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

NCT04122001 | Active Not Recruiting DMC FDA Device

• 2 other identifiers: IRB002291645R01AG068881
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

transcranial direct current stimulation (tDCS); Alzheimer's Disease (AD); verbal learning treatment; word list learning; logopenic Progressive Aphasia; episodic memory

Outcome Measures

Primary Outcomes (8)

• Change in auditory recall accuracy based on the sum of words recalled in Trials 1-5 of semantically related - trained word-lists

  Each trained word-list (practiced during the intervention period) will consist of 12 semantically related words (e.g., birds). Word lists will be constructed using psycholinguistic databases. There will be 5 Trials to learn each list. The investigators will compute the raw score of items correctly recalled by summing all scores from Trial 1 to Trial 5 and transforming to percent correct (range: 0-100%) at each time point of the study. Increase in scores is considered a benefit.

  Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks

• Change in auditory delayed recall accuracy of semantically related - trained word-lists

  Each trained word-list (practiced during the intervention period) will consist of 12 semantically related words (e.g., birds). Word lists will be constructed using psycholinguistic databases. There will be 5 Trials to recall each list, and then participants will be asked to recall that list 20 minutes later (delayed recall). The investigators will compute the raw score of items correctly recalled (delayed recall) and transform to percent correct (range: 0-100%) at each time point of the study. Increase in scores is considered a benefit.

  Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks

• Change in auditory recall accuracy based on the sum of words recalled in Trials 1-5 of semantically unrelated - trained word-lists

  Each trained word-list (practiced during the intervention period) will consist of 12 semantically unrelated words (as in RAVLT). Word lists will be constructed using psycholinguistic databases. There will be 5 Trials to learn each list. The investigators will compute the raw score of items correctly recalled by summing all scores from Trial 1 to Trial 5 and transforming to percent correct (range: 0-100%) at each time point of the study. Increase in scores is considered a benefit.

  Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks

• Change in auditory delayed recall accuracy of semantically unrelated - trained word-lists

  Each trained word-list (practiced during the intervention period) will consist of 12 semantically unrelated words (as in RAVLT). Word lists will be constructed using psycholinguistic databases. There will be 5 Trials to recall each list, and then participants will be asked to recall that list 20 minutes later (delayed recall). The investigators will compute the raw score of items correctly recalled (delayed recall) and transform to percent correct (range: 0-100%) at each time point of the study. Increase in scores is considered a benefit.

  Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks

• Change in auditory recall accuracy based the sum of words recalled in Trials 1-5 of semantically related - untrained word-lists

  Each untrained word-list (not practiced during the intervention period) will consist of 12 semantically related words (e.g., birds). Word lists will be constructed using psycholinguistic databases. There will be 5 Trials to learn each list. The investigators will compute the raw score of items correctly recalled by summing all scores from Trial 1 to Trial 5 and transforming to percent correct (range: 0-100%) at each time point of the study. Increase in scores is considered a benefit.

  Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks

• Change in auditory delayed recall accuracy of semantically related - untrained word-lists

  Each untrained word-list (not practiced during the intervention period) will consist of 12 semantically related words (e.g., birds). Word lists will be constructed using psycholinguistic databases. There will be 5 Trials to recall each list, and then participants will be asked to recall that list 20 minutes later (delayed recall). The investigators will compute the raw score of items correctly recalled (delayed recall) and transform to percent correct (range: 0-100%) at each time point of the study. Increase in scores is considered a benefit.

  Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks

• Change in auditory recall accuracy based on the sum of words recalled in Trials 1-5 of semantically unrelated - untrained word-lists

  Each untrained word-list (not practiced during the intervention period) will consist of 12 semantically unrelated words (as in RVLT). Word lists will be constructed using psycholinguistic databases. There will be 5 Trials to learn each list. The investigators will compute the raw score of items correctly recalled by summing all scores from Trial 1 to Trial 5 and transforming to percent correct (range: 0-100%) at each time point of the study. Increase in scores is considered a benefit.

  Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks

• Change in auditory delayed recall accuracy of semantically unrelated - untrained word-lists

  Each untrained word-list (not practiced during the intervention period) will consist of 12 semantically unrelated words (as in RVLT). Word lists will be constructed using psycholinguistic databases. There will be 5 Trials to recall each list, and then participants will be asked to recall that list 20 minutes later (delayed recall). The investigators will compute the raw score of items correctly recalled (delayed recall) and transform to percent correct (range: 0-100%) at each time point of the study. Increase in scores is considered a benefit.

  Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks

Secondary Outcomes (25)

• Change in Rey Auditory-Verbal Learning Test (RAVLT) score

  Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks

• Change in Mini Mental State Examination (MMSE)

  Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks

• Change in Mnemonic Similarity Task (MST) score

  Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks

• Change in word repetition score

  Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks

• Change in non-word repetition score

  Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks

Other Outcomes (1)

• Correlation of primary and secondary outcomes with sleep efficiency

  One week before intervention and one week post intervention, up to 8 weeks

Study Arms (2)

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

EXPERIMENTAL

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

Device: Active, in-person HD-tDCS or active remote tDCS; Device: Sham; Other: Word List Learning Intervention (WordLLI)

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

EXPERIMENTAL

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

Device: Active, in-person HD-tDCS or active remote tDCS; Device: Sham; Other: Word List Learning Intervention (WordLLI)

Interventions

Word List Learning Intervention (WordLLI) 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.

