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Physiological Evidence

Below is a list of articles that have been used to develop and support the science of specialized phototherapy.

Human Studies

Endo, T., Matsumura, R., Tokuda, I. T., Yoshikawa, T., Shigeyoshi, Y., Node, K., … & Akashi, M. (2020). Bright light improves sleep in patients with Parkinson’s disease: Possible role of circadian restoration. Scientific reports, 10(1), 1-10.

Videnovic, A., Klerman, E. B., Wang, W., Marconi, A., Kuhta, T., & Zee, P. C. (2017). Timed light therapy for sleep and daytime sleepiness associated with Parkinson disease: a randomized clinical trial. JAMA neurology, 74(4), 411-418.

Romenets, S. R., Creti, L., Fichten, C., Bailes, S., Libman, E., Pelletier, A., & Postuma, R. B. (2013). Doxepin and cognitive behavioural therapy for insomnia in patients with Parkinson’s disease–a randomized study. Parkinsonism & related disorders, 19(7), 670-675.

Willis, G. L., Moore, C., & Armstrong, S. M. (2012). A historical justification for and retrospective analysis of the systematic application of light therapy in Parkinson’s disease. Reviews in the Neurosciences, 23(2), 199-226.

Paus, S., Schmitz‐Hübsch, T., Wüllner, U., Vogel, A., Klockgether, T., & Abele, M. (2007). Bright light therapy in Parkinson’s disease: a pilot study. Movement disorders: official journal of the Movement Disorder Society, 22(10), 1495-1498.

Willis, G. L., & Turner, E. J. D. (2007). Primary and secondary features of Parkinson’s disease improve with strategic exposure to bright light: a case series study. Chronobiology international, 24(3), 521-537.

Artemenko, A. R., & IaI, L. (1996). The phototherapy of parkinsonism patients. Zhurnal Nevrologii i Psikhiatrii imeni SS Korsakova, 96(3), 63-66.

Raymackers, J. M., Andrade, M., Baey, E., Vanneste, M., & Evrard, F. (2019). Bright light therapy with a head-mounted device for anxiety, depression, sleepiness and fatigue in patients with Parkinson’s disease. Acta Neurologica Belgica, 119(4), 607-613.

Quirk, B. J., DeSmet, K. D., Henry, M., Buchmann, E., Wong-Riley, M., Eells, J. T., & Whelan, H. T. (2012). Therapeutic effect of near infrared (NIR) light on Parkinson’s disease models. Front Biosci (Elite Ed), 4, 818-823.

Sun, W., Yan, J., Wu, J., & Ma, H. (2022). Efficacy and Safety of Light Therapy as a Home Treatment for Motor and Non-Motor Symptoms of Parkinson Disease: A Meta-Analysis. Medical science monitor: international medical journal of experimental and clinical research, 28, e935074-1.

​Importance of Circadian Regulation

Roenneberg, T., & Merrow, M. (2016). The circadian clock and human health. Current biology, 26(10), R432-R443.

Panda, S. (2016). Circadian physiology of metabolism. Science, 354(6315), 1008-1015.

Butler, M. P., Kriegsfeld, L. J., & Silver, R. (2009). Circadian regulation of endocrine functions. Hormones, Brain and Behavior Online, 473-507.

Fishbein, A. B., Knutson, K. L., & Zee, P. C. (2021). Circadian disruption and human health. The Journal of Clinical Investigation, 131(19).

Rijo-Ferreira, F., & Takahashi, J. S. (2019). Genomics of circadian rhythms in health and disease. Genome medicine, 11(1), 1-16.

Rea, M. S., Bierman, A., Figueiro, M. G., & Bullough, J. D. (2008). A new approach to understanding the impact of circadian disruption on human health. Journal of circadian rhythms, 6(1), 1-14.

Abbott, S. M., Malkani, R. G., & Zee, P. C. (2020). Circadian disruption and human health: A bidirectional relationship. European Journal of Neuroscience, 51(1), 567-583.

Turner, P. L., & Mainster, M. A. (2008). Circadian photoreception: ageing and the eye’s important role in systemic health. British Journal of Ophthalmology, 92(11), 1439-1444.

Walker, W. H., Walton, J. C., DeVries, A. C., & Nelson, R. J. (2020). Circadian rhythm disruption and mental health. Translational psychiatry, 10(1), 1-13.

