Treatment of Cognitive Deficits in Multiple Sclerosis With High-Definition Transcranial Direct Current Stimulation

Study Overview
=================
Brief Summary
-----------------
The purpose of the study is to test whether low level electric stimulation, called transcranial Direct Current Stimulation (tDCS), on the part of the brain (i.e., presupplementary motor area) thought to aid in memory will improve verbal retrieval in multiple sclerosis patients. The primary outcome measures are neuropsychological assessments of verbal retrieval, and the secondary measures are neuropsychological assessments of other cognitive abilities and electroencephalography (EEG) measures. Additionally, the study will examine the degree to which baseline assessments of cognition and concussion history predict responses to treatment over time, both on assessments administered within the intervention period and at follow-up.

Detailed Description
-----------------
Using two treatment arms, the study will examine improvement of verbal retrieval and other cognitive deficits associated with multiple sclerosis by comparing (1) 1 milliamp transcranial direct current stimulation (tDCS) active treatment applied to presupplementary motor area for 20 minutes over 10 sessions to (2) sham tDCS following the same schedule. Additionally, after completing the initial active or sham treatment and immediate and 2-month follow-up testing sessions, selected participants will be invited back for newly assigned treatment conditions, 20 minutes over 10 sessions and will be re-evaluated at immediate and 2-month follow-up testing sessions. Patients with multiple sclerosis and observed cognitive deficits will be randomly assigned to one of the two treatment arms (and re-assigned for the second round of intervention, as described above). Primary outcome verbal retrieval measures, secondary neuropsychological and electroencephalography (EEG) measures, and prescreening assessments for study concussion history and contraindications for treatment will be collected prior to being assigned to a treatment arm (i.e., baseline). Primary outcome verbal retrieval measures and secondary neuropsychological and electroencephalography (EEG) measures will be at baseline and two times following treatment competition (i.e., immediate and 2-months). For participants selected for the second round of intervention, primary outcome verbal memory measures and secondary neuropsychological and electroencephalography (EEG) measures will be collected again two times immediately following completion of the last treatment and 2-months afterward.

Official Title
-----------------
Treatment of Cognitive Deficits in Multiple Sclerosis With High-Definition Transcranial Direct Current Stimulation

Conditions
-----------------
Multiple Sclerosis, Relapsing-Remitting

Intervention / Treatment
-----------------
* Device: Transcranial Direct Current Stimulation
* Device: Sham transcranial direct current stimulation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: º Diagnosed with relapsing-remitting multiple sclerosis (RRMS) º Memory retrieval deficit based on neuropsychological testing done in our lab º Must be fluent in speaking and reading English. Exclusion Criteria: º Relapse or acute MS exacerbation or a course of steroids in the two months preceding the testing º Participants using benzodiazepines must have been on a stable dose for at least two months º Potentially confounding psychological or neurological disorder, including: dementia of any type epilepsy or other seizure disorders severe traumatic brain injury brain tumor present drug abuse stroke blood vessel abnormalities in the brain Parkinson's disease Huntington's disease º inability to give informed consent º cranial implants º skull defects that affect tDCS administration º use of medications that interact with or potentially interact with tDCS effects, including: anti-convulsants L-dopa carbamazepine sulpiride pergolide lorazepam rivastigmine dextromethorphan D-cycloserine flunarizine ropinirole citalopram stimulants (dextroamphetamine/amphetamine/modafinil/armodafinil) must be stopped during enrollment

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 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: Parallel Assignment
Interventional Model Description: Participants will be randomly assigned to 1 of 2 treatment arms: (1) 1 milliamp transcranial direct current stimulation (tDCS) active treatment applied to presupplementary motor area for 20 minutes over 15 sessions to (2) sham tDCS following the same schedule. Additionally, after completing the initial active or sham treatment and immediate and 2-month follow-up testing sessions, selected participants will be invited back for newly assigned treatment conditions, 20 minutes over 15 sessions and will be and re-evaluated at immediate- and 2-months follow-up testing sessions.