Logopenic Progressive AphasiaNCT03887481
Targeting Language-specific and Executive-control Networks With Transcranial Direct Current Stimulation in Logopenic Variant PPA
A study testing High-definition active tDCS (HD-tDCS) + "Repeat After Me" (RAM) Treatment in people with Logopenic Progressive Aphasia and Primary Progressive Aphasia, run by Johns Hopkins University at 1 site in United States.
Trial summary
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). Read more about this study
- Who is it for?
- Ages 50 to 80 yearsHealthy volunteers can take part
- Conditions the study is for
- Logopenic Progressive Aphasia, Primary Progressive Aphasia
- What is being tested?
- High-definition active tDCS (HD-tDCS) + "Repeat After Me" (RAM) Treatment
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 60 participants
- Where
- 1 siteUnited States
- Study dates
- 15 Oct 2022to 31 Oct 2027
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 50 to 80 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
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- People with severe claustrophobia.
- People with cardiac pacemakers or ferromagnetic implants.
- Pregnant women.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Johns Hopkins Hospital
Baltimore, Maryland, 21287
Kyrana Tsapkini, PhD, 410-736-2940, tsapkini@jhmi.edu
Kyrana Tsapkini, PhD
About this study
Official title: Targeting Language-specific and Executive-control Networks With Transcranial Direct Current Stimulation in Aphasic AD (Logopenic Variant PPA)
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.
Read more
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.
Read the detailed description
This proposal will extend the investigators' previous award, which provided the first evidence from a clinical trial (double-blind, sham-controlled, crossover), on the beneficial effects of transcranial direct current stimulation (tDCS) over the left inferior frontal gyrus (L_IFG) in primary progressive aphasia (PPA), a debilitating neurodegenerative disorder affecting primarily language functions. The investigators' previous studies, although it established the augmentative effects of tDCS in PPA and shed light on its possible mechanisms, the investigators also revealed a fundamental gap in the investigators' knowledge, namely the effect different tDCS effects In this present study, the investigators will directly address this knowledge gap by stimulating two areas of atrophy in PPA, the parietal cortex, the epicenter of vSTM/WM within the language network, and the frontal cortex, a major executive and multi-domain area, to test the tDCS effects in PPA, uncover the mechanisms, and estimate tDCS predictors.
- Being tested
- High-definition active tDCS (HD-tDCS) + "Repeat After Me" (RAM) Treatment, Sham + "Repeat After Me" (RAM) Treatment
- Keywords
- transcranial direct current stimulation (tDCS), neurodegeneration, verbal short-term memory, non-fluent variant, logopenic variant, primary progressive aphasia
- Medical subject headings
- Aphasia, Primary Progressive, Nerve Degeneration
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
High-definition active tDCS (HD-tDCS) + "Repeat After Me" (RAM) TreatmentDevice
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.
Sham + "Repeat After Me" (RAM) TreatmentDevice
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.
| Study group | Role | What they receive |
|---|---|---|
| Active HD-tDCS + Language/Cognitive Intervention(s) first | Experimental | Participants will receive active HD-tDCS + Language/Cognitive Intervention(s) first and then receive Sham + Language/Cognitive Intervention(s) after a three-month washout period. Receives: Device: High-definition active tDCS (HD-tDCS) + "Repeat After Me" (RAM) Treatment; Device: Sham + "Repeat After Me" (RAM) Treatment |
| Sham + Language/Cognitive Intervention(s) first | Experimental | Participants will receive Sham + Language/Cognitive Intervention(s) first and then receive active HD-tDCS + Language/Cognitive Intervention(s) after a three-month washout period. Receives: Device: High-definition active tDCS (HD-tDCS) + "Repeat After Me" (RAM) Treatment; Device: Sham + "Repeat After Me" (RAM) Treatment |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in percent accuracy on word repetition (no delay) assessed by Temple Assessment of Language and Short-Term Memory in Aphasia (TALSA) Test 3
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.
Measured: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in percent accuracy on word repetition (with 5-sec delay) assessed by TALSA Test 3
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.
Measured: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in percent accuracy on word span assessed by TALSA Test 14
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.
Measured: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Secondary outcomes (19)
Change in TALSA sentence repetition (Test 7) score
This sentence repetition task comes from the TALSA (Test 7) with scoring based on percent of words in sentences correctly repeated. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%). Subsequently, the investigators will compute change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a near-transfer task (i.e., vSTM related, showing generalization to other vSTM tasks).
Measured: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in National Alzheimer's Coordinating Center's (NACC) sentence repetition score
This sentence repetition task comes from National Alzheimer's Coordinating Center's (NACC) FTLD Module with scoring based on percent of words in sentences correctly repeated. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%). Subsequently, the investigators will compute change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a near-transfer task (i.e., vSTM related, showing generalization to other vSTM tasks).
