Treating Primary Progressive Aphasia (PPA) Using tDCS

Study Overview
=================
Brief Summary
-----------------
This is a double-blind, sham-controlled, crossover study in which subjects with the non-fluent/agrammatic and semantic variants of primary progressive aphasia (naPPA and svPPA, respectively) will undergo language testing and structural and functional brain imaging before and after receiving 10 semi-consecutive daily sessions of real or sham transcranial direct current stimulation (tDCS) paired with modified constraint-induced language therapy (mCILT). Language testing and brain imaging will be repeated immediately after completion of and up-to 24 weeks following completion of treatment. The investigators will examine changes in language performance induced by tDCS + mCILT compared to sham tDCS + mCILT. The investigators will also use network science to analyze brain imaging (fMRI) data to identify network properties associated with baseline PPA severity and tDCS-induced changes in performance. This study will combine knowledge gained from our behavioral, imaging, and network data in order to determine the relative degrees to which these properties predict whether persons with PPA will respond to intervention.

Detailed Description
-----------------
The central framework for the project is a double-blind, sham-controlled, crossover study in which subjects with the non-fluent/agrammatic and semantic variants of primary progressive aphasia (naPPA and svPPA, respectively) will undergo language testing and structural and functional brain imaging before and after receiving 10 semi-consecutive daily sessions of real or sham transcranial direct current stimulation (tDCS) paired with modified constraint-induced language therapy (mCILT). Language testing and brain imaging will be repeated immediately after completion of and up-to 24 weeks following completion of treatment. Subjects with naPPA and svPPA will be randomized to one of two study arms: tDCS+mCILT or sham stimulation+mCILT paired with pre- and post-stimulation imaging and behavioral measures. Equal numbers of subjects with naPPA and svPPA will be randomized to the tDCS + mCILT and sham + mCILT study arms. The study is double-blinded, in that neither the subject nor the study personnel administering tDCS or sham stimulation will know which arm of the study the subject has been randomized into. Study coordinators will administer tDCS by entering a pre-determined code that has been programmed into the device by another member of the study team. Data will be digitally audio-recorded and analyzed off-line, such that study team members performing data coding and analysis will likewise be blinded to the treatment condition of each subject. Subject participation in this protocol will occur during 36 planned visits that will span approximately 12 months. The events of the study visits are described below: VISIT 1: Informed consent and screening VISIT 2: Baseline MRI VISIT 3 & 4: Baseline language assessment VISITS 5-14: tDCS+mCILT OR sham stimulation+mCILT, depending on the study arm to which they had been randomized. VISIT 15 & 16: Follow-up language assessment Follow-up MRI VISIT 17: 6-Week follow-up language assessment VISIT 18 & 19: 12-week follow-up language assessment 12-week follow-up MRI **CROSSOVER** VISIT 20: Crossover baseline language assessment VISITS 21-30: tDCS+mCILT or sham stimulation+mCILT VISIT 31 & 32: Follow-up language assessment Follow-up MRI VISIT 33: 6 Week follow-up language assessment VISIT 34 & 35: 12-week follow-up language assessment 12-week follow-up MRI VISIT 36: 24 week follow-up language assessment

Official Title
-----------------
Using Transcranial Direct Current Stimulation to Reveal Mechanisms of Language Loss and to Treat Progressive Aphasia Associated With FTD and Related Dementias

Conditions
-----------------
Primary Progressive Aphasia

Intervention / Treatment
-----------------
* Device: Transcranial Direct Current Stimulation (tDCS)
* Device: Sham tDCS
* Behavioral: Modified Contraint-Induced Language Therapy (mCILT)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Presence of aphasia attributable to the semantic variant (svPPA) or non- fluent/agrammatic variant (naPPA) of Primary Progressive Aphasia. Must be a native English speaker Exclusion Criteria: History of seizures or unexplained loss of consciousness Subjects with metallic objects in the face or head other than dental apparatus such as braces, ﬁllings, and implants. Subjects with Pacemakers or ICDs. Subjects with previous craniotomy or any breach in the skull Subjects with a history of other neurological disorder (stroke, TBI, Parkinson) Subjects with a history of small vessel disease

