tDCS Intervention in Primary Progressive Aphasia

Effects of Transcranial Direct Current Stimulation (tDCS) in Spoken and Written Production in Primary Progressive Aphasia (PPA)

Primary progressive aphasia (PPA) is a neurodegenerative disease that affects first and foremost language abilities. Mild cognitive impairment (MCI) is slowly progressive decline in a single domain of cognition (e.g. language) not attributable to motor or sensory loss, without impediment of social or occupational function. MCI can be an early sign of neurodegenerative disease, or can be due to normal aging. When language is the prominent affected domain in MCI, the person may later meet criteria for PPA or may progress to the clinical syndrome of Alzheimer's dementia. Spelling, naming, and working memory (e.g. repetition) are among the language abilities affected early in the course of PPA or language-centered MCI, and different variants have distinct deficits in these domains. This research project investigates the behavioral and neuromodulatory effects of high definition transcranial direct current stimulation (HD-tDCS) during language therapy in PPA participants over time. Anodal HD-tDCS targeting the left inferior frontal gyrus (IFG) administered in combination with language therapy is expected to be more beneficial when compared to language therapy alone. It will 1) improve language performance or decrease rate of decline, 2) have better-sustained effects at 2 weeks and 2 months post-treatment, and 3) produce generalization to untrained language items and some other cognitive functions. Resting-state fMRI, diffusion tensor imaging (DTI), and volumetric data are also collected to investigate changes in functional brain connectivity associated with HD-tDCS in individuals with PPA. A better understanding of the therapeutic and neuromodulatory mechanisms of HD-tDCS as an adjunct to language therapy in PPA may have a significant impact on the development of effective therapies for PPA and MCI, and may offer insight into ways of impeding neurodegeneration that may improve patients' quality of life, as well as extend their ability to work and manage their affairs.

Study Overview

• Status: Completed
• Conditions: Primary Progressive Aphasia; MCI; FTD
• Intervention / Treatment: Device: Active HD-tDCS plus Speech-Language Therapy; Device: Sham plus Speech-Language Therapy

Detailed Description

A. Evaluation Tasks

Language Tasks:

Participants will be administered baseline language and cognitive tasks, including 1 or more of the following, depending on their residual language and cognitive skills:

a) writing to dictation b) oral spelling c) oral and written naming of pictures d) word-picture matching f) written and oral picture description g) digit span h) spatial span i) verbal learning j) grammatical sentence production k) oral word repetition l) sentence comprehension

Quality of Life questionnaires:

Participants will be administered standardized and non-standardized quality-of-life questionnaires before, after, and at follow-up intervals of each experimental period. The purpose of these questionnaires is to assess whether the proposed interventions have affected participants' well-being and the general quality of their life.

B. Spoken and Written Word Production Therapy Interventions

Individuals with PPA will receive spoken and written word production intervention tailored to their degree of deficit. Two interventions (basic and advanced) will be implemented, treating the main lexical retrieval deficits in PPA, in oral and written modalities. The goal of the combined interventions is to promote interaction between phonological and orthographic representations and processes in the remediation of lexical retrieval deficits that are prominent in all PPA subtypes.

C. Assessment of Language Therapy Tasks:

Follow-up assessment will probe all sets of trained phoneme-grapheme correspondences, words, or other stimuli (e.g. sentences) to identify whether or not the patient has retained knowledge of the trained items. Differences in baseline measures in pre- and post-therapy accuracy for phoneme-grapheme correspondences for each patient will be evaluated using the following: percentages of total number of points correct, arithmetic differences between percentage scores, and permutation tests (Pearson's chi-square test; Fisher's exact test).

C. HD-tDCS Methods:

Participants will take part in 10-15 consecutive training sessions (3-5 per week), separated by 2 months. Anodal HD-tDCS has typically been shown to up-regulate neuronal excitability and produce enhancement of behavioral performance. A Soterix-CT device will be delivering current at an intensity of 1-2 milliamps(mA) (estimated current density 0.04 mA/cm2; estimated total charge 0.048C/cm2) for a maximum of 20 minutes in the HD-tDCS groups and for a maximum of 30 seconds in the Sham group. For both interventions (HD-tDCS and Sham) the electrical current will be increased in a ramp-like fashion at the onset of the stimulation eliciting a transient tingling sensation on the scalp that usually disappears over seconds.