Measured: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in digit span forward score
The digit span forward is a well-established task that assesses rote immediate verbal memory. Participants are presented with a series of digits and are instructed to repeat the digits in the same order. The investigators will compute the raw score of items correctly repeated (up to 9) and compute change in outcome between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a near-transfer task (i.e., vSTM related, showing generalization to other vSTM tasks).
Measured: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in visual rhyming score
The visual rhyming test assesses link between phonological and orthographic information. Participants are presented words orthographically only and must indicate whether two words rhyme (e.g., pair-spare). The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%). Subsequently, the investigators will compute change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a near-transfer task (i.e., vSTM related, showing generalization to other vSTM tasks).
Measured: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in Northwestern Anagram Test (NAT) score
The Northwestern Anagram Test (NAT) assesses accuracy of word order (syntax) in sentence production. Participants assemble individual words cards to create meaningful sentences. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%). Subsequently, the investigators will compute change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a near-transfer task (i.e., vSTM related, showing generalization to other vSTM tasks).
Measured: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in NAVS - Argument Structure Production Test (ASPT) score
The Northwestern Assessment of Verbs and Sentences (NAVS) Argument Structure Production Test (ASPT) assesses combination of verbs with arguments in a sentence production task. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%). Subsequently, the investigators will compute change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a near-transfer task (i.e., vSTM related, showing generalization to other vSTM tasks).
Measured: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in spelling of non-words to dictation score
Accuracy in spelling non-words using the Johns Hopkins Dysgraphia battery will be assessed. The investigators will compute the raw score of graphemes correct using a spelling scoring system accounting for additions, substitutions, and deletions, and transform to percent correct (range: 0-100%), computing change in outcome in percent difference before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a near-transfer task (i.e., vSTM related, showing generalization to other vSTM tasks).
Measured: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in Apraxia Battery of Adults-Second Edition (ABA-2) score
The presence and severity of apraxia of speech (AOS) is measured using the Apraxia Battery for Adults-Second Edition (ABA-2), specifically through repeating words of increasing length and complexity and describing pictures. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%). Subsequently, the investigators will compute change in outcome in percent difference between before intervention and each time point after. Decrease in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a near-transfer task (i.e., vSTM related, showing generalization to other vSTM tasks).
Measured: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in spelling of words to dictation score
Accuracy in spelling words using the Johns Hopkins Dysgraphia battery will be assessed. The investigators will compute the raw score of graphemes correct using a spelling scoring system accounting for additions, substitutions, and deletions, and transform to percent correct (range: 0-100%), computing change in outcome in percent difference before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a far-transfer task (i.e., unrelated to vSTM, showing generalization to other language \& cognitive tasks).
Measured: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in NAVS - Sentence Comprehension Test score
The Northwestern Assessment of Verbs and Sentences (NAVS) Sentence Comprehension Test (SCT) assesses comprehension of sentences given multiple types of sentences (e.g., canonical vs. non-canonical). The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%). Subsequently, the investigators will compute change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a far-transfer task (i.e., unrelated to vSTM, showing generalization to other language \& cognitive tasks).
Measured: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in Subject-Relative, Object-Relative, Active Passive (SOAP): Test of Syntactic Complexity score
The SOAP: Test of Syntactic Complexity assesses comprehension abilities given 4 syntactic construction types. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%). Subsequently, the investigators will compute change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a far-transfer task (i.e., unrelated to vSTM, showing generalization to other language \& cognitive tasks).
Measured: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in Boston Naming Test (Short-Version) score
The Boston Naming Test is a widely used picture naming test that detects lexical retrieval deficits in the oral modality. 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 between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a far-transfer task (i.e., unrelated to vSTM, showing generalization to other language \& cognitive tasks).
Measured: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in oral naming of action as assessed by Hopkins Assessment of Naming Actions (HANA)
The Hopkins Assessment of Naming Actions (HANA) assesses picture naming (specifically verbs) in the oral modality. 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 between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a far-transfer task (i.e., unrelated to vSTM, showing generalization to other language \& cognitive tasks).
Measured: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in category fluency score
Category fluency tasks involve generating as many words as possible in one minute for a given semantic category (fruits, animals, vegetables). Scoring will be based on number of words generated per minute. The investigators will compute the raw score of items correct and subsequently the percent difference between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a far-transfer task (i.e., unrelated to vSTM, showing generalization to other language \& cognitive tasks).
Measured: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in content & efficiency of connected speech
Using picture descriptions (e.g., Cookie Theft image from the Boston Diagnostic Aphasia Examination [BDAE]) and personal/procedural discourse tasks, investigators will obtain representative language samples. The investigators will compute the raw score of content (content information units [CIUs]) and efficiency (proportion of mazes: false starts, pauses) and transform to percent correct (range: 0-100%), computing change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a far-transfer task (i.e., unrelated to vSTM, showing generalization to other language \& cognitive tasks).
