Safety, Feasibility, and Potential Clinical Efficacy of 40 Hz Invisible Spectral Flicker versus Placebo in Patients with Mild-to-Moderate Alzheimer’s Disease: A Randomized, Placebo-Controlled, Double-Blinded, Pilot Study

Article type: Research Article

Authors: Agger, Mikkel Pejstrup^{a; b; *} | Danielsen, Else Rubæk^c | Carstensen, Marcus Schultz^d | Nguyen, N. Mai^e | Horning, Maibritt^{a; b} | Henney, Mark Alexander^f | Jensen, Christopher Boe Ravn^e | Baandrup, Anders Ohlhues^c | Kjær, Troels Wesenberg^{a; b} | Madsen, Kristoffer Hougaard^{f; g} | Miskowiak, Kamilla^h | Petersen, Paul Michael^d | Høgh, Peter^{a; b}

Affiliations: [a] Department of Neurology, Zealand University Hospital, Denmark | [b] Department of Clinical Medicine, University of Copenhagen, Denmark | [c] Department of Radiology Zealand University Hospital, Denmark | [d] Department of Photonics Engineering, Technical University of Denmark, Denmark | [e] OptoCeutics ApS, Kgs. Lyngby, Denmark | [f] Department of Applied Mathematics and Computer Science, Technical University of Denmark, Denmark | [g] Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital - Amager and Hvidovre, Copenhagen, Denmark | [h] Neurocognition and Emotion in Affective Disorders (NEAD) Group, Copenhagen Affective Disorder Research Centre (CADIC), Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Denmark

Correspondence: [*] Correspondence to: Mikkel Pejstrup Agger, Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark. Tel.: +45 41400108; E-mails: pwx803@sund.ku.dk and magge@regionsjaelland.dk.

Abstract: Background:Recent studies suggested induction of 40 Hz neural activity as a potential treatment for Alzheimer’s disease (AD). However, prolonged exposure to flickering light raises adherence and safety concerns, encouraging investigation of tolerable light stimulation protocols. Objective:To investigate the safety, feasibility, and exploratory measures of efficacy. Methods:This two-stage randomized placebo-controlled double-blinded clinical trial, recruited first cognitive healthy participants (n = 3/2 active/placebo), and subsequently patients with mild-to-moderate AD (n = 5/6, active/placebo). Participants were randomized 1:1 to receive either active intervention with 40 Hz Invisible Spectral Flicker (ISF) or placebo intervention with color and intensity matched non-flickering white light. Results:Few and mild adverse events were observed. Adherence was above 86.1% of intended treatment days, with participants remaining in front of the device for >51.3 min (60 max) and directed gaze >34.9 min. Secondary outcomes of cognition indicate a tendency towards improvement in the active group compared to placebo (mean: –2.6/1.5, SD: 6.58/6.53, active/placebo) at week 6. Changes in hippocampal and ventricular volume also showed no tendency of improvement in the active group at week 6 compared to placebo. At week 12, a potential delayed effect of the intervention was seen on the volume of the hippocampus in the active group compared to placebo (mean: 0.34/–2.03, SD: 3.26/1.18, active/placebo), and the ventricular volume active group (mean: –0.36/2.50, SD: 1.89/2.05, active/placebo), compared to placebo. Conclusion:Treatment with 40 Hz ISF offers no significant safety or adherence concerns. Potential impact on secondary outcomes must be tested in larger scale clinical trials.

Keywords: 40 Hz, Alzheimer’s disease, gamma entrainment, invisible spectral flicker, light-based neurostimulation

DOI: 10.3233/JAD-221238

Journal: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 653-665, 2023