HD-tDCS to Enhance Cognitive Training in Multiple Sclerosis

Study Overview
=================
Brief Summary
-----------------
Aim: to test the efficacy of this innovative cognitive remediation protocol for relapsing-remitting multiple sclerosis (RRMS) patients, characterized by a non-conventional focal high-definition transcranial direct current stimulation (HD-tDCS) on the left dorsolateral prefrontal cortex (DLPFC) to boost the effects of a computerised cognitive training (CCT) in improving frontal-executive abilities, in a randomized, double-blind, sham-controlled exploratory pilot study. Secondary objectives: assess protocol feasibility and safety; evaluate its medium/long-lasting effect; estimate the extent of changes in cognitive abilities; evaluate any neurophysiological changes; indagate any related changes in other clinic-behavioural measures. Materials: Forty-four RRMS patients with predominant deficits in information processing will be selected. They will be randomised and equally divided to: real HD-tDCS + CCT (experimental group) and sham HD-tDCS + CCT (control group). Methods: Study treatment will last 40 minutes/day, 5 day/week for 2 weeks. CCT will focus on improving fronto-executive skills. HD-tDCS will be administered on the left DLPFC with a 4x1 ring electrode placement and at an intensity of 2mA (real stimulation) for the first 20 minutes of the protocol. Pre- and post-treatment and at 3- and 6-months follow-ups, participants will undergo neuropsychological, neurological and neurophysiological measurements. To assess changes over time, a repeated-measures analysis of variance will be applied. Functional and effective cerebral network connectivity will be calculated using phase-based metrics and Granger causality analysis. The relationship between clinico-demographical measures and cognitive/behavioural/physiological measures will be assessed using the correlation coefficient. Descriptive analyses will be provided for feasibility (overall compliance) and for safety (any tDCS-related discomfort/side effect or adverse event). Expected results: an improvement in cognitive performance in both groups, boosted in the experimental arm and not confined to general frontal-cognitive abilities; potential changes would be reflected also by neurophysiological measures and in QoL. Discussion: Investigators hope to provide additional treatment tools for RRMS subjects, with a medium-long term efficacy and an extensive effect. This exploratory pilot study will help to set the rationale for future studies, providing preliminary data useful for selecting the best primary outcome and for calculating a better sample size.

Official Title
-----------------
Innovative Protocol Targeting Cognitive Dysfunction in Multiple Sclerosis: HD-tDCS to Enhance Cognitive Training in a Randomized, Double-blind, Controlled, Exploratory Pilot Study

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

Intervention / Treatment
-----------------
* Device: Real HD-tDCS + CCT
* Device: Sham HD-tDCS + CCT


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects with clinically definite diagnosis of relapsing remitting MS (RRMS); Male or female subjects, 18 to 65 years old; Expanded Disability Status Scale (EDSS) score ranging from 0 to 5.5 (included); Predominant deficits in either attention/information processing; Fluent Italian speakers; Normal or corrected-to-normal vision; Ability to understand the purpose and risk of the study and provide signed informed consent. Exclusion Criteria: MS patients in different phase of the disease (as primary/secondary progressive MS; benign MS) or Clinical Isolated Syndrome (CIS) patients; Exclusive cognitive impairment in different domains (e.g., memory); CT/neuromodulation program ongoing or in the preceding 6 months; Clinical exacerbations, neuroradiological activity of the disease, modification of EDSS score and disease modifying treatments/steroids during the last 3 months preceding study enrolment; Significant medical disorders or other major systemic, psychiatric, neurological disorders or alcohol/substance abuse that could interfere with cognitive functioning; Antidepressant/psychoactive drugs in the past 3 months; Contraindications to tDCS (intracranial metallic plates, implanted devices, skin disease, superficial injury and fracture or infraction of skull in the stimulation area, epilepsy, pregnancy, etc).