Measured: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in N-back (2-back) word score
The N-back task is a well-established task that assesses working memory and working memory capacity. Participants are presented with words in sequence and instructed to reply whether the current word matches the one presented 2 words ago. Scoring will be based on the total number of correct responses (hit rate) minus the number of incorrect responses (false alarm rate). The investigators will compute the change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a far-transfer task (i.e., unrelated to vSTM, showing generalization to other language \& cognitive tasks).
Measured: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in digit span backward score
The digit span backward is a well-established task that assesses rote immediate verbal memory and working memory. Participants are presented with a series of digits and are instructed to repeat the digits in the reverse order. The investigators will compute the raw score of items correctly repeated and compute change in outcome between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a far-transfer task (i.e., unrelated to vSTM, showing generalization to other language \& cognitive tasks).
Measured: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in functional connectivity of select brain regions (z-correlations)
Using resting stage functional MRI (rs-fMRI) investigators will detect activity of various brain regions under a resting/task-negative condition, which will help evaluate functional regional interactions as indicated by the z-correlations between the selected brain area. This outcome measure corresponds to Aim 2.
Measured: Before intervention, immediately after intervention, 3 months post intervention
Change in Gamma-Aminobutyric Acid (GABA) concentration at stimulated site
Using Magnetic Resonance Spectroscopy (MRS) investigators will measure metabolite (GABA) concentrations from select brain regions in international units (IU).
Measured: Before intervention, immediately after intervention, 3 months post intervention
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Mar 2019
- Study start15 Oct 2022
- Primary completion31 Oct 2027 (estimated)
- Study completion31 Oct 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for Logopenic Progressive AphasiaStudies of the same condition, open and under way.
- More trials run by Johns Hopkins UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- This is a crossover design of active HD-tDCS + Language/Cognitive Intervention that crossovers to Sham + Language/Cognitive Intervention in Arm 1 and Sham + Language/Cognitive Intervention that crossovers to active HD-tDCS + Language/Cognitive Intervention in Arm 2.
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Outcomes assessor
- Enrolment
- 60 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Johns Hopkins University
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute on Aging (NIA)
- Responsible party
- Sponsor
- Investigators
- Kyrana Tsapkini, PhD, Principal investigator, Johns Hopkins University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03887481
- Sponsor's protocol ID
- IRB00201027
- Other IDs
- R01AG075404
- Status last verified
- Sep 2026
- First submitted
- 21 Mar 2019
- Last updated
- 9 Sep 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- Yes
Publications
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.
PubMed 26097278Tsapkini 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.
PubMed 30258975Ficek 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.
PubMed 30009127Gorno-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.
PubMed 21325651Neophytou 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.
PubMed 31401078Champod AS, Petrides M. Dissociable roles of the posterior parietal and the prefrontal cortex in manipulation and monitoring processes. Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14837-42. doi: 10.1073/pnas.0607101104. Epub 2007 Sep 5.
PubMed 17804811Champod AS, Petrides M. Dissociation within the frontoparietal network in verbal working memory: a parametric functional magnetic resonance imaging study. J Neurosci. 2010 Mar 10;30(10):3849-56. doi: 10.1523/JNEUROSCI.0097-10.2010.
PubMed 20220020Riello 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.
PubMed 30425638
Study at a glance
From the registry record, last updated by the sponsor on 9 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Targeting Language-specific and Executive-control Networks With Transcranial Direct Current Stimulation in Aphasic AD (Logopenic Variant PPA)
- ClinicalTrials.gov ID
- NCT03887481
- Acronym / sponsor ID
- IRB00201027
- Keywords
- transcranial direct current stimulation (tDCS), neurodegeneration, verbal short-term memory, non-fluent variant, logopenic variant, primary progressive aphasia
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 60 participants (estimated)
- Lead sponsor
- Johns Hopkins UniversityUniversity, hospital or other
- Collaborators
- National Institute on Aging (NIA)
- Study start
- 15 Oct 2022 (actual)
- Primary completion
- 31 Oct 2027 (estimated)
- Study completion
- 31 Oct 2027 (estimated)
- First posted
- 25 Mar 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
This proposal will extend the investigators' previous award, which provided the first evidence from a clinical trial (double-blind, sham-controlled, crossover), on the beneficial effects of transcranial direct current stimulation (tDCS) over the left inferior frontal gyrus (L_IFG) in primary progressive aphasia (PPA), a debilitating neurodegenerative disorder affecting primarily language functions. The investigators' previous studies, although it established the augmentative effects of tDCS in PPA and shed light on its possible mechanisms, the investigators also revealed a fundamental gap in the investigators' knowledge, namely the effect different tDCS effects In this present study, the investigators will directly address this knowledge gap by stimulating two areas of atrophy in PPA, the parietal cortex, the epicenter of vSTM/WM within the language network, and the frontal cortex, a major executive and multi-domain area, to test the tDCS effects in PPA, uncover the mechanisms, and estimate tDCS predictors.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, care provider, outcomes assessor)
- Number of arms
- 2
- Model description
- This is a crossover design of active HD-tDCS + Language/Cognitive Intervention that crossovers to Sham + Language/Cognitive Intervention in Arm 1 and Sham + Language/Cognitive Intervention that crossovers to active HD-tDCS + Language/Cognitive Intervention in Arm 2.
