Multiple Sclerosis
Conditions
Brief summary
The focus of this work is the evaluation of a measure of cognitive functioning- intra-individual variability (IIV) - derived from a computer-based continuous reaction time (RT) task (Cogstate) as an early marker of prodromal MS.
Detailed description
This study is a prospective observational clinical study, where the researchers will recruit adults with early MS (n=60) to complete a cognitive assessment and an optional gait assessment using Runscribe and G-sensor. Thirty-five \[35\] participants will also have a single 60-minute investigational MRI combined with 20 minutes of simultaneous tDCS. The MRI will repeat the protocol from the researchers' current study (ClinicalTrials.gov Identifier: NCT03564496, IRB i18-00548) using simultaneous transcranial direct current stimulation (tDCS) during the imaging acquisition.
Interventions
DEVICEActive tDCS
The tDCS-MRI scan will last approximately one hour. The first 20 minutes of the MRI will not include tDCS stimulation. After 20 minutes, the tDCS device will ramp up to 2.0mA and deliver 2.0mA for 20 minutes. Then the tDCS will ramp down (30 seconds) and the final 20 minutes will be without stimulation.
Sponsors
National Multiple Sclerosis Society
NYU Langone Health
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SCREENING
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
23 Years to 59 Years
Healthy volunteers
No
Inclusion criteria
* Ages 23-59 years old (inclusive) * Prodromal MS (defined by radiologically isolated syndrome ≤ 6 months from first MRI or clinically isolated syndrome ≤ 3 months from first clinical event)
Exclusion criteria
* Below average estimated premorbid cognitive functioning (based on WRAT-4 reading recognition standard z-score \< 85). * Presence of severe cognitive impairment (based on SDMT age normative z-score \<-3.0). * Primary psychiatric disorder that would influence ability to participate. * Current uncontrolled seizure disorder. * Current substance abuse disorder. * History of head trauma in the past year (e.g., head injury, brain surgery) or medical device implanted in the head (such as Deep Brain Stimulator) or in the neck (such as a Vagus Nerve Stimulator). * Pregnant or breastfeeding Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cerebral Metabolic Rate of Oxygen (CMRO2) | Day 1 (Visit 1 - approximately 4 minutes) | CMRO2 is the amount of O2 the brain consumes per unit of time (in μmol O2/100g tissue per minute). To quantify absolute CMRO2, both TRUST MRI for quantification of venous oxygenation (Yv) and phase contrast (PC) MRI for quantification of total blows are needed. The total scan time for CMRO2 MRI is approximately 4 minutes. |
| Intra-Individual Variability (IIV) as Measured by Cogstate Brief Battery (CBB) | Day 1 (Visit 1) | The core Cogstate Reaction Time (RT) tasks involve a deck of cards on a green background screen and the participant answers yes or no by hitting a keyboard key (D or K) across repeated trials. Each task first includes instructions and practice period before the test begins and takes approximately 3-4 minutes to complete (for a total of \ 7 minutes). The representative timed RT scores are provided by the Detection task (indicating when a card is revealed; DET/simple RT), Identification task (is the card revealed black or red?; IDN/choice RT), and One-Back (Is this the card that you just saw?). Performance is characterized by near complete accuracy (i.e. all, or almost all, items are answered correctly), and validity checks are built into the scoring. IIV is calculated as intraindividual standardized deviations (ISD) in RTs across both tasks, measured in milliseconds and with log10 transformation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Brief International Cognitive Assessment for MS (BICAMS) Symbol Digit Modalities Test (SDMT) Z-Score | Day 1 (Visit 1) | SDMT is 90-second cognitive task in which the participant is shown a sheet containing rows of symbols. Each symbol corresponds to a specific number. The participant's task is to say out loud the number associated with each symbol. SDMT is used as a general cognitive screen to detect severe cognitive impairment. The raw score is the correct number of substitutions in 90 seconds, scores range between 0 and 110. The lower the score, the more severe the cognitive impairment. The raw score is converted to a Z-score with a central value of 0. Standard deviations below the mean indicate a worse outcome; a Z-score of -1.5 or lower suggests a significant deviation from the average performance, potentially indicating cognitive impairment. |
