Kathy Healey, MS Specialist and participating personnel on this study, is one of the MS providers at the Nebraska Medicine MS Clinic. She helped determine the following inclusion/exclusion criteria as well as the protocol. She has enlisted the help of her colleagues to help identify eligible subjects. Patients will be identified by their MS provider as having cognitive impairment, having relapsing remitting MS, being between the ages of 19-60, not having a relapse or DMT change in the last 6 months, an EDSS of 2-5.5 and not undergoing cognitive therapy. The provider will then ask the patient if they are interested in participating in a research study and if so pass on their contact information to the PI. If patients meet the inclusion/exclusion criteria they will be asked to sign the consent form and then undergo screening to include Montreal Cognitive Assessment (MoCA), Test of Premorbid Functioning (ToPF), Generalized Anxiety Disorder (GAD-7), Beck Depression Inventory (BDI-2) and Modified Fatigue Impact Score (MFIS). While these tests are being used for screening purposed only and will not be administered by a certified neuropsychologist, if a subject answered a 2 (I would like to kill myself) or a 3 (I would kill myself if I had the chance) on the suicidal thoughts question of the BDI-II then Dr. Erica Schmidt would be contacted and the patient would be notified that the research team has to break confidentiality to help them with a safety plan that could include contacting their medical provider or sending them to the ER. Dr. Schmidt is a certified neuropsychologist and is very capable of making the proper decisions if a subject discloses moderate to high risk of suicide to ensure the safety of all subjects. If a subject answered a 1 (I have thoughts of killing myself but would not carry them out) then the subject would be asked to complete the Columbia Suicide Severity Rating Scale (C-SSRS). If the subject has more than low risk based on the C-SSRS then they would be excluded from the study and Dr. Schmidt would be contacted. All subjects that answer a one, two or three on the BDI-II will also be given a pamphlet that has information regarding how to make an appointment with a neuropsychologist as well as suicide hotline numbers.

Once screened, those who meet the inclusion criteria based on their scores will be invited to continue on in the study. Eligible participants will be randomized using a block randomization table with group assignment: computerized cognitive training or control. Dr. Wichman, a biostatistician, has created a randomization chart to use to randomly assign the subjects. Since the PI is assigning BrainHQ programs to the participants she is unblinded and can use the randomization chart.

All randomized subjects will be asked to complete the Human Activity Profile29, a physical activity questionnaire, and the Perceived Deficits Questionnaire32. They will also be asked to do a baseline Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery. The BICAMS battery consists of the Symbol Digit Modalities Test (SDMT)33, the Brief Visuospatial Memory Test Revised (BVMT-R)34 and the California Verbal Learning Test 2nd edition (CVLT-II)35. The accelerometer will be given at the enrollment visit and participants asked to wear an accelerometer during waking hours over a 7 day period. Participants will return the device to researchers by mail. This visit will take approximately two hours.

All subjects will be asked to complete the prescribed activities through BrainHQ, whether it is the control activities or the cognitive activities. Subjects randomized to the intervention group will complete prescribed cognitive training activities 3 times a week for 20-30 minutes each time for 6 weeks. Subjects randomized to the control group will complete computerized control activities that are not cognitive training on BrainHQ 3 times a week for 20-30 minutes each time for 6 weeks. The BrainHQ activities will be done on a personal computer or tablet. Subjects will not be provided devices as one of the inclusion criteria is that the patient have access to a computer and the internet. The cognitive training will consist of different exercises that are meant to improve processing speed, verbal memory and visual memory which are the domains that BICAMS tests. The control activities will be games similar to candy crush, connect four, gem swap and battleship. The subjects will be provided log in information and will not be entering any personal information on the BrainHQ application.

After 6 weeks of BrainHQ programs, subjects will return for end-of-study testing that will take approximately one hour. They will complete the BICAMS battery again as well as fill out the Perceived Deficits Questionnaire.