed as a prospective, double-blind, placebo-controlled, randomized parallel-group study that will be completed at the clinical research facility at St. James' Hospital and at Trinity College Dublin, Ireland. A total of 100 amnestic mild cognitive impairment (aMCI) patients will receive a (real or control) non-invasive transcutaneous electrical stimulation procedure. Patients will be assigned to one of four groups. One group will receive active stimulation, while the three groups will be control groups. One groups will be receive sham stimulation (inactive control), while a second group will receive active stimulation and local anesthesia and a third group will stimulate a different nerve (active control; same sensation different nerve). The investigators will include three control groups to verify that the effect is real and location specific and cannot be associated to a sensation effect. The investigators have opted to use a parallel-group design as it is unclear what the carry-over effect and/or wash-out period will be for stimulation. To eliminate subjective bias, all patients and the investigator testing the endpoint measures will be blinded to the type of intervention. The primary outcome, i.e. memory recall, will be determined by a word association task recorded immediately after stimulation, 7 days after stimulation, and 28 days after stimulation. The secondary outcomes is neurophysiological changes determined by resting state EEG, which will be assessed immediately before and after stimulation in the first session. The investigators will conduct this study as follows:

1. 1.Screening aMCI patients.
2. 2.Randomly assigning aMCI patients to one of the four groups.
3. 3.Administering one session active stimulation (n = 25) or control (n = 25 in each of three control group) stimulation paired with a word-association task; administered by research assistant.
4. 4.Behavioral assessments after each of the three blocks of studying the word associations and neural measures immediately after the last session of Behavioral assessments (T0).
5. 5.Behavioral assessments at seven (T1) and 28 (T2) days after stimulation.

Conditions

Memory Impairment; Memory Disorders in Old Age; Mild Cognitive Impairment

Keywords

episodic memory; amnestic mild cognitive impairment; mild Alzheimer's disease; electrical stimulation; greater occipital nerve

Outcome Measures

Primary Outcomes (3)

• Word association task performance immediately after NITEGON/sham

  Patients will perform a Swahili-English word association task. Patients will be asked to learn a list of 50 Swahili-English word pairs. In a test phase, patients will be presented with the Swahili word and asked to type the correct English translation.

  Patients will be tested immediately after NITESGON/sham (T0)

• Word association task performance at 7 days

  Patients will be asked to return for a follow-up test 7 days later. The test will be identical to the test phase from T0 timepoint.

  7 days after NITESGON/sham (T1)

• Word association task performance at 28 days

  Patients will be asked to return for a follow-up test 28 days after NITESGON/sham. The test will be identical to the test phase from T0 timepoint.

  28 days after NITESGON/sham (T2)

Secondary Outcomes (1)

• EEG gamma oscillations

  Resting state EEG will be collected immediately before and immediately after NITESGON/sham.

Study Arms (4)

Active NITESGON

EXPERIMENTAL

One electrode each will be placed over the left and right C2 dermatomes. A constant current will be applied during the word association task.

Device: NITESGON

Sham NITESGON

SHAM COMPARATOR

For sham NITESGON (inactive control), placement of the electrodes will be identical to active NITESGON. Current intensity (ramp down) will gradually be reduced as soon as NITESGON reaches a current flow of 1.5 mA. The rationale behind this sham procedure is to mimic the transient skin sensation at the beginning of active NITESGON without producing any conditioning effects on the brain.

Device: Sham NITESGON

Active NITESGON + local anesthesia

ACTIVE COMPARATOR

For active NITESGON + local anesthesia (active control; local nerve anesthesia group), patients will receive NITESGON, in combination with a topical skin anesthetic (lidocaine/prilocaine cream) to reduce any potential contribution from transcutaneous stimulation of peripheral nerves. A current similar to active NITESGON will be applied.

Device: NITESGON; Drug: Lidocaine / Prilocaine Topical Cream

Active C5/C6

ACTIVE COMPARATOR

For the active C5/C6 group (active control; same sensation different nerve), the electrodes will be placed over cervical nerves five and six, to mimic the sensation, but change the location. A current similar to active NITESGON will be applied.

Device: C5/C6 stimulation

Interventions

C5/C6 stimulation DEVICE

The electrodes will be placed over cervical nerves five and six, to mimic the sensation, but change the location.

Active C5/C6

Sham NITESGON DEVICE

Sham NITESGON

Sham NITESGON

NITESGON DEVICE

NITESGON will be delivered by a specially developed, battery-driven, constant current stimulator via a pair of saline-soaked surface sponges on the scalp. One electrode each will be placed over the left and right C2 dermatomes. NITESGON will first be switched on in a ramp-up fashion over 30 seconds. For active NITESGON, stimulation will occur during the word association task. For sham the current intensity (ramp down) will gradually be reduced (over 5 seconds) as soon as NITESGON reaches a current flow of 1.5 mA. The rationale behind this sham procedure is to mimic the transient skin sensation at the beginning of active NITESGON without producing any conditioning effects on the brain.