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Transcranial direct current stimulation<br>Transcranial direct current stimulation will be delivered via a Neuroelectrics Starstim tES. Stimulation will consist of 1 milliamp stimulation, with anodal stimulation delivered at electrode Fz (International 10/10 System for electroencephalography electrode placement) and electrodes F7, FP1, FP2, and F8 as returns. All electrodes are 1 cm diameter Ag/AgCl electrodes and make contact with the scalp via connective gel. Stimulation will linearly ramp up from 0 milliamps to 1 milliamp over 60 seconds, then remain at 1 milliamp of stimulation over 20 minutes, and finally ramping down at to 0 milliamps over 60 seconds. Other Names: tDCS 1 milliamp tDCS High definition tDCS High definition transcranial direct current stimulator, Neuroelectrics Starstim tES, SN E20200930-10 | Device: Transcranial Direct Current Stimulation<br>* Transcranial direct current stimulation will be delivered via a Neuroelectrics Starstim tES. Stimulation will consist of 1 milliamp stimulation, with anodal stimulation delivered at electrode Fz (International 10/10 System for electroencephalography electrode placement) and electrodes F7, FP1, FP2, and F8 as returns. All electrodes are 1 cm diameter Ag/AgCl electrodes and make contact with the scalp via connective gel. Stimulation will linearly ramp up from 0 milliamps to 1 milliamp over 60 seconds, then remain at 1 milliamp of stimulation over 20 minutes, and finally ramping down at to 0 milliamps over 60 seconds.<br>* Other names: tDCS;|
| Sham Comparator: Sham transcranial direct current stimulation<br>Sham transcranial direct current stimulation will be delivered via a Neuroelectrics Starstim tES. The sham setup will consist of anodal electrode Fz (International 10/10 System for electroencephalography electrode placement) and electrodes F7, FP1, FP2, and F8 as returns. All electrodes are 1 cm diameter Ag/AgCl electrodes and make contact with the scalp via connective gel. Stimulation will linearly ramp up from 0 milliamps to 1 milliamp over 60 seconds, ramp down to 0 milliamps over 60 seconds and then be left off for 20 minutes. | Device: Sham transcranial direct current stimulation<br>* Sham transcranial direct current stimulation will be delivered via a Neuroelectrics Starstim tES. The sham setup will consist of anodal electrode Fz (International 10/10 System for electroencephalography electrode placement) and electrodes F7, FP1, FP2, and F8 as returns. All electrodes are 1 cm diameter Ag/AgCl electrodes and make contact with the scalp via connective gel. Stimulation will linearly ramp up from 0 milliamps to 1 milliamp over 60 seconds, ramp down to 0 milliamps over 60 seconds and then be left off for 20 minutes.<br>* Other names: Sham tDCS;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment group differences in change from Baseline to 1-week Post-Treatment on Category Fluency | Evaluation of treatment group differences in change on Category Fluency from baseline to 1-week post-treatment. Metric: Number of Correct Items Generated | Outcome measures will be assessed as change over a period of 6 weeks: Change from baseline to 1-week Post-Treatment | 
| Treatment group differences in change from Baseline to 2-months Post-Treatment on Category Fluency | Evaluation of treatment group differences in change on Category Fluency from baseline to 2-months post-treatment. Metric: Number of Correct Items Generated | Outcome measures will be assessed as change over a period of 13 weeks: Change from baseline to 2-month Post-Treatment | 
| Treatment group differences in change from Baseline to 1-week Post-Treatment on COWAT | Evaluation of treatment group differences in change on COWAT from baseline to 1-week post-treatment. Metric: Number of Correct Items Generated | Outcome measures will be assessed as change over a period of 6 weeks: Change from baseline to 1-week Post-Treatment | 
| Treatment group differences in change from Baseline to 2-months Post-Treatment on COWAT | Evaluation of treatment group differences in change on COWAT from baseline to 2-months post-treatment. Metric: Number of Correct Items Generated | Outcome measures will be assessed as change over a period of 13 weeks: Change from baseline to 2-months Post-Treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment group differences in change from Baseline to 1-week Post-Treatment on the Trail Making Test (Part A) | Evaluation of treatment group differences in change on the Trail Making Test (Part A) from baseline to 1-week post-treatment. Metric: Time to Solution | Outcome measures will be assessed as change over a period of 6 weeks: Change from baseline to 1-week Post-Treatment | 
| Treatment group differences in change from Baseline to 1-week Post-Treatment on the Trail Making Test (Part B) | Evaluation of treatment group differences in change on the Trail Making Test (Part B) from baseline to 1-week post-treatment. Metric: Time to Solution | Outcome measures will be assessed as change over a period of 6 weeks: Change from baseline to 1-week Post-Treatment | 
| Treatment group differences in change from Baseline to 1-week Post-Treatment on the Delis Kaplan Color Word Interference Test | Evaluation of treatment group differences in change on the Delis Kaplan Color Word Interference Test from baseline to 1-week post-treatment. Metric: Time to Name Items | Outcome measures will be assessed as change over a period of 6 weeks: Change from baseline to 1-week Post-Treatment | 
| Treatment group differences in change from Baseline to 1-week Post-Treatment on on the Digit Span Forward | Evaluation of treatment group differences in change on the on the Digit Span Forward from baseline to 1-week post treatment. Metric: Memory Span | Outcome measures will be assessed as change over a period of 6 weeks: Change from baseline to 1-week Post-Treatment | 