D. Imaging Methods:

Imaging will be performed at the beginning of enrollment, before and after each 12-to-15-day HD-tDCS treatment, and at follow-up intervals for up to 8 time points per individual on a 3T Philips system, and will consist of resting-state fMRI (rsfMRI), MPRAGE, and diffusion tensor imaging (DTI). Each scanning session will last approximately 1 hour.

E. Statistical Analyses:

In the within-subject crossover protocol, each participant will be administered three experimental conditions: Control (natural progression), IFG HD-tDCS+language (henceforth abbr. HD-tDCS treatment (word production) and sham HD-tDCS+language (henceforth abbr. sham treatment). To achieve an accurate estimate of degeneration and rate of decline in each participant at their particular stage of the disease progression, each participant will first be enrolled in the control condition (natural progression), such that for the first 12 weeks they will not receive any therapy. Then the participant will receive either the HD-tDCS treatment followed by sham, or vice versa. All analyses, behavioral and imaging, will be under the oversight of the study statisticians.

F. Study duration and number of study visits required of research participants.

Before any intervention, participants will be enrolled in a control condition for 12 weeks during which no therapy will be provided to enable us to assess their personal decline rate. After this period they will be randomly assigned to either sham or HD-tDCS experimental conditions. After 1-3 weeks of HD-tDCS application (3-5 sessions in a week, 10-15 sessions per stimulation site) there will be an interval of approximately 2 months and then we will implement the other two HD-tDCS conditions in a within-subject cross-over design. Participants will be followed up at 2-week and 2-month follow-up intervals.

G. Blinding, including justification for blinding or not blinding the trial, if applicable.

Participants will be blinded to the application of anodal or sham HD-tDCS. To achieve blinding, all participants will be fitted with the HD-tDCS electrodes placed over the left inferior frontal gyrus. The Soterix-CT device will be used for double-blinding purposes.

H. Justification of why participants will not receive routine care or will have current therapy stopped

Participation in this study will not disrupt any current care or therapy.

I. Justification for inclusion of a placebo or non-treatment group

All participants will undergo active and sham conditions, thus serving as their own control.

J. Definition of treatment failure or participant removal criteria

Participants will be removed from the study if they are unable to comply with task instructions or tolerate the HD-tDCS procedure.

K. Description of what happens to participants receiving therapy when the study ends or if a participant's participation in the study ends prematurely

When the study ends participants will continue to receive management with their neurologist as usual. If a patient's participation in the study ends prematurely s/he will still receive care as before. In sum, termination of the study or termination of participation in it will not affect the regular therapy he or she may be receiving.

L. Qualification of investigators:

The PI and co-investigators have extensive research and clinical experience with all study tasks: behavioral language therapy (including spelling, naming, and repetition therapy. The investigators have already published a tDCS study on the behavioral results for the improvement of spelling abilities.

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21204
      • Johns Hopkins Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 46 years to 86 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Must be clinically diagnosed with semantic variant PPA (svPPA), non-fluent variant PPA (nfvPPA), or logopenic variant PPA (lvPPA), unclassifiable PPA, or MCI. Diagnosis will be based on neuropsychological testing, language testing (most commonly the Western Aphasia Battery), MRI and clinical assessment.
• Must be right-handed.
• Must be speakers of English.
• Must have at least 9th grade education.

Exclusion Criteria:

• Uncorrected visual or hearing impairment by self report.
• Stroke/other premorbid neurological disorder affecting the brain.
• Any other language-based learning disorder other than PPA.
• Inability to follow directions for baseline tasks.
• Western Aphasia Battery Aphasia Quotient (AQ) <30 (indicating severe language impairment).

