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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.

​Importance of Circadian Regulation

Roenneberg, T., & Merrow, M. (2016). The circadian clock and human health. Current biology26(10), R432-R443.

Panda, S. (2016). Circadian physiology of metabolism. Science354(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 Investigation131(19).

Rijo-Ferreira, F., & Takahashi, J. S. (2019). Genomics of circadian rhythms in health and disease. Genome medicine11(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 rhythms6(1), 1-14.

Abbott, S. M., Malkani, R. G., & Zee, P. C. (2020). Circadian disruption and human health: A bidirectional relationship. European Journal of Neuroscience51(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 Ophthalmology92(11), 1439-1444.

Walker, W. H., Walton, J. C., DeVries, A. C., & Nelson, R. J. (2020). Circadian rhythm disruption and mental health. Translational psychiatry10(1), 1-13.

Circadian Dysfunction in Parkinson’s

Fifel, K. (2017). Alterations of the circadian system in Parkinson’s disease patients. Movement Disorders32(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 neurology75(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 neurology77(10), 1270-1278.

Gros, P., & Videnovic, A. (2020). Overview of sleep and circadian rhythm disorders in Parkinson disease. Clinics in geriatric medicine36(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 neurology71(4), 463-469.

Fifel, K. (2019). Neuropathology of circadian alterations in Parkinson disease. JAMA neurology76(1), 115-115.

Högl, B. (2017). Circadian rhythms and chronotherapeutics—underappreciated approach to improving sleep and wakefulness in Parkinson disease. JAMA neurology74(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 sciences6(3), 52.

Saeed, Y., & Abbott, S. M. (2017). Circadian disruption associated with Alzheimer’s disease. Current neurology and neuroscience reports17(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 Disease2010.

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 psychiatry74(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 medicine1(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 Longevity1(3), e96-e105.

Kondratova, A. A., & Kondratov, R. V. (2012). The circadian clock and pathology of the ageing brain. Nature Reviews Neuroscience13(5), 325-335.

Hood, S., & Amir, S. (2017). Neurodegeneration and the circadian clock. Frontiers in aging neuroscience9, 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 Neurology10(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 management5(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 Neuroscience25(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 disorders16(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 Neuroscience32(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. Science295(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 Neurology497(3), 326-349.

Gooley, J. J., Lu, J., Fischer, D., & Saper, C. B. (2003). A broad role for melanopsin in nonvisual photoreception. Journal of Neuroscience23(18), 7093-7106.

Benarroch, E. E. (2011). The melanopsin system: Phototransduction, projections, functions, and clinical implications. Neurology76(16), 1422-1427.

Lazzerini Ospri, L., Prusky, G., & Hattar, S. (2017). Mood, the circadian system, and melanopsin retinal ganglion cells. Annual review of neuroscience40, 539-556.

Gaggioni, G., Maquet, P., Schmidt, C., Dijk, D. J., & Vandewalle, G. (2014). Neuroimaging, cognition, light and circadian rhythms. Frontiers in systems neuroscience8, 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 sciences20(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 neurology8, 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 reports8(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 neurology88(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 Disorders33(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


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 reports10(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 neurology74(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 disorders19(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 Neurosciences23(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 Society22(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 international24(3), 521-537.

Artemenko, A. R., & IaI, L. (1996). The phototherapy of parkinsonism patients. Zhurnal Nevrologii i Psikhiatrii imeni SS Korsakova96(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 Belgica119(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 research28, e935074-1.