ArticleCell research2024
40 Hz light flickering promotes sleep through cortical adenosine signaling.
Article in Cell research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers, 1 of them a synthesis that pooled it.
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The trial behind it
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Who cites it
40 citing papers in PubMed, 1 synthesis or guideline pooled it, 53 citations in OpenAlex.
- The safety and efficacy of gamma frequency auditory and visual stimulation in the treatment of alzheimer's disease: a systematic review and meta-analysis.Translational psychiatry · 2025Pooled it
- The sleep-wake cycle: molecular mechanisms, disorders, and therapeutic targets in the context of energy metabolism.Signal transduction and targeted therapy · 2026Review
- High intensity 40 Hz flicker improves amyloid pathology and cognition with autophagy in 3xTg mice.iScience · 2026Article
- Glymphatic system impairment in neurological disorders: potential mechanisms and therapeutic targets.Molecular biomedicine · 2026Review
- 40 Hz light flickering alleviates chronic pain via adenosine signaling in the retina-amygdala pathway.Cell research · 2026Article
- Superior colliculus modulates the compulsion in a model of addiction with foot-shock.Translational psychiatry · 2026Article
- Sequential visual stimuli increase high frequency power in the visual cortex.Scientific reports · 2026Article
- 40 Hz flicker preconditioning protects nonarteritic anterior ischemic optic neuropathy via adenosine signaling.Communications biology · 2026Article
- Retinal Amyloid Clearance Enhanced by 40-Hz Light Flicker via MHC-II+ Microglia Regulation in Mice.Investigative ophthalmology & visual science · 2026Article
- A locus coeruleus-centric framework for novelty, salience, and gamma oscillations: implications for neurostimulation, aging, and disease.Frontiers in aging neuroscience · 2026Article
- Physical factor therapies for insomnia: a narrative review of mechanisms, clinical evidence, and phenotype-guided applications.Frontiers in psychiatry · 2026Review
- Exploring the potential effects of different frequencies of flashing light stimulation on alleviating mental fatigue: a behavioral and EEG study.Frontiers in human neuroscience · 2026Article
- Intraoperative 40 Hz gamma frequency auditory stimulation for postoperative sleep disturbance in patients undergoing laparoscopic gynecological surgery: protocol for a randomized controlled trial.Frontiers in medicine · 2026Article
- Noninvasive Terahertz Wave Binocular Stimulation Improves Cognition in Amyloid-β-Related Dementia.Research (Washington, D.C.) · 2026Article
- Light-based 40 Hz sensory therapy for brain disorders: physiological basis, therapeutic mechanisms, and future prospects.Frontiers in medicine · 2026Review
- Targeting glymphatic-associated pathways for Alzheimer's disease: a review of non-invasive modulation strategies, mechanisms, and emerging evidence.Frontiers in immunology · 2026Review
- Meningeal lymphatics as a therapeutic target for neurodegenerative disorders.Translational neurodegeneration · 2025Review
- Review
- Adenosine in the Brain: Recent Progress on Detection, Function, and Translation.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Review
- Cortical astrocyte histamine-1-receptors regulate intracellular calcium and extracellular adenosine dynamics across sleep and wake.PLoS biology · 2025Article
Corrections and comments
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Authors and funding
24 authors at 6 institutions in 3 countries.
Funding
Abstract
Flickering light stimulation has emerged as a promising non-invasive neuromodulation strategy to alleviate neuropsychiatric disorders. However, the lack of a neurochemical underpinning has hampered its therapeutic development. Here, we demonstrate that light flickering triggered an immediate and sustained increase (up to 3 h after flickering) in extracellular adenosine levels in the primary visual cortex (V1) and other brain regions, as a function of light frequency and intensity, with maximal effects observed at 40 Hz frequency and 4000 lux. We uncovered cortical (glutamatergic and GABAergic) neurons, rather than astrocytes, as the cellular source, the intracellular adenosine generation from AMPK-associated energy metabolism pathways (but not SAM-transmethylation or salvage purine pathways), and adenosine efflux mediated by equilibrative nucleoside transporter-2 (ENT2) as the molecular pathway responsible for extracellular adenosine generation. Importantly, 40 Hz (but not 20 and 80 Hz) light flickering for 30 min enhanced non-rapid eye movement (non-REM) and REM sleep for 2-3 h in mice. This somnogenic effect was abolished by ablation of V1 (but not superior colliculus) neurons and by genetic deletion of the gene encoding ENT2 (but not ENT1), but recaptured by chemogenetic inhibition of V1 neurons and by focal infusion of adenosine into V1 in a dose-dependent manner. Lastly, 40 Hz light flickering for 30 min also promoted sleep in children with insomnia by decreasing sleep onset latency, increasing total sleep time, and reducing waking after sleep onset. Collectively, our findings establish the ENT2-mediated adenosine signaling in V1 as the neurochemical basis for 40 Hz flickering-induced sleep and unravel a novel and non-invasive treatment for insomnia, a condition that affects 20% of the world population.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.