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

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

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

Sham 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.

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

Eligibility Criteria

• Age: 45 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Johns Hopkins University: lead
• National Institute on Aging (NIA): collaborator

Study Sites (1)

Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

Related Publications (11)

• Tsapkini K, Frangakis C, Gomez Y, Davis C, Hillis AE. Augmentation of spelling therapy with transcranial direct current stimulation in primary progressive aphasia: Preliminary results and challenges. Aphasiology. 2014;28(8-9):1112-1130. doi: 10.1080/02687038.2014.930410.

  PMID: 26097278 BACKGROUND

• Tsapkini K, Webster KT, Ficek BN, Desmond JE, Onyike CU, Rapp B, Frangakis CE, Hillis AE. Electrical brain stimulation in different variants of primary progressive aphasia: A randomized clinical trial. Alzheimers Dement (N Y). 2018 Sep 5;4:461-472. doi: 10.1016/j.trci.2018.08.002. eCollection 2018.

  PMID: 30258975 BACKGROUND

• Ficek BN, Wang Z, Zhao Y, Webster KT, Desmond JE, Hillis AE, Frangakis C, Vasconcellos Faria A, Caffo B, Tsapkini K. The effect of tDCS on functional connectivity in primary progressive aphasia. Neuroimage Clin. 2018 May 21;19:703-715. doi: 10.1016/j.nicl.2018.05.023. eCollection 2018.

  PMID: 30009127 BACKGROUND

• Reis J, Schambra HM, Cohen LG, Buch ER, Fritsch B, Zarahn E, Celnik PA, Krakauer JW. Noninvasive cortical stimulation enhances motor skill acquisition over multiple days through an effect on consolidation. Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1590-5. doi: 10.1073/pnas.0805413106. Epub 2009 Jan 21.

  PMID: 19164589 BACKGROUND

• Huey ED, Probasco JC, Moll J, Stocking J, Ko MH, Grafman J, Wassermann EM. No effect of DC brain polarization on verbal fluency in patients with advanced frontotemporal dementia. Clin Neurophysiol. 2007 Jun;118(6):1417-8. doi: 10.1016/j.clinph.2007.02.026. Epub 2007 Apr 23. No abstract available.

  PMID: 17452012 BACKGROUND

• Antal A, Terney D, Poreisz C, Paulus W. Towards unravelling task-related modulations of neuroplastic changes induced in the human motor cortex. Eur J Neurosci. 2007 Nov;26(9):2687-91. doi: 10.1111/j.1460-9568.2007.05896.x. Epub 2007 Oct 26.

  PMID: 17970738 BACKGROUND

• Segrave RA, Arnold S, Hoy K, Fitzgerald PB. Concurrent cognitive control training augments the antidepressant efficacy of tDCS: a pilot study. Brain Stimul. 2014 Mar-Apr;7(2):325-31. doi: 10.1016/j.brs.2013.12.008. Epub 2013 Dec 19.

  PMID: 24486425 BACKGROUND

• McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):263-9. doi: 10.1016/j.jalz.2011.03.005. Epub 2011 Apr 21.

  PMID: 21514250 BACKGROUND

• Gorno-Tempini ML, Hillis AE, Weintraub S, Kertesz A, Mendez M, Cappa SF, Ogar JM, Rohrer JD, Black S, Boeve BF, Manes F, Dronkers NF, Vandenberghe R, Rascovsky K, Patterson K, Miller BL, Knopman DS, Hodges JR, Mesulam MM, Grossman M. Classification of primary progressive aphasia and its variants. Neurology. 2011 Mar 15;76(11):1006-14. doi: 10.1212/WNL.0b013e31821103e6. Epub 2011 Feb 16.

  PMID: 21325651 BACKGROUND

• Neophytou K, Wiley RW, Rapp B, Tsapkini K. The use of spelling for variant classification in primary progressive aphasia: Theoretical and practical implications. Neuropsychologia. 2019 Oct;133:107157. doi: 10.1016/j.neuropsychologia.2019.107157. Epub 2019 Aug 8.

  PMID: 31401078 BACKGROUND

• Riello M, Faria AV, Ficek B, Webster K, Onyike CU, Desmond J, Frangakis C, Tsapkini K. The Role of Language Severity and Education in Explaining Performance on Object and Action Naming in Primary Progressive Aphasia. Front Aging Neurosci. 2018 Oct 30;10:346. doi: 10.3389/fnagi.2018.00346. eCollection 2018.

  PMID: 30425638 BACKGROUND

MeSH Terms

Conditions

Alzheimer Disease

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Study Officials

• Kyrana Tsapkini, PhD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a crossover design of active High-Definition tDCS (HD-tDCS) + Word List Learning Intervention (WordLLI) that crossovers to sham + WordLLI in Arm 1, and sham +WordLLI that crossovers to active HD-tDCS + WordLLI in Arm 2.

Study Record Dates

• First Submitted: October 8, 2019
• First Posted: October 10, 2019
• Study Start: August 17, 2020
• Primary Completion (Estimated): October 30, 2026
• Study Completion (Estimated): October 30, 2026
• Last Updated: May 19, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)