Virtual reality-based cognitive-motor training for middle-aged adults at high Alzheimer's disease risk: A randomized controlled trial

Abstract

Introduction: Ubiquity of Alzheimer's disease (AD) coupled with relatively ineffectual pharmacologic treatments has spurred interest in nonpharmacologic lifestyle interventions for prevention or risk reduction. However, evidence of neuroplasticity notwithstanding, there are few scientifically rigorous, ecologically relevant brain training studies focused on building cognitive reserve in middle age to protect against cognitive decline. This pilot study will examine the ability of virtual reality (VR) cognitive training to improve cognition and cerebral blood flow (CBF) in middle-aged individuals at high AD risk due to parental history.

Methods: The design is an assessor-blind, parallel group, randomized controlled trial of VR cognitive-motor training in middle-aged adults with AD family history. The experimental group will be trained with adaptive "real-world" VR tasks targeting sustained and selective attention, working memory, covert rule deduction, and planning, while walking on a treadmill. One active control group will perform the VR tasks without treadmill walking; another will walk on a treadmill while watching scientific documentaries (nonspecific cognitive stimulation). A passive (waitlist) control group will not receive training. Training sessions will be 45 minutes, twice/week for 12 weeks. Primary outcomes are global cognition and CBF (from arterial spin labeling [ASL]) at baseline, immediately after training (training gain), and 3 months post-training (maintenance gain). We aim to recruit 125 participants, including 20 passive controls and 35 in the other groups.

Discussion: Current pharmacologic therapies are for symptomatic AD patients, whereas nonpharmacologic training is administrable before symptom onset. Emerging evidence suggests that cognitive training improves cognitive function. However, a more ecologically valid cognitive-motor VR setting that better mimics complex daily activities may augment transfer of trained skills. VR training has benefited clinical cohorts, but benefit in asymptomatic high-risk individuals is unknown. If effective, this trial may help define a prophylactic regimen for AD, adaptable for home-based application in high-risk individuals.

Keywords: Alzheimer's disease; Arterial spin labeling; Cerebral blood flow; Cognition; Cognitive training; MRI; Neuroplasticity; Prevention; Virtual reality.

Figures

Fig. 1

Study design and flow. The design is an assessor-blind, parallel group, randomized controlled trial of a cognitive-motor virtual reality (VR) training program in middle-aged adults with a parental family history of Alzheimer's disease (AD). Participants meeting inclusion/exclusion criteria will complete a baseline assessment including cognitive and neurobiological measures (Supplementary Table 1). Following randomization, participants in the experimental and active control groups will complete 24 training sessions over 12 weeks (45 minutes/session). Participants will repeat the assessment following the training period and again after an additional 3 months. Primary outcomes will be global cognition and cerebral blood flow (CBF) from magnetic resonance imaging (MRI) arterial spin labeling (ASL). For an exploratory analysis, participants will also undergo positron emission tomography amyloid imaging once during the study.

Fig. 2

Virtual reality (VR) training setup. The experimental group (Group 1, VR + T) is trained with a set of “real-world” tasks presented on a large monitor while walking on an instrumented split-belt treadmill (R-Mill; ForceLink, The Netherlands). A VR system (V-Gait; Motek Medical, The Netherlands) synchronizes the treadmill (i.e., including embedded force plates) with the visual scene, and a motion capture system (Vicon, Oxford, UK) covering the space occupied by the treadmill captures kinematic data (sampling rate: 120 Hz) via a set of cameras and passive markers affixed to the top of the participant's right and left hands, respectively. One active control group (Group 2, VR − T) stands rather than walks on the treadmill, and the other active control group (Group 3, TV + T) views an episode of a scientific documentary rather than completing the VR tasks. Green arrows represent data flow; black arrows indicate system components.

Fig. 3

The virtual reality (VR) training tasks. The training tasks developed for the current trial were designed to mimic the complex demands of everyday life. Five tasks are set in a virtual supermarket where the participant must collect products from the middle shelf (see Fig. 4). The products to be collected vary depending on the particular task. In the road task, participants hit virtual balls bouncing in space as they walk rapidly down a virtual road. Task difficulty is manipulated by incrementally adjusting the load/complexity of the cognitive task or the speed of the visual flow/treadmill. For details on the individual tasks, refer to Table 2 and Supplementary Material 2.

Fig. 4

Product collection process in supermarket virtual reality (VR) training tasks. To collect a product during the five supermarket VR training tasks (Table 2; Fig. 3), the participant moves the virtual hand until touching it (fourth frame), at which point the product disappears from the shelf (fifth frame), indicating that it has been successfully collected.