Introduction We and collaborators discovered that flickering lights and sound at gamma frequency (40 Hz) reduce Alzheimer's disease (AD) pathology and alter immune cells and signaling in mice. To determine the feasibility of this intervention in humans we tested the safety, tolerability, and daily adherence to extended audiovisual gamma flicker stimulation. Methods Ten patients with mild cognitive impairment due to underlying AD received 1‐hour daily gamma flicker using audiovisual stimulation for 4 or 8 weeks at home with a delayed start design. Results Gamma flicker was safe, tolerable, and adherable. Participants’ neural activity entrained to stimulation. Magnetic resonance imaging and cerebral spinal fluid proteomics show preliminary evidence that prolonged flicker affects neural networks and immune factors in the nervous system. Discussion These findings show that prolonged gamma sensory flicker is safe, tolerable, and feasible with preliminary indications of immune and network effects, supporting further study of gamma stimulation in AD.

Accurate wayfinding is essential to the survival of many animal species and requires the ability to maintain spatial orientation during locomotion. One of the ways that humans and other animals stay spatially oriented is through path integration, which operates by integrating self-motion cues over time, providing information about total displacement from a starting point. The neural substrate of path integration in mammals may exist in grid cells, which are found in dorsomedial entorhinal cortex and presubiculum and parasubiculum in rats. Grid cells have also been found in mice, bats, and monkeys, and signatures of grid cell activity have been observed in humans. We demonstrate that distance estimation by humans during path integration is sensitive to geometric deformations of a familiar environment and show that patterns of path integration error are predicted qualitatively by a model in which locations in the environment are represented in the brain as phases of arrays of grid cells with unique periods and decoded by the inverse mapping from phases to locations. The periods of these grid networks are assumed to expand and contract in response to expansions and contractions of a familiar environment. Biases in distance estimation occur when the periods of the encoding and decoding grids differ. Our findings explicate the way in which grid cells could function in human path integration.

Previous studies from psychology, neuroscience and geography showed that environmental barriers fragment the representation of the environment, reduce spatial navigation efficiency, distort distance estimation and make spatial updating difficult. Despite these negative effects, limited research has examined how to overcome barriers and if individual differences mediate their causes and potential interventions. We hypothesize that the reduced visibility caused by barriers plays a major role in accumulating error in spatial updating and encoding spatial relationships. We tested this using virtual navigation to grant participants ‘X-ray’ vision during environment encoding (i.e., barriers become translucent) and quantifying cognitive mapping benefits of counteracting fragmented visibility. We found that compared to the participants trained with naturalistic environment visibility, participants trained in the translucent environment had better performance in wayfinding and pointing tasks, which are theorized to measure navigation efficiency and cognitive mapping. Interestingly, these benefits were only observed in participants with high self-report sense of direction. Together, our results provide important insight into (1) how perceptual barrier effects manifest, even when physical fragmentation of space is held constant, (2) establish a novel intervention that can improve spatial learning, and (3) provide evidence that individual differences modulate perceptual barrier effects and the efficacy of such interventions.

Highlights d Human participants engaged in a non-memory-based VR foraging task d Grid-cell-like representations are observed in open-field environments d Grid-cell-like representations are disrupted in environments with hairpin barriers d Entorhinal signals develop a 4-fold periodicity in barrier environments Authors Qiliang He, Thackery I. Brown