NCT03887481 · Johns Hopkins University
Targeting Language-specific and Executive-control Networks With Transcranial Direct Current Stimulation in Logopenic Variant PPA
What this study is about
AD afflicts over 5.5. million Americans and is one of the most expensive diseases worldwide. In AD the variant in which language functions are most affected are referred to as 'logopenic variant Primary Progressive Aphasia' (lvPPA). Language deficits dramatically impair communication and quality of life for both patients and caregivers.
View original scientific description
AD afflicts over 5.5. million Americans and is one of the most expensive diseases worldwide. In AD the variant in which language functions are most affected are referred to as 'logopenic variant Primary Progressive Aphasia' (lvPPA). Language deficits dramatically impair communication and quality of life for both patients and caregivers. PPA usually has an early onset (50-65 years of age), detrimentally affecting work and family life. Studies have identified verbal short-term memory/working memory (vSTM/WM) as a primary deficit and cause of language impairment. In the first cycle of this award, the investigators asked the question of whether language therapy effects could be augmented by electrical stimulation. The investigators conducted the largest to-date randomized, double-blind, sham-controlled, crossover, clinical trial to determine the effects of transcranial direct current stimulation (tDCS) in PPA. The investigators found that tDCS over the left inferior frontal gyrus (L\_IFG), one of the major language hubs in the brain, significantly enhanced the effects of a written naming and spelling intervention. In addition, findings demonstrated that tDCS modulates functional connectivity between the stimulated area and other networks (e.g. functionally and structurally connected areas), and that tDCS modulates the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). In terms of tDCS, the investigators have been identified several predictors to determine the beneficience of tDCS including (a) PPA variant, (b) initial performance on cognitive/language tasks, particularly vSTM/WM, and (c) initial white-matter integrity and structure. These findings support the notion that tDCS benefits generalize beyond the treatment tasks and has led to the important question of the present study: How can we implement treatments to product benefits that maximally generalize to untrained but vital language/cognitive functions. To address the above question, the investigators will test recent neuroplasticity theories that claim that the benefits of neuromodulation to language-specific areas generalize to other language functions within the language network, while neuromodulation of a domain-general/multiple-demands area generalizes to both domain-general, executive and language functions. The two areas to be stimulated will be the supramarginal gyrus (SMG) and left dorsolateral prefrontal cortex (DLPFC) respectively. The left supramarginal gyrus (L\_SMG) in particular, specializes in phonological processing, namely phonological verbal short-term memory (vSTM), i.e., the ability to temporarily store phonological (and graphemic) information in order. The domain of vSTM affects many language tasks (repetition, naming, syntax), which makes it an ideal treatment target and the L\_SMG an ideal stimulation target, since generalization of tDCS effects to other language tasks is driven by the function (computation) of the stimulated area. By testing a fundamental principle of neuromodulation in a devastating neurodegenerative disorder, the investigators will significantly advance the field of neurorehabilitation in early-onset dementias. Aim 1: To determine whether vSTM/WM behavioral therapy combined with high definition (HD)-tDCS over the L\_SMG will induce more generalization to language-specific tasks than to executive tasks, whereas stimulation over the LDPFC will induce equivalent generalization to both executive and language-specific tasks. Aim 2: To understand the mechanism of tDCS by measuring tDCS-induced changes in network functional connectivity (FC) and GABA in the LSMG and LDPFC. The investigators will carry out resting-state functional magnetic resonance imaging (rsfMRI), (MPRAGE), diffusion-weighted imaging (DWI), perfusion imaging (pCASL), and magnetic resonance spectroscopy (MRS), before, after, and 3-months post-intervention. Aim 3: To identify the neural, cognitive, physiological, clinical and demographic characteristics (biomarkers) that predict sham, tDCS, and tDCS vs. sham effects on vSTM and related language tasks in PPA. The investigators will evaluate neural (functional and structural connectivity, cortical volume, neuropeptides, and perfusion), cognitive (memory, attention, executive) and language functions, clinical (severity), physiological (sleep), and demographic (age, gender) characteristics, and the investigators will analyze the effects on vSTM and other language/cognitive outcomes immediately after intervention and at 3 months post-intervention.
Interventions
DEVICE
High-definition active tDCS (HD-tDCS) + "Repeat After Me" (RAM) Treatment
Device: Active HD-tDCS \& "Repeat After Me" (RAM) Treatment Stimulation will be delivered by a battery-driven constant current stimulator. Electrical current will be administered to left supramarginal gyrus (L\_SMG). 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. Participants will receive RAM consisting of word span repetition span (increasing length, with/without response delay). Span tasks will be manipulated in terms of list length (single words, pair, triplets) and response delay (1 sec, 5 sec). Each list will consist of 10 spans. During each trial, participants will be asked to repeat words in the span after a response delay.