| Treatment group differences in change from Baseline to 1-week Post-Treatment on the Digit Span Backward | Evaluation of treatment group differences in change on the Digit Span Backward from baseline to 1-week post treatment. Metric: Memory Span | Outcome measures will be assessed as change over a period of 6 weeks: Change from baseline to 1-week Post-Treatment | 
| Treatment group differences in change from Baseline to 1-week Post-Treatment on on the the Rey-Osterrieth Complex Figure Test | Evaluation of treatment group differences in change on the Rey-Osterrieth Complex Figure Test from baseline to 1-week post treatment. Metric: Score | Outcome measures will be assessed as change over a period of 6 weeks: Change from baseline to 1-week Post-Treatment | 
| Treatment group differences in change from Baseline to 1-week Post-Treatment on the Digit Symbol Substitution Test | Evaluation of treatment group differences in change on the on the the Digit Symbol Substitution Test from baseline to 1-week post treatment. Metric: Number of Items | Outcome measures will be assessed as change over a period of 6 weeks: Change from baseline to 1-week Post-Treatment | 
| Treatment group differences in change from Baseline to 1-week Post-Treatment on the Grooved Pegboard Test | Evaluation of treatment group differences in change on the Grooved Pegboard Test from baseline to 1-week post-treatment. Metric: Completion Time | Outcome measures will be assessed as change over a period of 6 weeks: Change from baseline to 1-week Post-Treatment | 
| Treatment group differences in change from Baseline to 1-week Post-Treatment on the Semantic Object Retrieval Test | Evaluation of treatment group differences in change on the Semantic Object Retrieval Test from baseline to 1-week post-treatment. Metric: Number of Correct Names Retrieved | Outcome measures will be assessed as change over a period of 6 weeks: Change from baseline to 1-week Post-Treatment | 
| Treatment group differences in change from Baseline to 1-week Post-Treatment on the Boston Naming Test | Evaluation of treatment group differences in change on the Boston Naming Test from baseline to 1-week post-treatment. Metric: Number of Items Correctly Named | Outcome measures will be assessed as change over a period of 6 weeks: Change from baseline to 1-week Post-Treatment | 
| Treatment group differences in change from Baseline to 1-week Post-Treatment on the Auditory Verbal Learning Test | Evaluation of treatment group differences in change on the Auditory Verbal Learning Test from baseline to 1-week post-treatment. Metric: Number of Items Remembered | Outcome measures will be assessed as change over a period of 6 weeks: Change from baseline to 1-week Post-Treatment | 
| Treatment group differences in change from Baseline to 2-months Post-Treatment on the Trail Making Test (Part A) | Evaluation of treatment group differences in change on the Trail Making Test (Part A) from baseline to 2-months post-treatment. Metric: Time to Solution | Outcome measures will be assessed as change over a period of 13 weeks: Change from baseline to 2-months Post-Treatment | 
| Treatment group differences in change from Baseline to 2-months Post-Treatment on the Trail Making Test (Part B) | Evaluation of treatment group differences in change on the Trail Making Test (Part B) from baseline to 2-months post-treatment. Metric: Time to Solution | Outcome measures will be assessed as change over a period of 13 weeks: Change from baseline to 2-months Post-Treatment | 
| Treatment group differences in change from Baseline to 2-months Post-Treatment on the Delis Kaplan Color Word Interference Test | Evaluation of treatment group differences in change on the Delis Kaplan Color Word Interference Test from baseline to 2-months post-treatment. Metric: Time to Name Items | Outcome measures will be assessed as change over a period of 13 weeks: Change from baseline to 2-months Post-Treatment | 
| Treatment group differences in change from Baseline to 2-months Post-Treatment on the Digit Span Forward | Evaluation of treatment group differences in change on the on the Digit Span Forward from baseline to 2-months post-treatment. Metric: Memory Span | Outcome measures will be assessed as change over a period of 13 weeks: Change from baseline to 2-months Post-Treatment | 
| Treatment group differences in change from Baseline to 2-months Post-Treatment on the Digit Span Backward | Evaluation of treatment group differences in change on the on the Digit Span Backward from baseline to 2-months post-treatment. Metric: Memory Span | Outcome measures will be assessed as change over a period of 13 weeks: Change from baseline to 2-months Post-Treatment | 
| Treatment group differences in change from Baseline to 2-months Post-Treatment on the Rey-Osterrieth Complex Figure Test | Evaluation of treatment group differences in change on the on the Rey-Osterrieth Complex Figure Test from baseline to 2-months post-treatment. Metric: Score | Outcome measures will be assessed as change over a period of 13 weeks: Change from baseline to 2-months Post-Treatment | 
| Treatment group differences in change from Baseline to 2-months Post-Treatment on the Digit Symbol Substitution Test | Evaluation of treatment group differences in change on the on the the Digit Symbol Substitution Test from baseline to 2-months post treatment. Metric: Number of Items | Outcome measures will be assessed as change over a period of 13 weeks: Change from baseline to 2-months Post-Treatment | 