Exclusion Criteria for MRI Participation:

• Severe claustrophobia.
• Cardiac pacemakers or ferromagnetic implants.
• Pregnant women.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active HD-tDCS plus Speech-Language Therapy; Active HD-tDCS will be applied at the beginning of 45min speech-language therapy session and will last for 20 min.	Device: Active HD-tDCS plus Speech-Language Therapy; 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 (inferior frontal gyrus). The stimulation will be delivered at an intensity of 2mA (estimated current density 0.04 mA/cm2; estimated total charge 0.048C/cm2) in a ramp-like fashion for a maximum of 20 minutes. Speech-language therapy will be oral and written naming.
Sham Comparator: Sham plus Speech-Language Therapy; Sham HD-tDCS will be applied at the beginning of 45min speech-language therapy session.	Device: Sham plus Speech-Language Therapy; Speech-language therapy will be administered during sham stimulation. Current will be administered in a ramp-line fashion but after the ramping the intensity will drop to 0 mA. Speech-language therapy will be oral and written naming.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Percent Change in Written Naming (Trained Items)	The primary outcome measure was the absolute percentage change in the number of correct letters in the written response, compared to the target response in the trained word lists. This calculation reflects the change in accuracy between two timepoints. For letter accuracy scoring, a rule-based system was used where each letter was assigned one point if correct. Points were deducted for errors such as deletions, additions, substitutions, transpositions, or movements of letters. A second reviewer independently scored the responses and resolved any discrepancies through discussion to ensure consensus. Interrater reliability for letter accuracy scoring was 95%. Average letter accuracy per word was calculated for all trained items. Then the absolute percentage change was calculated by subtracting the earlier time point value (e.g., baseline) from the later one (e.g., immediately after treatment, 2 weeks post, and 2 months post), reflecting the change in accuracy.	Change from Baseline to Immediately after treatment (3 weeks), 2 weeks post treatment (5 weeks), and 2 months post-treatment (11 weeks) for each period of intervention
Absolute Percent Change in Written Naming (Untrained Items)	The primary outcome measure was the absolute percentage change in the number of correct letters in the written response, compared to the target response in the untrained word lists.This calculation reflects the change in accuracy between two timepoints. For letter accuracy scoring, a rule-based system was used where each letter was assigned one point if correct. Points were deducted for errors such as deletions, additions, substitutions, transpositions, or movements of letters. A second reviewer independently scored the responses and resolved any discrepancies through discussion to ensure consensus. Interrater reliability for letter accuracy scoring was 95%. Average letter accuracy per word was calculated for all untrained items. Then the absolute percentage change was calculated by subtracting the earlier time point value (e.g., baseline) from the later one (e.g., immediately after treatment, 2 weeks post, and 2 months post), reflecting the change in accuracy.	Change from Baseline to Immediately after treatment (3 weeks), 2 weeks post treatment (5 weeks), and 2 months post-treatment (11 weeks) for each period of intervention
Absolute Percent Change in Oral Naming (Trained Items)	The percent accuracy for each participant's trained oral naming list was calculated, with scores ranging from 0% to 100%. A score of 0% indicates no correct responses, while 100% represents perfect accuracy. Higher percentages reflect better performance. To assess changes in performance from pre- to post-treatment, the percent accuracy for untrained items was compared before and after the intervention. The absolute percentage change was then calculated by subtracting the accuracy at the baseline time point (e.g., baseline) from the accuracy at the later time points (e.g., immediately after treatment, 2 weeks post, and 2 months post). This reflects the change in the participant's ability to name trained items, expressed as absolute percent change. A positive difference indicates improvement in naming accuracy, with a larger change reflecting greater improvement. A negative difference indicates a decline, with a larger change reflecting greater deterioration in naming ability.	Change from Baseline to Immediately after treatment (3 weeks), 2 weeks post treatment (5 weeks), and 2 months post-treatment (11 weeks) for each period of intervention
Absolute Percent Change in Oral Naming (Untrained Items)	The percent accuracy for each participant's untrained oral naming list was calculated, with scores ranging from 0% to 100%. A score of 0% indicates no correct responses, while 100% represents perfect accuracy. Higher percentages reflect better performance. To assess changes in performance from pre- to post-treatment, the percent accuracy for untrained items was compared before and after the intervention. The absolute percentage change was then calculated by subtracting the accuracy at the baseline time point (e.g., baseline) from the accuracy at the later time points (e.g., immediately after treatment, 2 weeks post, and 2 months post). This reflects the change in the participant's ability to name trained items, expressed as absolute percent change. A positive difference indicates improvement in naming accuracy, with a larger change reflecting greater improvement. A negative difference indicates a decline, with a larger change reflecting greater deterioration in naming ability.	Change from Baseline to Immediately after treatment (3 weeks), 2 weeks post treatment (5 weeks), and 2 months post-treatment (11 weeks) for each period of intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Sentence Comprehension as Measured by the Subject Object Active Passive (SOAP) Test	The SOAP test is a test that has been shown to measure comprehension of simple and complex sentence structures. It contains sentences with different syntactic complexities: subject relatives, object relative, active and passive voice. The participant has to listen to a sentence and choose the correct picture that corresponds to its meaning amongst 3 alternatives. Scores range from 0-40 with higher scores indicating better comprehension. For each participant in each group absolute change from before to after treatment was calculated and the mean absolute change for the group was calculated.	Change from baseline to immediate follow-up (3 weeks).
Change in Functional Connectivity	Using resting-state functional magnetic resonance imaging (rsfMRI), investigators will investigate whether tDCS intervention will result in different changes in connectivity between the targeted area (left inferior frontal gyrus) and other nodes in the brain. Global connectivity is measured through the participation coefficient. The participation coefficient is scored on a scale from -1 to +1. Compared with healthy controls a score closer to +1 was associated with worse dementia severity.	Change from before treatment to immediate follow up (3 weeks)