Circadian Dysfunction in Parkinson’s

Fifel, K. (2017). Alterations of the circadian system in Parkinson’s disease patients. Movement Disorders, 32(5), 682-692.

De Pablo-Fernández, E., Courtney, R., Warner, T. T., & Holton, J. L. (2018). A histologic study of the circadian system in Parkinson disease, multiple system atrophy, and progressive supranuclear palsy. JAMA neurology, 75(8), 1008-1012.

Leng, Y., Blackwell, T., Cawthon, P. M., Ancoli-Israel, S., Stone, K. L., & Yaffe, K. (2020). Association of circadian abnormalities in older adults with an increased risk of developing Parkinson disease. JAMA neurology, 77(10), 1270-1278.

Gros, P., & Videnovic, A. (2020). Overview of sleep and circadian rhythm disorders in Parkinson disease. Clinics in geriatric medicine, 36(1), 119-130.

Videnovic, A., Noble, C., Reid, K. J., Peng, J., Turek, F. W., Marconi, A., … & Zee, P. C. (2014). Circadian melatonin rhythm and excessive daytime sleepiness in Parkinson disease. JAMA neurology, 71(4), 463-469.

Fifel, K. (2019). Neuropathology of circadian alterations in Parkinson disease. JAMA neurology, 76(1), 115-115.

Högl, B. (2017). Circadian rhythms and chronotherapeutics—underappreciated approach to improving sleep and wakefulness in Parkinson disease. JAMA neurology, 74(4), 387-388.

Circadian Dysfunction in Other Neurodegenerative diseases

Homolak, J., Mudrovčić, M., Vukić, B., & Toljan, K. (2018). Circadian rhythm and Alzheimer’s disease. Medical sciences, 6(3), 52.

Saeed, Y., & Abbott, S. M. (2017). Circadian disruption associated with Alzheimer’s disease. Current neurology and neuroscience reports, 17(4), 1-8.

Weldemichael, D. A., & Grossberg, G. T. (2010). Circadian rhythm disturbances in patients with Alzheimer’s disease: a review. International Journal of Alzheimer’s Disease, 2010.

Coogan, A. N., Schutová, B., Husung, S., Furczyk, K., Baune, B. T., Kropp, P., … & Thome, J. (2013). The circadian system in Alzheimer’s disease: disturbances, mechanisms, and opportunities. Biological psychiatry, 74(5), 333-339.

Ancoli-Israel, S., Gehrman, P., Martin, J. L., Shochat, T., Marler, M., Corey-Bloom, J., & Levi, L. (2003). Increased light exposure consolidates sleep and strengthens circadian rhythms in severe Alzheimer’s disease patients. Behavioral sleep medicine, 1(1), 22-36.

Li, P., Gao, L., Gaba, A., Yu, L., Cui, L., Fan, W., … & Hu, K. (2020). Circadian disturbances in Alzheimer’s disease progression: a prospective observational cohort study of community-based older adults. The Lancet Healthy Longevity, 1(3), e96-e105.

Kondratova, A. A., & Kondratov, R. V. (2012). The circadian clock and pathology of the ageing brain. Nature Reviews Neuroscience, 13(5), 325-335.

Hood, S., & Amir, S. (2017). Neurodegeneration and the circadian clock. Frontiers in aging neuroscience, 9, 170.

Musiek, E. S. (2015). Circadian clock disruption in neurodegenerative diseases: cause and effect?. Frontiers in pharmacology, 29.

Videnovic, A., Lazar, A. S., Barker, R. A., & Overeem, S. (2014). ‘The clocks that time us’—circadian rhythms in neurodegenerative disorders. Nature Reviews Neurology, 10(12), 683-693.

van Wamelen, D. J., Roos, R. A., & Aziz, N. A. (2015). Therapeutic strategies for circadian rhythm and sleep disturbances in Huntington disease. Neurodegenerative disease management, 5(6), 549-559.

Morton, A. J., Wood, N. I., Hastings, M. H., Hurelbrink, C., Barker, R. A., & Maywood, E. S. (2005). Disintegration of the sleep-wake cycle and circadian timing in Huntington’s disease. Journal of Neuroscience, 25(1), 157-163.

