Novel Invisible Spectral Flicker Induces 40 Hz Neural Entrainment with Similar Spatial Distribution as 40 Hz Stroboscopic Light

Mikkel Pejstrup Agger, Marcus Schultz Carstensen, Mark Alexander Henney, Luna Skytte Hansen, Anders Ohlhues Baandrup, Mai Nguyen, Paul Michael Petersen, Kristoffer Hougaard Madsen, Troels Wesenberg Kjær, Mikkel Pejstrup Agger, Marcus Schultz Carstensen, Mark Alexander Henney, Luna Skytte Hansen, Anders Ohlhues Baandrup, Mai Nguyen, Paul Michael Petersen, Kristoffer Hougaard Madsen, Troels Wesenberg Kjær

Abstract

Background: Exposure to 40 Hz stroboscopic light, for one hour a day, has previously been published as a potential treatment option for Alzheimer's disease in animal models. However, exposure for an hour a day to 40 Hz stroboscopic light can be strenuous and examining other types of 40 Hz inducing stimuli is paramount if chronic treatment is wanted.

Objective: A core assumption behind ensuring a therapeutic outcome is that the visual stimuli can induce 40 Hz gamma entrainment. Here, we examine whether a specific visual stimulus, 40 Hz invisible spectral flicker (ISF), can induce gamma entrainment and how it differs from both continuous light (CON) and 40 Hz stroboscopic light (STROBE).

Methods: The study included non-simultaneous EEG-fMRI neuroimaging of 13 young healthy volunteers during light exposure. Each light condition (i.e., CON, ISF, or STROBE) was active for 30 seconds followed immediately by the next.

Results: Entrainment of 40 Hz neural activity were significantly higher signal-to-noise ratio during exposure to ISF (mean: 3.03, 95% CI 2.07 to 3.99) and STROBE (mean: 12.04, 95% CI 10.18 to 13.87) compared to CON. Additionally STROBE had a higher entrainment than ISF (mean: 9.01, 95% CI 7.16 to 12.14).

Conclusion: This study presents a novel method of 40 Hz entrainment using ISF. This enables the possibility of future randomized placebo-controlled clinical trials with acceptable double blinding due to the essentially imperceivable flicker, which is expected to substantially reduce discomfort compared to interventions with stroboscopic flicker.

Keywords: 40 Hz; Alzheimer’s disease; GENUS; electroencephalograph; functional MRI; gamma entrainment; invisible spectral flicker; light-based neurostimulation; steady state visually evoked potentials.

Conflict of interest statement

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/22-0081r1).

Figures

Fig. 1
Fig. 1
Experimental design. A) Normalized spectral irradiance of the different light conditions used, top panel: non-flickering light (CON), middle panel: 40 Hz ISF, lower panel: 40 Hz stroboscopic light. B) Normalized spectral irradiance of the 1st and 2nd half cycle of the different conditions. C) Color temperature of the three light conditions used. D) Illustration of the AB and ABC paradigms.
Fig. 2
Fig. 2
Experimental setup in the MR scanner. Fiber optic cables projected light to the eyes of the subject within the MR scanner. Each fiber optic cable was positioned 5 cm from the medial corner of each eye to achieve equal light intensity at the level of the eyes to that used in the EEG setup.
Fig. 3
Fig. 3
40 Hz neural activity from the AB paradigm. A) Shows the PSD for both continuous non-flickering light (CON) and 40 Hz ISF (ISF). The lower panel is zoomed in to more accurately represents frequencies around 40 Hz. B) Boxplot of signal-to-noise ratios (SNR) for both conditions. C) Topographical distribution of 40 Hz activity during exposure to continuous non-flickering light. D) As C, but for exposure to 40 Hz ISF. Note the difference in color bar to better visualize the spatial distributions of the induced 40 Hz neural activity.
Fig. 4
Fig. 4
40 Hz neural activity from the ABC paradigm. A) Shows the PSD for both continuous non-flickering light (CON), 40 Hz ISF (ISF), and 40 Hz stroboscopic light. The lower panel is zoomed in to more accurately represent frequencies around 40 Hz. B) Boxplot of signal-to-noise ratios for all three conditions. C) Topographical distribution of 40 Hz activity during exposure to continuous non-flickering light. D) As C, but for exposure to 40 Hz ISF. E) As C and D, but for 40 Hz stroboscopic light. Note the difference in color bar to better visualize the spatial distributions of the induced 40 Hz neural activity.
Fig. 5
Fig. 5
Confusion matrices of the multivariate pattern analysis of within-subject comparison with 1000 permutations. A) AB paradigm comparing non-flickering continuous light to 40 Hz ISF. B) ABC paradigm comparing non-flickering continuous light to 40 Hz ISF. C) ABC paradigm comparing non-flickering continuous light to 40 Hz Stroboscopic light. D) Control paradigm testing no light stimulus against non-flickering lights.

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