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: National Institutes of Health (NIH); National Institute on Deafness and Other Communication Disorders (NIDCD)
• Investigators: Principal Investigator: Kyrana Tsapkini, PhD, Johns Hopkins University

Publications and helpful links

General Publications

• Tippett DC, Hillis AE, Tsapkini K. Treatment of Primary Progressive Aphasia. Curr Treat Options Neurol. 2015 Aug;17(8):362. doi: 10.1007/s11940-015-0362-5.
• Herrmann O, Ficek B, Webster KT, Frangakis C, Spira AP, Tsapkini K. Sleep as a predictor of tDCS and language therapy outcomes. Sleep. 2022 Mar 14;45(3):zsab275. doi: 10.1093/sleep/zsab275.
• Tao Y, Ficek B, Rapp B, Tsapkini K. Different patterns of functional network reorganization across the variants of primary progressive aphasia: a graph-theoretic analysis. Neurobiol Aging. 2020 Dec;96:184-196. doi: 10.1016/j.neurobiolaging.2020.09.007. Epub 2020 Sep 8.
• 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.
• 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.

Helpful Links

• Tsapkini 2014
• Tsapkini 2015

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Actual): July 12, 2023
• Study Completion (Actual): August 11, 2023

Study Registration Dates

• First Submitted: November 11, 2015
• First Submitted That Met QC Criteria: November 13, 2015
• First Posted (Estimated): November 17, 2015

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 2, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: neurodegeneration; transcranial direct current stimulation (tDCS); language therapy; Primary Progressive Aphasia (PPA)
• Additional Relevant MeSH Terms: Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Metabolic Diseases; Neurobehavioral Manifestations; Neurocognitive Disorders; Dementia; Neurodegenerative Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Communication Disorders; Language Disorders; Speech Disorders; Frontotemporal Lobar Degeneration; Aphasia; Frontotemporal Dementia; Aphasia, Primary Progressive; Pick Disease of the Brain
• Other Study ID Numbers: NA_00071337; R01DC014475 (U.S. NIH Grant/Contract)