Aziz, N. A., Anguelova, G. V., Marinus, J., Lammers, G. J., & Roos, R. A. (2010). Sleep and circadian rhythm alterations correlate with depression and cognitive impairment in Huntington’s disease. Parkinsonism & related disorders, 16(5), 345-350.

Melanopsin Responsible for Circadian Entrainment

Güler AD, Ecker JL, Lall GS, et al. Melanopsin cells are the principal conduits for rod-cone input to non-image-forming vision. Nature 2008;453:102-105.

Gooley, J. J., Mien, I. H., Hilaire, M. A. S., Yeo, S. C., Chua, E. C. P., van Reen, E., … & Lockley, S. W. (2012). Melanopsin and rod–cone photoreceptors play different roles in mediating pupillary light responses during exposure to continuous light in humans. Journal of Neuroscience, 32(41), 14242-14253.

Melanopsin Association with Additional Physiological Function

Hattar, S., Liao, H. W., Takao, M., Berson, D. M., & Yau, K. W. (2002). Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science, 295(5557), 1065-1070.

Hattar, S., Kumar, M., Park, A., Tong, P., Tung, J., Yau, K. W., & Berson, D. M. (2006). Central projections of melanopsin‐expressing retinal ganglion cells in the mouse. Journal of Comparative Neurology, 497(3), 326-349.

Gooley, J. J., Lu, J., Fischer, D., & Saper, C. B. (2003). A broad role for melanopsin in nonvisual photoreception. Journal of Neuroscience, 23(18), 7093-7106.

Benarroch, E. E. (2011). The melanopsin system: Phototransduction, projections, functions, and clinical implications. Neurology, 76(16), 1422-1427.

Lazzerini Ospri, L., Prusky, G., & Hattar, S. (2017). Mood, the circadian system, and melanopsin retinal ganglion cells. Annual review of neuroscience, 40, 539-556.

Gaggioni, G., Maquet, P., Schmidt, C., Dijk, D. J., & Vandewalle, G. (2014). Neuroimaging, cognition, light and circadian rhythms. Frontiers in systems neuroscience, 8, 126.

Melanopsin Damage in Neurodegenerative Diseases

La Morgia, C., Carelli, V., & Carbonelli, M. (2018). Melanopsin retinal ganglion cells and pupil: clinical implications for neuro-ophthalmology. Frontiers in neurology, 1047.

Lax, P., Ortuño-Lizarán, I., Maneu, V., Vidal-Sanz, M., & Cuenca, N. (2019). Photosensitive melanopsin-containing retinal ganglion cells in health and disease: implications for circadian rhythms. International journal of molecular sciences, 20(13), 3164.

La Morgia, C., Carelli, V., & Sadun, A. A. (2021). Retina and melanopsin neurons. In Handbook of Clinical Neurology (Vol. 179, pp. 315-329). Elsevier.

La Morgia, C., Ross-Cisneros, F. N., Sadun, A. A., & Carelli, V. (2017). Retinal ganglion cells and circadian rhythms in Alzheimer’s disease, Parkinson’s disease, and beyond. Frontiers in neurology, 8, 162.

Joyce, D. S., Feigl, B., Kerr, G., Roeder, L., & Zele, A. J. (2018). Melanopsin-mediated pupil function is impaired in Parkinson’s disease. Scientific reports, 8(1), 1-9.

Ortuño‐Lizarán, I., Sánchez‐Sáez, X., Lax, P., Serrano, G. E., Beach, T. G., Adler, C. H., & Cuenca, N. (2020). Dopaminergic retinal cell loss and visual dysfunction in Parkinson disease. Annals of neurology, 88(5), 893-906.

Ortuño‐Lizarán, I., Beach, T. G., Serrano, G. E., Walker, D. G., Adler, C. H., & Cuenca, N. (2018). Phosphorylated α‐synuclein in the retina is a biomarker of Parkinson’s disease pathology severity. Movement Disorders, 33(8), 1315-1324.

PhotoPharmics Phase 2 study

Videnovic A, Rutten S, Croft W, Erickson H, Groves J, Havemann C, …&Van den Heuvel O. (2018).  Double-blind controlled trial of Spectramax™ light therapy for the treatment of Parkinson’s disease patients on stable dopaminergic therapy. International Movement Disorders Society 2018 International Congress. Abstract Number: 429

PhotoPharmics Planned Phase 3 Study

ClinicalTrials.gov