| BICAMS Rey Auditory Verbal Learning Test (RAVLT) Z-Score | Day 1 (Visit 1) | RAVLT is a well-recognized measure of a person's ability to encode, combine, store and recover verbal information in different stages of immediate memory. consists of presenting a list of 15 words across consecutive trials. The list is read aloud to the participant, and then the participant is immediately asked to recall as many words as one remembers. This procedure is repeated for 5 consecutive trials (Trials 1 to 5). The total score is the sum of trials 1-5 and ranges from 0-75. The lower the score, the more severe the cognitive impairment. The raw score is converted to a Z-score with a central value of 0. Standard deviations below the mean indicate a worse outcome; a Z-score of -1.5 or lower indicates impairment, meaning the individual's performance is significantly below the average of their peer group. |
| BICAMS Brief Visuospatial Memory Test Revised (BVMT-R) Z-Score | Day 1 (Visit 1) | Visual/spatial memory is assessed in BICAMS using the BVMT-R. In this test, six abstract designs are presented for 10 sec. The display is removed from view and patients render the stimuli via pencil on paper manual responses. Each design receives from 0 to 2 points representing accuracy and location. There are three Learning Trials, and the score is reported as the total number of points earned over the trials. Thus, scores range from 0 to 12 per trial; total score range is 0 to 36 for all three trials. The lower the score, the more severe the cognitive impairment. The raw score is converted to a Z-score with a central value of 0. Standard deviations below the mean indicate a worse outcome; a Z-score of -1.5 or lower on the BVMT-R is generally considered indicative of cognitive impairment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group With tDCS-MRI Participants will have a cognitive assessment, an optional gait assessment, and a 1-hour MRI brain scan combined with 20 minutes of simultaneous tDCS. Participants may also complete the MRI on a separate visit.
Active tDCS: The tDCS-MRI scan will last approximately one hour. The first 20 minutes of the MRI will not include tDCS stimulation. After 20 minutes, the tDCS device will ramp up to 2.0mA and deliver 2.0mA for 20 minutes. Then the tDCS will ramp down (30 seconds) and the final 20 minutes will be without stimulation. | 30 |
| Group Without tDCS- MRI Participants will have include a cognitive assessment and an optional gait assessment | 29 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
Baseline characteristics
| Characteristic | Group With tDCS-MRI | Total | Group Without tDCS- MRI |
|---|---|---|---|
| Age, Continuous | 34 years STANDARD_DEVIATION 8.3 | 36 years STANDARD_DEVIATION 8.8 | 37 years STANDARD_DEVIATION 8.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 19 Participants | 22 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 24 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 13 Participants | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 14 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants | 17 Participants | 9 Participants |
| Race (NIH/OMB) White | 12 Participants | 28 Participants | 16 Participants |
| Region of Enrollment United States | 30 participants | 59 participants | 29 participants |
| Sex: Female, Male Female | 22 Participants | 45 Participants | 23 Participants |
| Sex: Female, Male Male | 8 Participants | 14 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 29 |
| other Total, other adverse events | 1 / 30 | 0 / 29 |
| serious Total, serious adverse events | 0 / 30 | 0 / 29 |
Outcome results
Primary
Cerebral Metabolic Rate of Oxygen (CMRO2)
CMRO2 is the amount of O2 the brain consumes per unit of time (in μmol O2/100g tissue per minute). To quantify absolute CMRO2, both TRUST MRI for quantification of venous oxygenation (Yv) and phase contrast (PC) MRI for quantification of total blows are needed. The total scan time for CMRO2 MRI is approximately 4 minutes.
Time frame: Day 1 (Visit 1 - approximately 4 minutes)
Population: Note - assessed in the Group with tDCS-MRI arm only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group With tDCS-MRI | Cerebral Metabolic Rate of Oxygen (CMRO2) | 8.17 micro-mol/100g/min | Standard Deviation 12.99 |
Primary
Intra-Individual Variability (IIV) as Measured by Cogstate Brief Battery (CBB)
The core Cogstate Reaction Time (RT) tasks involve a deck of cards on a green background screen and the participant answers yes or no by hitting a keyboard key (D or K) across repeated trials. Each task first includes instructions and practice period before the test begins and takes approximately 3-4 minutes to complete (for a total of \ 7 minutes). The representative timed RT scores are provided by the Detection task (indicating when a card is revealed; DET/simple RT), Identification task (is the card revealed black or red?; IDN/choice RT), and One-Back (Is this the card that you just saw?). Performance is characterized by near complete accuracy (i.e. all, or almost all, items are answered correctly), and validity checks are built into the scoring. IIV is calculated as intraindividual standardized deviations (ISD) in RTs across both tasks, measured in milliseconds and with log10 transformation.