| Treatment group differences in change from Baseline to 2-months Post-Treatment on the Grooved Pegboard Test | Evaluation of treatment group differences in change on the Grooved Pegboard Test from baseline to 2-months post-treatment. Metric: Completion Time | Outcome measures will be assessed as change over a period of 13 weeks: Change from baseline to 2-months Post-Treatment | 
| Treatment group differences in change from Baseline to 2-months Post-Treatment on the Semantic Object Retrieval Test | Evaluation of treatment group differences in change on the Semantic Object Retrieval Test from baseline to 2-months post-treatment. Metric: Number of Correct Names Retrieved | Outcome measures will be assessed as change over a period of 13 weeks: Change from baseline to 2-months Post-Treatment | 
| Treatment group differences in change from Baseline to 2-months Post-Treatment on the Boston Naming Test | Evaluation of treatment group differences in change on the Boston Naming Test from baseline to 2-months post-treatment. Metric: Number of Items Correctly Named | Outcome measures will be assessed as change over a period of 13 weeks: Change from baseline to 2-months Post-Treatment | 
| Treatment group differences in change from Baseline to 2-months Post-Treatment on the Auditory Verbal Learning Test | Evaluation of treatment group differences in change on the Auditory Verbal Learning Test from baseline to 2-months post-treatment. Metric: Number of Items Remembered | Outcome measures will be assessed as change over a period of 13 weeks: Change from baseline to 2-months Post-Treatment | 
| Treatment group differences in change from Baseline to 1-week Post-Treatment on the Semantic Inhibition Task EEG spectral power | Evaluation of treatment group differences in change on the Semantic Inhibition Task EEG from baseline to 1-week post-treatment. Metric: EEG spectral (theta) power | Outcome measures will be assessed as change over a period of 6 weeks: Change from baseline to 2-months Post-Treatment | 
| Treatment group differences in change from Baseline to 2-months Post-Treatment on the Semantic Inhibition Task EEG spectral power | Evaluation of treatment group differences in change on the Semantic Inhibition Task EEG from baseline to 2-months post-treatment. Metric: EEG spectral (theta) power | Outcome measures will be assessed as change over a period of 13 weeks: Change from baseline to 2-months Post-Treatment | 
| Treatment group differences in change from Baseline to 1-week Post-Treatment on the Semantic Inhibition Task EEG Event-Related Potential (N2/P3) | Evaluation of treatment group differences in change on the Semantic Inhibition Task EEG from baseline to 1-week post-treatment. Metric: EEG N2/P3 event-related potential amplitude | Outcome measures will be assessed as change over a period of 6 weeks: Change from baseline to 1-week Post-Treatment | 
| Treatment group differences in change from Baseline to 2-months Post-Treatment on the Semantic Inhibition Task EEG Event-Related Potential (N2/P3) | Evaluation of treatment group differences in change on the Semantic Inhibition Task EEG from baseline to 2-months post-treatment. Metric: EEG N2/P3 event-related potential amplitude | Outcome measures will be assessed as change over a period of 13 weeks: Change from baseline to 2-months Post-Treatment | 
| Treatment group differences in change from Baseline to 1-week Post-Treatment on the Semantic Object Retrieval EEG spectral power | Evaluation of treatment group differences in change on the Semantic Object Retrieval EEG from baseline to 1-week post-treatment. Metric: EEG spectral (theta) power | Outcome measures will be assessed as change over a period of 6 weeks: Change from baseline to 1-week Post-Treatment | 
| Treatment group differences in change from Baseline to 2-months Post-Treatment on the Semantic Object Retrieval EEG spectral power | Evaluation of treatment group differences in change on the Semantic Object Retrieval EEG from baseline to 2-months post-treatment. Metric: EEG event-related potential amplitude | Outcome measures will be assessed as change over a period of 13 weeks: Change from baseline to 1-week Post-Treatment | 
| Treatment group differences in change from Baseline to 1-week Post-Treatment on the Semantic Object Retrieval EEG event-related potential | Evaluation of treatment group differences in change on the Semantic Object Retrieval EEG from baseline to 1-week post-treatment. Metric: EEG late-onset (750 ms) event-related potential | Outcome measures will be assessed as change over a period of 6 weeks: Change from baseline to 1-week Post-Treatment | 
| Treatment group differences in change from Baseline to 2-months Post-Treatment on the Semantic Object Retrieval EEG event-related potential | Evaluation of treatment group differences in change on the Semantic Object Retrieval EEG from baseline to 2-months post-treatment. Metric: EEG late-onset (750 ms) event-related potential | Outcome measures will be assessed as change over a period of 13 weeks: Change from baseline to 2-months Post-Treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
transcranial direct current stimulation (tDCS), multiple sclerosis, electroencephalography (EEG)