Long-Term Memory Decline, Mild Cognitive Impairment
Conditions
Keywords
amnestic MCI without dementia, cognitive training
Brief summary
Therapeutic treatment is yet available for declining memory, which is an impairment affecting the quality of life for many older adults and patients with cognitive impairment. Cognitive training with an immersive video game promises to drive hippocampal-cortical plasticity and associated gains that can restore memory capability or provide therapeutic treatment for memory deficits.
Detailed description
A hallmark of higher cognition is the capability for flexible association of diverse bits of information stored in memory, such that experiences can be remembered in detailed and distinct terms (i.e., high-fidelity long-term memory (LTM)). Interventions capable of sustaining improved learning and flexible association of new information into LTM remain elusive. Interventions have yet to be developed to attenuate the decline of high-fidelity LTM in normal aging or provide therapeutic treatment for patients with cognitive impairment without dementia (i.e., MCI). This project applies a translational neuroscience approach in development of a cognitive training intervention that targets sustained improvement in capabilities for LTM and cognitive control. Treatments use commercially available head-mounted display Virtual Reality (VR) technology and tablet computers to present a deeply immersive spatial wayfinding video game. Based on preliminary results, the hypothesis is that immersion in a game to navigate errands through unfamiliar, visually complex neighborhoods (i.e., wayfinding) will be an effective means to environmental enrichment, which refers to a process whereby new and complex experiences bring change to brain and behavior. The significance of this platform is from the effects in brain and behavior arising from cognitive training, which can generalize to improvements in untrained capability for high-fidelity LTM. Research in rodents and humans shows that learning a new, enriched environment spurs the healthy function of the hippocampus and supports lifelong neurogenesis. Adult-borne hippocampal neurogenesis has been linked as the neurobiological basis for the formation of new, high-fidelity memories. The Labyrinth spatial wayfinding game was developed in-house to incorporate full scientific rigor, as with procedures in any properly controlled behavioral experiment. The game uses 3D and 2.5D computer graphics tools, as well as numerous levels of adaptive challenge, to deliver a dynamic, engaging experience for participants throughout the training regimen. Training can be administered with and without participant ambulation in movement through wayfinding runs. A participant's pre- and post-training assessments will occur promptly before and after their 15 to 20-hour training regimen, including collection of functional MRI (fMRI) and structural MRI data. Cognitive outcome measures will assess capabilities for high-fidelity LTM retrieval. The a priori hypothesis is that effectiveness of the wayfinding game intervention would be evidenced by post-training improvements in retrieval of high-fidelity LTM and associated cognitive control capabilities. FMRI results associated with the measured cognitive improvements will localize changes in functional brain networks that support gains in memory capabilities. Structural MRI measures will assess morphometric and volumetric changes from pre- to post-training assessments.
Interventions
DEVICELabyrinthVR
Head-mounted display virtual reality game designed to induce environmental enrichment in an adaptive, immersive regimen of wayfinding in novel urban and village neighborhoods.
DEVICEPlacebo Games
Commercially-available, narrative computer games marketed as cognitively enriching.
DEVICECoherence
Head-mounted display virtual reality game designed to present an adaptive rhythm training routine.
DEVICETablet
Tablet computer playing Labyrinth VR game but in 2.5D
Sponsors
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Outcomes Assessor)
Masking description
After recruitment, participants are randomly assigned to treatment arms. Participants and experimenters with whom they interact during the experiments are blind to the purpose of the randomly-assigned arm. First-level analysis performed blind to participant's treatment arm.
Eligibility
Sex/Gender
ALL
Age
62 Years to 85 Years
Healthy volunteers
Yes
Inclusion criteria
* fluent speakers of English * completed 12 or more years of education * normal or corrected-to-normal vision * dexterity to comfortably operate the scanner-compatible response box * freedom from physical and neurological conditions contra-indicated for fMRI * must confirm physical stamina and comfort for 45-minute, brisk walks on level ground
Exclusion criteria
* use of psychotropic medications * history of concussions or dizziness, vestibular or balance problems * significant discomfort with virtual reality experiences
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| MDT Change in Mnemonic Discrimination | baseline immediately before and post-assessment immediately after training regimen is completed | Mnemonic discrimination task testing recognition memory for common objects, as reported in scores on a scale of the Lure Discrimination Index ranging from 0.00 to 1.00 where higher values show better performance. |
| WALK Change in Recall | baseline immediately before and post-assessment immediately after training regimen is completed | Encoding and test of recent autobiographical long-term memory, as reported in scores on a scale of Percentage of Items Recalled ranging from 0.00 to 1.00 where higher values show better performance. |
| Changes in Volumetric-based Brain Morphometry Associated With Training-induced Changes in Mnemonic Discrimination | during collection of Outcome 1, baseline immediately before and post-assessment immediately after training regimen is completed | Structural MRI T1 data will be analyzed in terms of volumetric-based morphometry and compared between treatment arms and timepoints. |