Time frame: Day 1 (Visit 1)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group With tDCS-MRI | Intra-Individual Variability (IIV) as Measured by Cogstate Brief Battery (CBB) | 0.37 log10(ms) | Standard Deviation 0.64 |
| Group Without tDCS- MRI | Intra-Individual Variability (IIV) as Measured by Cogstate Brief Battery (CBB) | 0.34 log10(ms) | Standard Deviation 0.64 |
Secondary
BICAMS Brief Visuospatial Memory Test Revised (BVMT-R) Z-Score
Visual/spatial memory is assessed in BICAMS using the BVMT-R. In this test, six abstract designs are presented for 10 sec. The display is removed from view and patients render the stimuli via pencil on paper manual responses. Each design receives from 0 to 2 points representing accuracy and location. There are three Learning Trials, and the score is reported as the total number of points earned over the trials. Thus, scores range from 0 to 12 per trial; total score range is 0 to 36 for all three trials. The lower the score, the more severe the cognitive impairment. The raw score is converted to a Z-score with a central value of 0. Standard deviations below the mean indicate a worse outcome; a Z-score of -1.5 or lower on the BVMT-R is generally considered indicative of cognitive impairment.
Time frame: Day 1 (Visit 1)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group With tDCS-MRI | BICAMS Brief Visuospatial Memory Test Revised (BVMT-R) Z-Score | 0.14 Z-score | Standard Deviation 1.33 |
| Group Without tDCS- MRI | BICAMS Brief Visuospatial Memory Test Revised (BVMT-R) Z-Score | -0.02 Z-score | Standard Deviation 0.85 |
Secondary
BICAMS Rey Auditory Verbal Learning Test (RAVLT) Z-Score
RAVLT is a well-recognized measure of a person's ability to encode, combine, store and recover verbal information in different stages of immediate memory. consists of presenting a list of 15 words across consecutive trials. The list is read aloud to the participant, and then the participant is immediately asked to recall as many words as one remembers. This procedure is repeated for 5 consecutive trials (Trials 1 to 5). The total score is the sum of trials 1-5 and ranges from 0-75. The lower the score, the more severe the cognitive impairment. The raw score is converted to a Z-score with a central value of 0. Standard deviations below the mean indicate a worse outcome; a Z-score of -1.5 or lower indicates impairment, meaning the individual's performance is significantly below the average of their peer group.
Time frame: Day 1 (Visit 1)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group With tDCS-MRI | BICAMS Rey Auditory Verbal Learning Test (RAVLT) Z-Score | -0.17 Z-score | Standard Deviation 0.87 |
| Group Without tDCS- MRI | BICAMS Rey Auditory Verbal Learning Test (RAVLT) Z-Score | -0.25 Z-score | Standard Deviation 0.91 |
Secondary
Brief International Cognitive Assessment for MS (BICAMS) Symbol Digit Modalities Test (SDMT) Z-Score
SDMT is 90-second cognitive task in which the participant is shown a sheet containing rows of symbols. Each symbol corresponds to a specific number. The participant's task is to say out loud the number associated with each symbol. SDMT is used as a general cognitive screen to detect severe cognitive impairment. The raw score is the correct number of substitutions in 90 seconds, scores range between 0 and 110. The lower the score, the more severe the cognitive impairment. The raw score is converted to a Z-score with a central value of 0. Standard deviations below the mean indicate a worse outcome; a Z-score of -1.5 or lower suggests a significant deviation from the average performance, potentially indicating cognitive impairment.
Time frame: Day 1 (Visit 1)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group With tDCS-MRI | Brief International Cognitive Assessment for MS (BICAMS) Symbol Digit Modalities Test (SDMT) Z-Score | -1.09 Z-score | Standard Deviation 1.25 |
| Group Without tDCS- MRI | Brief International Cognitive Assessment for MS (BICAMS) Symbol Digit Modalities Test (SDMT) Z-Score | -1.03 Z-score | Standard Deviation 1.28 |