Aging
Conditions
Brief summary
A two-phase adaptive randomized clinical trial will examine the individual and combined impact of pairing cognitive training with transcranial direct current stimulation (tDCS). tDCS is a method of non-invasive brain stimulation that directly stimulates brain regions involved in active cognitive function and could enhance neural plasticity when paired with a training task. We will compare changes in cognitive and brain function resulting from CT and ET combined with tDCS using a comprehensive neurocognitive, clinical, and multimodal neuroimaging assessment of brain structure, function, and metabolic state. Functional magnetic resonance imaging (FMRI) will be used to assess brain response during working memory, attention, and memory encoding; the active cognitive abilities trained by CT. Proton magnetic resonance spectroscopy (MRS) will assess cerebral metabolites, including GABA concentrations sensitive to neural plasticity. We hypothesize that: 1) tDCS will enhance neurocognitive function, brain function, and functional outcomes from CT, with combined CT and tDCS providing the most benefit; 2) Effects of tDCS on CT will be maintained up to 12 months following training, and 3) Neuroimaging biomarkers of cerebral metabolism, neural plasticity (GABA concentrations) and functional brain response (FMRI) during resting vs. active cognitive tasks will predict individual response to tDCS.
Interventions
BEHAVIORALCognitive Training
Cognitive Training employs an eight component, PositScience BrainHQ suite via its researcher portal.
A Soterix Clinical Trials Direct Current Stimulator will apply 20 minutes of 2.0mA direct current through two biocarbon rubber electrodes encased in saline soaked 5cm x 7cm sponges (8cc of 0.9% saline solution per sponge) placed over the frontal cortices at F3 and F4 (10-20 system).
DEVICEtDCS (sham stimulation)
Sham stimulation is performed with the same device and all procedures will be identical except for the duration of stimulation. Participants will receive 30 seconds of 2 mA of direct current stimulation at the beginning of the session. Participants habituate to the sensation of tDCS within 30-60 seconds of stimulation. This procedure provides the same sensation of tDCS without the full duration of stimulation, making it a highly effective sham procedure.
BEHAVIORALEducational Training
Educational training involves watching educational videos produced by the National Geographic Channel, which cover a range of topics such as history, nature, and wildlife. Participants will be asked to complete questions on the content of the videos to ensure sustained attention.
Sponsors
University of Arizona
National Institute on Aging (NIA)
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
65 Years to 89 Years
Healthy volunteers
Yes
Inclusion criteria
1. Age 65 to 89 years; this age group was selected because it is at high risk of age-related cognitive decline and have a sufficiently long life expectancy to participate in the study. 2. Evidence of age-related cognitive decline in the Cognitive Training assessment defined by performance below the 80th percentile. 3. Ability to participate in the intervention and attend training sessions; willingness to be randomized to either treatment group.
Exclusion criteria
1. Neurological disorders (e.g., dementia, stroke, seizures, traumatic brain injury). 2. Evidence of cognitive impairment (as defined by NACC UDS performance below 1.5 standard deviations on age/sex/education normative data in at least one cognitive domain). 3. Past opportunistic brain infection. 4. Major psychiatric illness (schizophrenia, intractable affective disorder, current substance dependence diagnosis or severe major depression and/or suicidality. 5. Unstable (e.g., cancer other than basal cell skin) and chronic (e.g. severe diabetes) medical conditions. 6. MRI contraindications (e.g., claustrophobia, metal implants). 7. Physical impairment precluding motor response or lying still for 1 hr and inability to walk two blocks without stopping. 8. Currently on GABA-ergic or glutamatergic medications, or on sodium channel blockers. 9. Left-handedness.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Improvement in Cognitive Ability. | Change from baseline to post assessment (3 months). | Composite measure of cognitive ability as defined by NIH toolbox fluid cognition fully corrected T-score. Minimum change = -13, Maximum change = 26. Higher scores mean a better outcome. The minimum and maximum for Cognitive Training + Active Stimulation, Cognitive Training + Sham Stimulation, Educational Training + Active Stimulation and Educational Training + Sham Stimulation are (-13, 20) and (-10, 26), respectively. This outcome is measured for the participants who received cognitive training, including both Phase I and Phase II participants, N=334 (Phase I N=42, Phase II N=292). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase I POSIT BrainHQ Cognitive Training Composite Performance Measure.(Phase I POSIT Z-Score) | Baseline to post assessment (3 months). | POSIT BrainHQ Cognitive Training Composite Performance measure involves performance on the 8 selected cognitive training tasks set to the medium difficulty level and provides a measure of proximal performance on cognitive training tasks central to the cognitive training condition. The higher score indicates better performance. The range of POSIT Z-Score at 3-month is -1.04 to 1.75. the minimum and maximum for Cognitive training group and Education training group are (-0.24, 1.75) and (-1.04, 1.39), respectively. |
Countries
United States
Participant flow
Recruitment details
Participant flow is reported with three periods. Period 1 includes all randomized participants (combined Phase I and Phase II). Period 2 contains only the Phase I participants. Period 3 contains only the Phase II participants. In Phase II the two education training arms were eliminated, hence the allocation of 0 to those groups. Participants who were enrolled in Phase I education training were not randomized again in Phase II (there is no crossover).