Ages Eligible for Study
-----------------
Minimum Age: 45 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Crossover assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: tDCS + CILT<br>Participants will undergo 10 daily sessions (Monday-Friday, x2 weeks) of tDCS for 20 minutes using a montage in which an anode (1.5 mA) is placed over F7 (left frontotemporal lobe) and the cathode will be place on O1 (left occipital) using the 10-20 EEG mapping system. Subjects will participate in a modified constraint-induced language therapy. | Device: Transcranial Direct Current Stimulation (tDCS)<br>* tDCS is a type of non-invasive brain stimulation in which small electrical currents are applied to the scalp via 2 electrodes. The current, 1.5 mA, is approximately of the same intensity as the current provided by a 9-volt battery. To deliver the current, electrodes that are placed in saline soaked sponges. They will be attached to the left side of your head; they will be held in place with an elastic cap. For both real and sham stimulation the electrodes will be placed on the scalp.<br>Behavioral: Modified Contraint-Induced Language Therapy (mCILT)<br>* Modified constraint-induced language therapy (mCILT) is a behavioral language therapy that invokes use-dependent learning in communicative interactions by requiring spoken output and restricting use of alternative forms of communication, such as gestures, as a substitute for spoken output. Other key elements of CILT include massed practice of goal-directed speech and shaping of desired responses by increasing response demands as participants improve. MCILT differs from traditional constraint-induced language therapy (CILT) in three ways: 1) it will be done as an individual therapy with the examiner in the role of a communication partner; 2) treatment will be delivered in short sessions (1 hour rather than a more typical 3-4 hour session); 3) targeting nouns + semantically related verbs to generate noun + verb phrases in treatment, a modification that may be better suited to addressing syntactic structure.<br>|
| Sham Comparator: Sham tDCS + CILT<br>Participants will undergo 10 daily sessions (Monday-Friday, x2 weeks) of sham tDCS for 20 minutes using a montage in which an anode is placed of F7 and cathose is placed over O1. Subjects will participate in a modified constraint-induced language therapy, | Device: Sham tDCS<br>* tDCS is a type of non-invasive brain stimulation in which small electrical currents are applied to the scalp via 2 electrodes. During sham stimulation, the current, 1.5 mA, will be delivered for a short amount of time and then turn-off. To deliver the current, electrodes that are placed in saline soaked sponges. They will be attached to the left side of your head; they will be held in place with an elastic cap. For both real and sham stimulation the electrodes will be placed on the scalp. Most people cannot tell the difference between real and sham stimulation.<br>Behavioral: Modified Contraint-Induced Language Therapy (mCILT)<br>* Modified constraint-induced language therapy (mCILT) is a behavioral language therapy that invokes use-dependent learning in communicative interactions by requiring spoken output and restricting use of alternative forms of communication, such as gestures, as a substitute for spoken output. Other key elements of CILT include massed practice of goal-directed speech and shaping of desired responses by increasing response demands as participants improve. MCILT differs from traditional constraint-induced language therapy (CILT) in three ways: 1) it will be done as an individual therapy with the examiner in the role of a communication partner; 2) treatment will be delivered in short sessions (1 hour rather than a more typical 3-4 hour session); 3) targeting nouns + semantically related verbs to generate noun + verb phrases in treatment, a modification that may be better suited to addressing syntactic structure.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Western Aphasia Battery (WAB) | The primary outcome measure will be the change in score on the WAB-AQ, a score assessing overall aphasia recovery. Scores can range from 0-100. 0-25 is very severe, 26-50 is severe, 51-75 is moderate, and 76-above is mild. A score of 93 or higher is considered recovered. | Baseline to 24 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
non-invasive brain stimulation, transcranial direct current stimulation (tDCS), speech therapy