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Real HD-tDCS + CCT<br>40 min/day of computerised cognitive training (CCT) + 20 min/day of real anodal high definition transcranial direct current stimulation (HD-tDCS). In the first 20 min of the 40 min-intervention, HD-tDCS and CCT will be provided simultaneously. | Device: Real HD-tDCS + CCT<br>* 40 min/day of computerised cognitive training (CCT) + 20 min/day of real anodal high definition transcranial direct current stimulation (HD-tDCS). In the first 20 min of the 40 min-intervention, real anodal HD-tDCS and CCT will be provided simultaneously.<br>|
| Sham Comparator: Sham HD-tDCS + CCT<br>40 min/day of CCT + 20 min/day of apparent (sham) HD-tDCS. In the first 20 min of the 40 min-intervention, HD-tDCS and CCT will be provided simultaneously. | Device: Sham HD-tDCS + CCT<br>* 40 min/day of computerised cognitive training (CCT) + 20 min/day of apparent (sham) HD-tDCS. In the first 20 min of the 40 min-intervention, sham HD-tDCS and CCT will be provided simultaneously.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Symbol Digit Modalities Test (SDMT) | Change in target cognitive test assessing information processing (i.e., SDMT) | Day 0 (baseline, T0), Week 2 (end of treatment, T1), Follow-up at 3 months (FU3) and follow-up at 6 months (FU6) | 
| Change in Paced Auditory Serial Addition Test (PASAT) | Change in target cognitive test assessing information processing (i.e., PASAT) | Day 0 (baseline, T0), Week 2 (end of treatment, T1), Follow-up at 3 months (FU3) and follow-up at 6 months (FU6) | 
| Change in Wisconsin Card Sorting Test (WCST) | Change in target cognitive test assessing frontal executive functions (i.e., WCST) | Day 0 (baseline, T0), Week 2 (end of treatment, T1), Follow-up at 3 months (FU3) and follow-up at 6 months (FU6) | 
| Change in Stroop test | Change in target cognitive test assessing frontal executive functions (i.e., Stroop test) | Day 0 (baseline, T0), Week 2 (end of treatment, T1), Follow-up at 3 months (FU3) and follow-up at 6 months (FU6) | 
| Change in Digit Spans | Change in target cognitive tests assessing information processing and frontal executive functions (i.e., digit spans) | Day 0 (baseline, T0), Week 2 (end of treatment, T1), Follow-up at 3 months (FU3) and follow-up at 6 months (FU6) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of sessions done by esch participants (Feasibility) | Overall compliance of the protocol, assessed by number of sessions done by esch participants (Feasibility) | Day 0 (baseline, T0), Week 2 (end of treatment, T1) | 
| Number tDCS-related of discomfort or side effects experienced by each participants (Safety) | Any tDCS-related discomfort or side effect after each daily session | Day 0 (baseline, T0), Week 2 (end of treatment, T1) | 
| Changes in Brief Repeatable Battery of Neuropsychological Tests (BRBN-T) | Changes in single subtest of the BRBN-T | Day 0 (baseline, T0), Week 2 (end of treatment, T1), Follow-up at 3 months (FU3) and follow-up at 6 months (FU6) | 
| Changes in Beck Depression Inventory (BDI) | 21-question multiple-choice self-report inventory, higher score means worse depressive score. | Day 0 (baseline, T0), Week 2 (end of treatment, T1), Follow-up at 3 months (FU3) and follow-up at 6 months (FU6) | 
| Changes in Expanded Disability Status Scale (EDSS) measurements | 10 points scale, higher score means worse disease progression. | Day 0 (baseline, T0), Week 2 (end of treatment, T1), Follow-up at 3 months (FU3) and follow-up at 6 months (FU6) | 
| Changes in Multiple Sclerosis Functional Composite (MFSC) | Three component parts, higher scores means worse functional symptoms. | Day 0 (baseline, T0), Week 2 (end of treatment, T1), Follow-up at 3 months (FU3) and follow-up at 6 months (FU6) | 
| Changes in Modified Fatigue Impact Scale (MFIS) | three subscales (physical, cognitive, and psychosocial), as well as into a total MFIS score. higher scores indicate a greater impact of fatigue | Day 0 (baseline, T0), Week 2 (end of treatment, T1), Follow-up at 3 months (FU3) and follow-up at 6 months (FU6) | 
| Changes in Multiple Sclerosis Quality of Life (MSQOL-54) | Two summary scores - physical health and mental health - can be derived from a weighted combination of scale scores. | Day 0 (baseline, T0), Week 2 (end of treatment, T1), Follow-up at 3 months (FU3) and follow-up at 6 months (FU6) | 
| Changes in alpha oscillations measured with Electroencephalogram (EEG) Resting State From Baseline | Comparison of alpha oscillation power from resting state EEG recordings on the first and last day of protocol. EEG data also recorded at 3- and 6-month follow up visits. Each of the four EEG recordings will serve to analyze alpha frequency activity for derivation of EEG biomarkers in this observational pilot study. | Day 0 (baseline, T0), Week 2 (end of treatment, T1), Follow-up at 3 months (FU3) and follow-up at 6 months (FU6) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HD-tDCS, Multiple sclerosis, Relapsing remitting multiple sclerosis, Cognitive training, Cognitive rehabilitation, Cognitive remediation, Neuromodulation, Transcranial direct current stimulation, Focal tDCS