Effects of Electrical Stimulation on Verbal Learning in Typical and Atypical Alzheimer's Disease

NCT ID: NCT04122001

Last Updated: 2025-09-09

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 90 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-08-17
• Study Completion Date: 2026-05-31

Brief Summary

Alzheimer's disease (AD) is the leading neurodegenerative disease of aging characterized by multiple cognitive impairments. Given the recent failures of disease-modifying drugs, the current focus is on preventing or mitigating synaptic damage that correlates with cognitive decline in AD patients. Transcranial Direct Current Stimulation (tDCS) is a safe, non-invasive, non-painful electrical stimulation of the brain that is shown to act as a primer at the synaptic level when administered along with behavioral therapy, mostly involving language, learning and memory. Previous studies have shown that tDCS over the left angular gyrus (AG) improves language associative learning in the elderly through changes in functional connectivity between the AG and the hippocampus. The investigators' previous clinical trial on the effects of tDCS in neurodegenerative disorders has also shown augmented effects of lexical retrieval for tDCS. In the present study the investigators will compare the effects of active vs. sham tDCS over the AG-an area that is part of the default mode network but also a language area, particularly important for semantic integration and event processing-in two predominant AD variants: probable AD with amnesic phenotype (amnesic/typical AD) and probable AD with non-amnesic (language deficit) phenotype also described as logopenic variant PPA with AD pathology (aphasic/atypical AD). The investigators aim to: (1) determine whether active high-definition tDCS (HD-tDCS) targeting the left AG combined with a Word-List Learning Intervention (WordLLI) will improve verbal learning; (2) identify the changes in functional connectivity between the stimulated area (AG) and other structurally and functionally connected areas using resting-state functional magnetic resonance imaging; (3) identify changes in the inhibitory neurotransmitter GABA at the stimulation site using magnetic resonance spectroscopy. Furthermore, the investigators need to determine the characteristics of the people that may benefit from the new neuromodulatory approaches. For this reason, the investigators will evaluate neural and cognitive functions as well as physiological characteristics such as sleep, and will analyze the moderating effects on verbal learning outcomes. Study results can help provide treatment alternatives as well as a better understanding of the therapeutic and neuromodulatory effects of tDCS in AD, thus improving patients' and caregivers' quality of life.

Detailed Description

The investigation implements a double-blind, sham-controlled, within-subject, cross-over design that allows for the evaluation of the cognitive and neural effects of word-list learning as modulated by tDCS compared to sham stimulation. Participants in all groups will receive word-list learning intervention (WordLLI)+ High-Definition tDCS (HD-tDCS) or WordLLI+ sham in Period 1 or 2, randomized for the Period 1 stimulation condition. Each learning Period will last 2 weeks, with 5 learning sessions per week (for a total of 10 learning sessions per Period) with a 3-month (stimulation-free) wash-out period between the two Periods. The intensity, total number of learning sessions and number of learning items is consistent with most other tDCS studies in neurodegenerative disorders and the investigators have used this design successfully over the past 7 years in neurodegenerative disorders (PPA, mild AD). Stimulation is implemented every weekday to take advantage of the long-term potentiation induced by tDCS as found in early multi-session studies. A tDCS-only condition (without any intervention) is not implemented in this design because no study to date has shown improvement on motor, cognitive, or language performance after anodal tDCS-only for 2 or even more weeks. After each period the investigators will perform 1-month and 3-month follow-up sessions for evaluation purposes. For those participants who are long-distance, at the 1-month time point only the investigators may use a video conferencing tool such as GoToMeeting to administer the assessments. This is to mitigate the costs of travel for a short appointment.

Conditions

Alzheimer Disease, Early Onset; Atypical Alzheimer's Disease; Logopenic Progressive Aphasia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Active HD-tDCS+word intervention then Sham+word intervention

Participants will receive active HD-tDCS + Word List Learning Intervention (WordLLI) and then receive Sham + WordLLI after a three-month washout period.

Group Type: EXPERIMENTAL

Active, in-person HD-tDCS or active remote tDCS

Intervention Type: DEVICE

Stimulation will be delivered by a battery-driven constant current stimulator. The electrical current will be administered to a pre-specified region of the brain (angular gyrus). The stimulation will be delivered at an intensity of 2 milliamperes (mA) (estimated current density 0.04 mA/cm2; estimated total charge 0.048 Coulombs/cm2) in a ramp-like fashion for a maximum of 20 minutes. In the active, in-person HD-tDCS the current is delivered in a ring configuration. In the active remote tDCS current is delivered in one electrode patch.

Sham

Intervention Type: DEVICE

Current will be administered in a ramp-like fashion but after the ramping the intensity will drop to 0 mA. Current under the Sham condition will last for a maximum of 30 seconds.

Word List Learning Intervention (WordLLI)

Intervention Type: OTHER

Participants will receive a word list learning intervention (WordLLI) of semantically related and unrelated word lists. Word lists are presented across 10 trials, with an additional trial after a 10-minute delay to assess delayed recall. Immediately following verbal presentation of word lists during each trial, participants will be instructed to recall as many of the words from the list as possible. Participants may use the written modality as a strategy during recall. Word lists include 12 words matched based on psycholinguistics attributes (e.g., imageability, frequency). This task is designed to help participants improve memory via enhancing list learning capabilities.

Sham+word intervention then active HD-tDCS+word intervention

Participants will receive Sham + Word List Learning Intervention (WordLLI) and then active HD-tDCS + WordLLI after a three-month washout period.