Participants by arm
| Arm | Count |
|---|---|
| Cognitive Training + Active Stimulation This arm receives cognitive training combined with active tDCS.
Cognitive Training: Cognitive Training employs an eight component, PositScience BrainHQ suite via its researcher portal.
tDCS (active stimulation): A Soterix Clinical Trials Direct Current Stimulator will apply 20 minutes of 2.0mA direct current through two biocarbon rubber electrodes encased in saline soaked 5cm x 7cm sponges (8cc of 0.9% saline solution per sponge) placed over the frontal cortices at F3 and F4 (10-20 system). | 168 |
| Cognitive Training + Sham Stimulation This arm receives cognitive training combined with sham tDCS.
Cognitive Training: Cognitive Training employs an eight component, PositScience BrainHQ suite via its researcher portal.
tDCS (sham stimulation): Sham stimulation is performed with the same device and all procedures will be identical except for the duration of stimulation. Participants will receive 30 seconds of 2 mA of direct current stimulation at the beginning of the session. Participants habituate to the sensation of tDCS within 30-60 seconds of stimulation. This procedure provides the same sensation of tDCS without the full duration of stimulation, making it a highly effective sham procedure. | 166 |
| Educational Training + Active Stimulation This arm receives educational training combined with active tDCS.
tDCS (active stimulation): A Soterix Clinical Trials Direct Current Stimulator will apply 20 minutes of 2.0mA direct current through two biocarbon rubber electrodes encased in saline soaked 5cm x 7cm sponges (8cc of 0.9% saline solution per sponge) placed over the frontal cortices at F3 and F4 (10-20 system).
Educational Training: Educational training involves watching educational videos produced by the National Geographic Channel, which cover a range of topics such as history, nature, and wildlife. Participants will be asked to complete questions on the content of the videos to ensure sustained attention. | 23 |
| Educational Training + Sham Stimulation This arm receives educational training combined with sham tDCS.
tDCS (sham stimulation): Sham stimulation is performed with the same device and all procedures will be identical except for the duration of stimulation. Participants will receive 30 seconds of 2 mA of direct current stimulation at the beginning of the session. Participants habituate to the sensation of tDCS within 30-60 seconds of stimulation. This procedure provides the same sensation of tDCS without the full duration of stimulation, making it a highly effective sham procedure.
Educational Training: Educational training involves watching educational videos produced by the National Geographic Channel, which cover a range of topics such as history, nature, and wildlife. Participants will be asked to complete questions on the content of the videos to ensure sustained attention. | 22 |
| Total | 379 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall (Phase I + Phase II) | COVID-19 lockdown, no reason specified | 4 | 5 | 0 | 0 |
| Overall (Phase I + Phase II) | Lost to Follow-up | 0 | 1 | 0 | 0 |
| Overall (Phase I + Phase II) | Physician Decision | 18 | 16 | 0 | 1 |
| Overall (Phase I + Phase II) | Withdrawal by Subject | 20 | 17 | 0 | 3 |
| Phase I | Physician Decision | 0 | 0 | 0 | 1 |
| Phase I | Withdrawal by Subject | 2 | 1 | 0 | 3 |
| Phase II | COVID-19 lockdown, no reason specified | 4 | 5 | 0 | 0 |
| Phase II | Lost to Follow-up | 0 | 1 | 0 | 0 |
| Phase II | Physician Decision | 18 | 16 | 0 | 0 |
| Phase II | Withdrawal by Subject | 18 | 16 | 0 | 0 |
Baseline characteristics
| Characteristic | Cognitive Training + Active Stimulation | Cognitive Training + Sham Stimulation | Educational Training + Active Stimulation | Educational Training + Sham Stimulation | Total |
|---|---|---|---|---|---|
| Age, Continuous | 71.5 years STANDARD_DEVIATION 5.4 | 71.5 years STANDARD_DEVIATION 4.8 | 70.0 years STANDARD_DEVIATION 5.1 | 73.1 years STANDARD_DEVIATION 4.7 | 71.5 years STANDARD_DEVIATION 5.1 |
| Average POSIT z-score: | -0.18 z-score STANDARD_DEVIATION 0.44 | -0.20 z-score STANDARD_DEVIATION 0.46 | -0.11 z-score STANDARD_DEVIATION 0.47 | -0.44 z-score STANDARD_DEVIATION 0.55 | -0.20 z-score STANDARD_DEVIATION 0.46 |