| Arm | Type | Receives |
|---|---|---|
| Active HD-tDCS + Language/Cognitive Intervention(s) first | Experimental | Device: High-definition active tDCS (HD-tDCS) + "Repeat After Me" (RAM) Treatment, Device: Sham + "Repeat After Me" (RAM) TreatmentParticipants will receive active HD-tDCS + Language/Cognitive Intervention(s) first and then receive Sham + Language/Cognitive Intervention(s) after a three-month washout period. |
| Sham + Language/Cognitive Intervention(s) first | Experimental | Device: High-definition active tDCS (HD-tDCS) + "Repeat After Me" (RAM) Treatment, Device: Sham + "Repeat After Me" (RAM) TreatmentParticipants will receive Sham + Language/Cognitive Intervention(s) first and then receive active HD-tDCS + Language/Cognitive Intervention(s) after a three-month washout period. |
Who may qualify
- Ages
- 50 to 80 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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.
Key exclusion criteria (9 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| High-definition active tDCS (HD-tDCS) + "Repeat After Me" (RAM) TreatmentDevice: 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 | Active HD-tDCS + Language/Cognitive Intervention(s) first, Sham + Language/Cognitive Intervention(s) first |
| Sham + "Repeat After Me" (RAM) TreatmentDevice: 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. | Device | Active HD-tDCS + Language/Cognitive Intervention(s) first, Sham + Language/Cognitive Intervention(s) first |
Primary outcome
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.
19 secondary outcomes
Change in TALSA sentence repetition (Test 7) score
Time frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in National Alzheimer's Coordinating Center's (NACC) sentence repetition score
Time frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in digit span forward score
Time frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in visual rhyming score
Time frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in Northwestern Anagram Test (NAT) score
Time frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in NAVS - Argument Structure Production Test (ASPT) score
Time frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in spelling of non-words to dictation score
Time frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in Apraxia Battery of Adults-Second Edition (ABA-2) score
Time frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in spelling of words to dictation score
Time frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in NAVS - Sentence Comprehension Test score
Time frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in Subject-Relative, Object-Relative, Active Passive (SOAP): Test of Syntactic Complexity score
Time frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in Boston Naming Test (Short-Version) score
Time frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in oral naming of action as assessed by Hopkins Assessment of Naming Actions (HANA)
Time frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in category fluency score
Time frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in content & efficiency of connected speech
Time frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in N-back (2-back) word score
Time frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in digit span backward score
Time frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention
Change in functional connectivity of select brain regions (z-correlations)
Time frame: Before intervention, immediately after intervention, 3 months post intervention
Change in Gamma-Aminobutyric Acid (GABA) concentration at stimulated site
Time frame: Before intervention, immediately after intervention, 3 months post intervention
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Sep 2026.
- Background: PubMed 26097278Tsapkini 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.
- Background: PubMed 30258975Tsapkini 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.
- Background: PubMed 30009127Ficek 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.
- Background: PubMed 21325651Gorno-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.
- Background: PubMed 31401078Neophytou 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.
- Background: PubMed 17804811Champod AS, Petrides M. Dissociable roles of the posterior parietal and the prefrontal cortex in manipulation and monitoring processes. Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14837-42. doi: 10.1073/pnas.0607101104. Epub 2007 Sep 5.
- Background: PubMed 20220020Champod AS, Petrides M. Dissociation within the frontoparietal network in verbal working memory: a parametric functional magnetic resonance imaging study. J Neurosci. 2010 Mar 10;30(10):3849-56. doi: 10.1523/JNEUROSCI.0097-10.2010.
- Background: PubMed 30425638Riello 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Kyrana Tsapkini, PhD principal investigator
Johns Hopkins University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing High-definition active tDCS (HD-tDCS) + "Repeat After Me" (RAM) Treatment in people with Logopenic Progressive Aphasia and Primary Progressive Aphasia, run by Johns Hopkins University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 9 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Cesia Diaz ((410) 417 - 8230, cesiad@jhmi.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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 study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03887481, which also lists 8 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Sep 2026.