Group Type: EXPERIMENTAL

Active, in-person HD-tDCS or active remote tDCS

Intervention Type: DEVICE

Stimulation will be delivered by a battery-driven constant current stimulator. The electrical current will be administered to a pre-specified region of the brain (angular gyrus). The stimulation will be delivered at an intensity of 2 milliamperes (mA) (estimated current density 0.04 mA/cm2; estimated total charge 0.048 Coulombs/cm2) in a ramp-like fashion for a maximum of 20 minutes. In the active, in-person HD-tDCS the current is delivered in a ring configuration. In the active remote tDCS current is delivered in one electrode patch.

Sham

Intervention Type: DEVICE

Current will be administered in a ramp-like fashion but after the ramping the intensity will drop to 0 mA. Current under the Sham condition will last for a maximum of 30 seconds.

Word List Learning Intervention (WordLLI)

Intervention Type: OTHER

Participants will receive a word list learning intervention (WordLLI) of semantically related and unrelated word lists. Word lists are presented across 10 trials, with an additional trial after a 10-minute delay to assess delayed recall. Immediately following verbal presentation of word lists during each trial, participants will be instructed to recall as many of the words from the list as possible. Participants may use the written modality as a strategy during recall. Word lists include 12 words matched based on psycholinguistics attributes (e.g., imageability, frequency). This task is designed to help participants improve memory via enhancing list learning capabilities.

Interventions

Active, in-person HD-tDCS or active remote tDCS

Stimulation will be delivered by a battery-driven constant current stimulator. The electrical current will be administered to a pre-specified region of the brain (angular gyrus). The stimulation will be delivered at an intensity of 2 milliamperes (mA) (estimated current density 0.04 mA/cm2; estimated total charge 0.048 Coulombs/cm2) in a ramp-like fashion for a maximum of 20 minutes. In the active, in-person HD-tDCS the current is delivered in a ring configuration. In the active remote tDCS current is delivered in one electrode patch.

Intervention Type: DEVICE

Sham

Current will be administered in a ramp-like fashion but after the ramping the intensity will drop to 0 mA. Current under the Sham condition will last for a maximum of 30 seconds.

Intervention Type: DEVICE

Word List Learning Intervention (WordLLI)

Participants will receive a word list learning intervention (WordLLI) of semantically related and unrelated word lists. Word lists are presented across 10 trials, with an additional trial after a 10-minute delay to assess delayed recall. Immediately following verbal presentation of word lists during each trial, participants will be instructed to recall as many of the words from the list as possible. Participants may use the written modality as a strategy during recall. Word lists include 12 words matched based on psycholinguistics attributes (e.g., imageability, frequency). This task is designed to help participants improve memory via enhancing list learning capabilities.

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

For the aphasic/atypical AD participants:

• Must be between 45-85 years of age.
• Must be right-handed.
• Must be proficient in English.
• Must have a minimum of high-school education.
• Must be diagnosed as logopenic variant Primary Progressive Aphasia (PPA) with Alzheimer's Disease (AD) biomarkers. Other possible diagnosis for the 'aphasic AD' variant would be Mild Cognitive Impairment (MCI) or 'possible AD' according to 2011 guidelines with AD biomarkers (CSF or positron emission tomography (PET) amyloid-beta or fluorodeoxyglucose (FDG)-positron emission tomography (PET) with unihemispheric atrophy).
• Participants will be diagnosed from PPA and early dementias clinics at Johns Hopkins University or other specialized centers in US using current consensus criteria. Diagnosis will be based on neuropsychological testing, language testing (most commonly the Western Aphasia Battery), MRI and clinical assessment. The investigators will also use two new variant classification tests the investigators have developed at the lab which discriminate PPA variants with great accuracy (above 80%): a spelling test and a speech production test (i.e.,Cookie Theft picture description task).

For the amnesic/typical AD participants:

• Must be between 45-85 years of age.
• Must be right-handed.
• Must be proficient in English.
• Must have a minimum of high-school education.
• Must be diagnosed with 'probable AD' in specialized diagnostic centers with neuropsychological (e.g., RAVLT) and AD biomarkers according to 2011 guidelines.
• The investigators will also perform extensive testing in the investigators' test battery including the Mnemonic Similarity Test (MST) that discriminates and measures the most salient hippocampal deficit-pattern separation (PS).

Exclusion Criteria

• People with previous neurological disease including vascular dementia (e.g., stroke, developmental dyslexia, dysgraphia or attentional deficit).
• People with hearing loss (> 25 decibel, using audiometric hearing screen).
• People with uncorrected visual acuity loss.
• People with advanced dementia or severe language impairments (MMSE < 15, or Montreal Cognitive Assessment <10, or language Frontotemporal Dementia-specific Clinical Dementia Rating (FTD-CDR) = 3).
• Left handed individuals.
• People with pre-existing psychiatric disorders such as behavioral disturbances, severe depression, or schizophrenia that do not allow these people to comply or follow the study schedule and requirements such as repeated evaluation and therapy.

• People with severe claustrophobia.
• People with cardiac pacemakers or ferromagnetic implants.
• Pregnant women.

• Minimum Eligible Age: 45 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute on Aging (NIA)

NIH

Sponsor Role: collaborator

Johns Hopkins University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Kyrana Tsapkini, PhD

Role: PRINCIPAL_INVESTIGATOR

Johns Hopkins University

Locations

Johns Hopkins Hospital

Baltimore, Maryland, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Kelly Eun

Role: CONTACT

krmeun@jhmi.edu

(410) 929 - 0279

Jessica Gallegos

Role: CONTACT

jgallegos@jhmi.edu

Facility Contacts

Kyrana Tsapkini, PhD

Role: primary

tsapkini@jhmi.edu

410-736-2940

References

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Reference Type: BACKGROUND

PMID: 26097278 (View on PubMed)

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Reference Type: BACKGROUND

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Other Identifiers

5R01AG068881

Identifier Type: NIH

Identifier Source: secondary_id

View Link

IRB00229164

Identifier Type: -

Identifier Source: org_study_id