Also known as: non-invasive transcutaneous electrical stimulation of the greater occipital nerve, transcutaneous electrical stimulation, tES, stimulation

Active NITESGON; Active NITESGON + local anesthesia

Lidocaine / Prilocaine Topical Cream DRUG

A topical skin anesthetic (lidocaine/prilocaine cream) will be used to reduce any potential contribution from transcutaneous stimulation of peripheral nerves. This lidocaine/prilocaine preparation blocks sodium channels in peripheral nerves in the skin and thereby stabilizes the membrane potential and increases the threshold for firing an action potential.

Also known as: lidocaine/prilocaine cream, local anesthetic

Active NITESGON + local anesthesia

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥50 years
• Diagnosis of probable aMCI or mild AD
• Montreal Cognitive Assessment between 18-25
• Mini Mental State Examination score \>21
• Stable AChl medication \>3 months
• Adequate visual and auditory acuity
• Capacity to understand and sign informed consent

You may not qualify if:

• Any cause of cognitive decline or dementia that is not Alzheimer's disease related including parkinsonism related dementias, vascular dementia, fronto-temporal dementia.
• Enrolment in an ongoing investigational medicinal product study
• History in the past 2 years of epileptic seizures
• Any current major psychiatric disorder
• Evidence of brain damage, including significant trauma, stroke, hydrocephalus, intellectual disability, or serious neurological disorder.
• History of alcoholism or drug abuse within the last 12 months
• Medical devices not eligible for MRI scanning

Sponsors & Collaborators

• Alzheimer's Association: collaborator
• University of Dublin, Trinity College: lead

Study Sites (1)

TCIN

Dublin, Dublin 2, Ireland

Location

Related Publications (4)

• Brunoni AR, Amadera J, Berbel B, Volz MS, Rizzerio BG, Fregni F. A systematic review on reporting and assessment of adverse effects associated with transcranial direct current stimulation. Int J Neuropsychopharmacol. 2011 Sep;14(8):1133-45. doi: 10.1017/S1461145710001690. Epub 2011 Feb 15.

  PMID: 21320389 BACKGROUND

• Luckey AM, McLeod SL, Robertson IH, To WT, Vanneste S. Greater Occipital Nerve Stimulation Boosts Associative Memory in Older Individuals: A Randomized Trial. Neurorehabil Neural Repair. 2020 Nov;34(11):1020-1029. doi: 10.1177/1545968320943573. Epub 2020 Sep 23.

  PMID: 32964776 BACKGROUND

• Vanneste S, Mohan A, Yoo HB, Huang Y, Luckey AM, McLeod SL, Tabet MN, Souza RR, McIntyre CK, Chapman S, Robertson IH, To WT. The peripheral effect of direct current stimulation on brain circuits involving memory. Sci Adv. 2020 Nov 4;6(45):eaax9538. doi: 10.1126/sciadv.aax9538. Print 2020 Nov.

  PMID: 33148657 BACKGROUND

• Adcock KS, Lawlor B, Robertson IH, Vanneste S. Diminishing accelerated long-term forgetting in mild cognitive impairment: Study protocol for a prospective, double-blind, placebo-controlled, randomized controlled trial. Contemp Clin Trials Commun. 2022 Sep 2;30:100989. doi: 10.1016/j.conctc.2022.100989. eCollection 2022 Dec.

  PMID: 36117569 DERIVED

MeSH Terms

Conditions

Cognitive Dysfunction; Memory Disorders

Interventions

Transcutaneous Electric Nerve Stimulation; Lidocaine; Anesthetics, Local

Condition Hierarchy (Ancestors)

Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Electric Stimulation Therapy; Therapeutics; Physical Therapy Modalities; Rehabilitation; Analgesia; Anesthesia and Analgesia; Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Anesthetics; Central Nervous System Depressants; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses; Sensory System Agents; Peripheral Nervous System Agents; Central Nervous System Agents; Therapeutic Uses

Study Officials

• Sven Vanneste, PhD

  University of Dublin, Trinity College

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: The investigators have opted to use a parallel-group design as it is unclear what the carry-over effect and/or wash-out period will be for NITESGON. Patients will be randomized after the baseline evaluation and will be assigned to receive one of the four possible types of NITESGON. To eliminate subjective bias, all patients and the investigator testing the endpoint measures will be blinded to the type of intervention.

Study Record Dates

• First Submitted: February 22, 2022
• First Posted: March 21, 2022
• Study Start: September 1, 2022
• Primary Completion: December 31, 2025
• Study Completion: January 1, 2026
• Last Updated: January 26, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

IE (1)