| Changes in Task-based Cortical Functional Connectivity Associated With Training-induced Changes in Mnemonic Discrimination | during collection of Outcome 1, baseline immediately before and post-assessment immediately after training regimen is completed | functional MRI data will be analyzed in terms of beta-series correlations between co-active cortical regions of interest and compared between treatment arms and timepoints. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Remote Cognitive Module (RCM) | baseline immediately before and post-assessment immediately after training regimen is completed | A tablet application using a speech-to-text interface to administer neuropsychological tests comparable to CVLT-II verbal memory, verbal fluency, digit span and Trail Making Test-B. Raw scores from the tasks will be transformed to z-scores, relative to population normative values, and a participant's z-scores will be the uniform measures of their performance across RCM tasks. THESE DATA WERE NOT COLLECTED OR ANALYZED DUE TO FUNDING CONSTRAINTS |
| Test of Visual Attention Change in Top-down Control | baseline immediately before and post-assessment immediately after training regimen is completed | test of speed and accuracy of visual attention and impulsivity |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LabyrinthVR Trackers Participants who completed the intervention active training game using head-mounted display virtual reality headset. | 24 |
| Placebo Controls Participants who completed the intervention control games using a tablet computer. | 21 |
| Total | 45 |
Baseline characteristics
| Characteristic | LabyrinthVR Trackers | Placebo Controls | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 23 Participants | 20 Participants | 43 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Continuous | 69.1 years | 68.3 years | 68.7 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 12 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 8 Participants | 14 Participants |
| Region of Enrollment United States | 24 Participants | 21 Participants | 45 Participants |
| Sex: Female, Male Female | 10 Participants | 10 Participants | 20 Participants |
| Sex: Female, Male Male | 14 Participants | 11 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 24 |
| other Total, other adverse events | 0 / 25 | 0 / 24 |
| serious Total, serious adverse events | 0 / 25 | 0 / 24 |
Outcome results
Primary
Changes in Task-based Cortical Functional Connectivity Associated With Training-induced Changes in Mnemonic Discrimination
functional MRI data will be analyzed in terms of beta-series correlations between co-active cortical regions of interest and compared between treatment arms and timepoints.
Time frame: during collection of Outcome 1, baseline immediately before and post-assessment immediately after training regimen is completed
Population: THESE DATA WERE NOT COLLECTED OR ANALYZED DUE TO FUNDING CONSTRAINTS
Primary
Changes in Volumetric-based Brain Morphometry Associated With Training-induced Changes in Mnemonic Discrimination
Structural MRI T1 data will be analyzed in terms of volumetric-based morphometry and compared between treatment arms and timepoints.
Time frame: during collection of Outcome 1, baseline immediately before and post-assessment immediately after training regimen is completed
Population: THESE DATA WERE NOT COLLECTED OR ANALYZED DUE TO FUNDING CONSTRAINTS
Primary
MDT Change in Mnemonic Discrimination
Mnemonic discrimination task testing recognition memory for common objects, as reported in scores on a scale of the Lure Discrimination Index ranging from 0.00 to 1.00 where higher values show better performance.
Time frame: baseline immediately before and post-assessment immediately after training regimen is completed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LabyrinthVR Trackers | MDT Change in Mnemonic Discrimination | 0.09 LDI score on a scale | Standard Error 0.03 |
| Placebo Controls | MDT Change in Mnemonic Discrimination | 0.01 LDI score on a scale | Standard Error 0.03 |
p-value: =0.01695% CI: [-0.06, 0.06]ANOVA
Primary
WALK Change in Recall
Encoding and test of recent autobiographical long-term memory, as reported in scores on a scale of Percentage of Items Recalled ranging from 0.00 to 1.00 where higher values show better performance.
Time frame: baseline immediately before and post-assessment immediately after training regimen is completed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LabyrinthVR Trackers | WALK Change in Recall | 0.03 Items Recalled score on a scale | Standard Error 0.02 |
| Placebo Controls | WALK Change in Recall | 0.00 Items Recalled score on a scale | Standard Error 0.02 |
p-value: =0.2295% CI: [-0.03, 0.03]ANOVA
Secondary
Remote Cognitive Module (RCM)
A tablet application using a speech-to-text interface to administer neuropsychological tests comparable to CVLT-II verbal memory, verbal fluency, digit span and Trail Making Test-B. Raw scores from the tasks will be transformed to z-scores, relative to population normative values, and a participant's z-scores will be the uniform measures of their performance across RCM tasks. THESE DATA WERE NOT COLLECTED OR ANALYZED DUE TO FUNDING CONSTRAINTS
Time frame: baseline immediately before and post-assessment immediately after training regimen is completed
Population: THESE DATA WERE NOT COLLECTED OR ANALYZED DUE TO FUNDING CONSTRAINTS
Secondary
Test of Visual Attention Change in Top-down Control
test of speed and accuracy of visual attention and impulsivity
Time frame: baseline immediately before and post-assessment immediately after training regimen is completed
Population: THESE DATA WERE NOT COLLECTED OR ANALYZED DUE TO FUNDING CONSTRAINTS