DEVICE
Sham + "Repeat After Me" (RAM) Treatment
Device: Sham Current will be administered in a ramp-like fashion but after the ramping phase the intensity will drop to 0 mA. Current under the Sham condition will last for a maximum of 30 seconds. Participants will receive RAM consisting of word span repetition span (increasing length, with/without response delay). Span tasks will be manipulated in terms of list length (single words, pair, triplets) and response delay (1 sec, 5 sec). Each list will consist of 10 spans. During each trial, participants will be asked to repeat words in the span after a response delay.
Primary outcome measures
Change in percent accuracy on word repetition (no delay) assessed by Temple Assessment of Language and Short-Term Memory in Aphasia (TALSA) Test 3
Time frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
The investigators will assess any changes in performance from pre- to post-treatment and 1- and 3- month follow-up intervals in percent accuracy on word repetition with no delay. This will be measured using the Temple Assessment of Language and Short-Term Memory (TALSA) Test 3: Word and Non-Word Repetition Test. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%), computing change in outcome in percent difference as well as other arithmetic differences between percentage scores before intervention and each time point after. Increase in scores is considered a benefit. This outcome measure corresponds to Aim 1.
Change in percent accuracy on word repetition (with 5-sec delay) assessed by TALSA Test 3
Time frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
The investigators will assess any changes in performance from pre- to post-treatment and 1- and 3- month follow-up intervals in percent accuracy on word repetition with delay (5-sec). This will be measured using the TALSA Test 3: Word and Non-Word Repetition Test. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%), computing change in outcome in percent difference as well as other arithmetic differences between percentage scores before intervention and each time point after. Increase in scores is considered a benefit. This outcome measure corresponds to Aim 1.
Change in percent accuracy on word span assessed by TALSA Test 14
Time frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
The investigators will assess any changes in performance from pre- to post-treatment and 1- and 3- month follow-up intervals in percent accuracy on word span. This will be measured using the TALSA Test 14: Word and Non-Word Repetition Span Test. The investigators will use the span calculation outlined in the TALSA. Span calculations consist of two numbers: the number of the last list length (LL) passed (e.g., 2 for pairs), and the proportion of correct strings out of the required strings to pass (5) of the next list. The highest spans obtainable for this test is 5.00. Increase in scores is considered a benefit. This outcome measure corresponds to Aim 1.
Who can participate
This study lists these criteria on ClinicalTrials.gov. A study coordinator reviews eligibility during screening — this page does not determine whether you qualify.
Inclusion criteria
- Must be between 50-80 years of age.
- Must be right-handed.
- Must be proficient in English.
- Must have a minimum of high-school education.
- Must be diagnosed with Primary Progressive Aphasia (PPA) or dementia.
- Participants will be diagnosed with PPA or with any of the PPA variants in specialized or early dementias clinics at Johns Hopkins University or other specialized centers in the US based on the current consensus criteria.
- Healthy age- and education-matched controls: The investigators will include 30 healthy age- and education-matched controls, usually spouses, to maximize similarity in terms of other demographic or life-style factors that contribute to language and cognitive performance.
Exclusion criteria
- People with previous neurological disease including vascular dementia (e.g., stroke, developmental dyslexia, dysgraphia or attentional deficit).
- People with uncorrected hearing loss
- People with uncorrected visual acuity loss.
- People with advanced dementia or severe language impairments: Mini Mental State -Examination (MMSE)\<18, or Montreal Cognitive Assessment (MOCA)\<15, or language Frontotemporal Dementia specific - Clinical Dementia Rating (FTD-CDR)\<=2.
- 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. Exclusion Criteria for MRI Participation:
- People with severe claustrophobia.
- People with cardiac pacemakers or ferromagnetic implants.
- Pregnant women.
Where
- Baltimore, Maryland
Collaborators
National Institute on Aging (NIA)
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Frequently asked questions
What is a clinical trial?
A clinical trial is a research study that tests new medical treatments, drugs, devices, or procedures to determine their safety and effectiveness. Trials are carefully designed and monitored to protect participants while advancing medical knowledge.
Is it safe to participate?
Clinical trials follow strict safety guidelines and ethical standards. Trials must be reviewed and approved, and participants are closely monitored by medical professionals throughout the study. You can withdraw at any time if you choose.
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Many clinical trials offer compensation for your time, travel expenses, and inconvenience. The specific compensation varies by study and will be discussed during the screening process. All study-related medical care is typically provided at no cost to participants.
Will I receive a placebo instead of treatment?
When effective treatment exists, participants typically receive either the standard treatment plus the study intervention, or the standard treatment plus placebo. You would not be denied effective care. Placebos are primarily used when no proven treatment is available, or in addition to standard care. Your trial consent form will clearly explain what treatments you may receive.
Can I leave a trial if I change my mind?
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Trial duration varies widely depending on the study design and purpose. Some trials last just a few weeks, while others may continue for months or years. The study coordinator will provide specific timeline information during your screening call.
Data: ClinicalTrials.gov · synced Sep 15, 2025 · Source of record for eligibility and locations