| BDI-II Total Score | 4.0 units on a scale STANDARD_DEVIATION 4.8 | 3.4 units on a scale STANDARD_DEVIATION 3.9 | 2.4 units on a scale STANDARD_DEVIATION 3.1 | 3.1 units on a scale STANDARD_DEVIATION 3.7 | 3.6 units on a scale STANDARD_DEVIATION 4.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants | 8 Participants | 1 Participants | 2 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 154 Participants | 158 Participants | 22 Participants | 20 Participants | 354 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| MOCA Total Score | 26.7 units on a scale STANDARD_DEVIATION 2 | 26.8 units on a scale STANDARD_DEVIATION 1.9 | 26.9 units on a scale STANDARD_DEVIATION 1.7 | 26.1 units on a scale STANDARD_DEVIATION 2.1 | 26.7 units on a scale STANDARD_DEVIATION 1.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 5 Participants | 1 Participants | 0 Participants | 9 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 3 Participants | 1 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 8 Participants | 0 Participants | 2 Participants | 21 Participants |
| Race (NIH/OMB) More than one race | 5 Participants | 2 Participants | 0 Participants | 2 Participants | 9 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) White | 146 Participants | 148 Participants | 20 Participants | 18 Participants | 332 Participants |
| Region of Enrollment United States | 168 participants | 166 participants | 23 participants | 22 participants | 0 participants |
| Sex: Female, Male Female | 104 Participants | 111 Participants | 10 Participants | 11 Participants | 236 Participants |
| Sex: Female, Male Male | 64 Participants | 55 Participants | 13 Participants | 11 Participants | 143 Participants |
| Years of Education | 16.3 years STANDARD_DEVIATION 2.3 | 16.4 years STANDARD_DEVIATION 2.4 | 16.7 years STANDARD_DEVIATION 2.1 | 15.6 years STANDARD_DEVIATION 2.4 | 16.3 years STANDARD_DEVIATION 2.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 168 | 0 / 166 | 0 / 23 | 0 / 22 |
| other Total, other adverse events | 69 / 168 | 75 / 166 | 12 / 23 | 12 / 22 |
| serious Total, serious adverse events | 16 / 168 | 19 / 166 | 4 / 23 | 5 / 22 |
Outcome results
Primary
Improvement in Cognitive Ability.
Composite measure of cognitive ability as defined by NIH toolbox fluid cognition fully corrected T-score. Minimum change = -13, Maximum change = 26. Higher scores mean a better outcome. The minimum and maximum for Cognitive Training + Active Stimulation, Cognitive Training + Sham Stimulation, Educational Training + Active Stimulation and Educational Training + Sham Stimulation are (-13, 20) and (-10, 26), respectively. This outcome is measured for the participants who received cognitive training, including both Phase I and Phase II participants, N=334 (Phase I N=42, Phase II N=292).
Time frame: Change from baseline to post assessment (3 months).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cognitive Training + Active Stimulation | Improvement in Cognitive Ability. | 4.7 units on a scale | Standard Deviation 6.5 |
| Cognitive Training + Sham Stimulation | Improvement in Cognitive Ability. | 4.5 units on a scale | Standard Deviation 6.1 |
Comparison: Null hypothesis: The combination of cognitive training (12 weeks) and active stimulation (over the dorsolateral prefrontal cortex) will not lead to beneficial changes on the NIH Toolbox Cognition Battery.~The study is designed to have at least 90% power to detect a difference of effect size 0.42 between cognitive training+tDCS and cognitive training+sham, using a normal inverse combination test at one-sided 0.025 level.p-value: <0.0595% CI: [-0.91, 1.56]Regression, Linear
Secondary
Phase I POSIT BrainHQ Cognitive Training Composite Performance Measure.(Phase I POSIT Z-Score)
POSIT BrainHQ Cognitive Training Composite Performance measure involves performance on the 8 selected cognitive training tasks set to the medium difficulty level and provides a measure of proximal performance on cognitive training tasks central to the cognitive training condition. The higher score indicates better performance. The range of POSIT Z-Score at 3-month is -1.04 to 1.75. the minimum and maximum for Cognitive training group and Education training group are (-0.24, 1.75) and (-1.04, 1.39), respectively.
Time frame: Baseline to post assessment (3 months).
Population: Adults were between the ages of 65-89, right-handed, fluent in English, and had evidence of age-related cognitive decline. Analysis includes all 87 participants from Phase I.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cognitive Training + Active Stimulation | Phase I POSIT BrainHQ Cognitive Training Composite Performance Measure.(Phase I POSIT Z-Score) | 0.95 units on a scale | Standard Deviation 0.41 |
| Cognitive Training + Sham Stimulation | Phase I POSIT BrainHQ Cognitive Training Composite Performance Measure.(Phase I POSIT Z-Score) | -0.06 units on a scale | Standard Deviation 0.47 |