"The human brain, per se, is sensitive to light"
This hypothesis was the starting point of Valkee's scientific research, in cooperation with research team from the University of Oulu, Finland, in 2007.
The studies, all placebo-controlled, conducted since mid-2012, focused on the responses and applications of Transcranial Bright Light (TBL).
Between 2008-2010, researchers at the University of Oulu, Finland, discovered that in addition to eyes, areas of the human brain are also sensitive to light. This sensitivity is due to the photoreceptor-proteins in the brain, which are similar to those found in the eyes, a discovery that had been made by researchers in the U.K. and the U.S. 10 years earlier. University of Oulu researchers found that brain areas can be reached by light through ear canals, ear tissues and bones of skull. The skull of large mammals, including humans, lets light pass through naturally. In ordinary daylight and daytime conditions the brain is constantly being exposed to light.
Please find below a summary of the science behind the HumanCharger®. For more information please download the Summary of published, peer-reviewed findings.
Abstract: Light acts as the most important regulating and entraining factor of the mammalian circadian rhythm. This rhythm has evolved to set phases, in which different physiological and behavioral events occur at the right time of the day to synchronize the organism. The mechanism of light transduction via eyes to the brain and its effects on circadian rhythmicity is well known. Yet, it has also been shown that light is able to penetrate the skull bone directly, but it is still unknown, whether transcranial light is able to affect molecules regulating circadian rhythmicity. Monoamines and especially opsins have been shown to act as important regulators in circadian rhythmicity. Both group of molecules can mediate the effects of light on regulation and entrainment. In this thesis, mice and hamsters have been illuminated transcranially and the expression of three different opsins and the concentrations of several monoamines have been measured. The animals were illuminated under anesthesia either just after the onset of the light period or just after the beginning of the dark period. The opsin expression in rodent brain were measured by western blot and the monoamine concentrations from mouse brain, plasma and adrenal gland were measured by HPLC. It was observed that both opsin expression and monoamine concentrations can be influenced by transcranial illumination. The effect varied depending on the studied molecule, tissue and time of illumination. The findings of this study demonstrate that opsins, which are considered to be the most important molecules regulating circadian rhythmicity, can be directly and specifically affected not only via the eyes but also by light illuminated through the skull. Furthermore, monoamine production can be altered in both the central nervous system and the peripheral tissues by transcranial illumination. This thesis demonstrates an alternate pathway for circadian entrainment and regulation by light involving specific molecular mediators such as opsins and monoamines.
Abstract: In addition to the visual information, external light causes non-image-forming (NIF) effects that modulate brain function and induce psychophysiological effects. The light signal is traditionally assumed to only be mediated via the eyes. Recent studies have suggested the existence of putatively light sensitive structures in the rodent and human brain and penetration of light into the skull and brain tissue has been observed. The brain activation observed during transcranial bright light (TBL) exposure indicates a direct light responsivity of brain tissue. The aim of this thesis was to explore the psychophysiological responses related to TBL. The studies comprising this thesis were conducted in healthy subjects and patients suffering from seasonal affective disorder. TBL exposure was administered via the ear canals in all study settings using light-emitting diodes (LEDs). The comparisons in studies I, II, and III were conducted against the inactivated sham device. Study IV explored the effect of TBL dose. Neither melatonin nor cortisol secretions were altered when acutely exposed to nocturnal TBL. Circadian profiles in TBL setting were in parallel to control conditions for both hormones. Intermittent TBL exposure led to alleviation of jet lag symptoms. Overall post-travel jet lag symptoms as well as subjective feelings of fatigue, inertia, and forgetfulness were reduced. The time to execute the motor response i.e. motor time with a visual warning signal was improved by the TBL treatment. TBL alleviated both depressive and anxiety symptoms related to seasonal affective disorder (SAD). A dose-response relationship regarding the intensity of dose administered via the ear canals was not found. Altogether, TBL seems to affect human brain function by alleviating symptoms of jet lag and SAD and improving psychomotor performance. The acute effect is suggested to be mediated via structures unrelated to acute melatonin secretion i.e. the retinohypotalamic tract (RHT). These results support the light sensitivity of the human brain although the mechanism of action is not yet established.
Summary: This is the first study to show that melanopsin (OPN4) exist at protein level outside the retinohypothalamic tract (RHT) in human brain. Main finding of this study is that OPN4 is actually widely distributed in human brain given that it was expressed, in general, in all investigated 18 brain areas, including those with importance to the regulation of essential body functions and also new evolved part like neocortex. These results are in line with the earlier findings of Allen Institute for Brain Science showing widely distributed OPN4 gene activity in human brain (Hawrylycz et al.2012). Western blotting and immunohistochemistry, as well as immunoelectron microscopy, were used to analyze the existence and distribution of OPN4 protein in 18 investigated areas of the human brain in samples obtained in forensic autopsies from 10 male subjects. The wide distribution of OPN4 in central areas of the human brain evokes a question whether ambient light has important straight targets in the human brain outside the RHT.
Summary: Light is the main signal that entrains the mammalian circadian system. One of the key molecules transmitting light information and entraining the circadian clock is melanopsin (OPN4). Thirty visually blind adult (8-10 weeks old at the beginning of the study) male mice were used in this study. The mice were randomly assigned to three different groups: control, morning-light group and evening-light group. Transcranial light was given under anesthesia via ear canals for 4 weeks, five times a week, 8 minutes per mouse. The control group was anesthetized and headphones were inserted, but no light was given. The results of this study show that transcranial light has a significant effect on OPN4 expression in the mouse brain. The amount of OPN4 increased significantly in transcranially illuminated mice when compared to controls. This study also shows that serotonin concentration in the cortex is affected by light illumination. Results are able to show the connection between transcranial light and circadian rhythmicity, since the results of the expression level of OPN4 in the cerebellum differed between the test groups. Based on the findings of this study, light-activated molecules of the brain can be stimulated with transcranial light.
Summary: This study demonstrates that extraocular light affects human brain functioning. Extraocular light modulated attention-related brain responses, specifically related to emotion-attention interaction. Study confirms that light is capable of penetrating the human skull via ear canals and reach the temporal lobe of the brain. Because the brain is floating in cerebrospinal fluid, transmitted light might be widely dispersed, thus illuminating the basal surface of temporal lobe. Penetration of light through ear canals was investigated on a human cadaver after the brain was removed upon autopsy. Light penetration of the skull was visible when viewed both in lighted and dark conditions. Light was able to reach intracranial space through the ear canals and was visible at the base of the skull under the temporal lobes.
Summary: This randomized, double-blind, placebo-controlled field study demonstrates that intermittent transcranial bright light (TBL) exposure via ear canals alleviates jet lag symptoms. A total 55 healthy male subjects completed the study. Subjects were required to travel by plane from Finland (time zone: +2) to North America (time zone: -5 to -8) and stay a minimum of 1 week in their destination time zone. During the post-travel period, subjects were exposed to TBL or placebo treatment four times per day 12 min each at predetermined times. TBL or placebo exposures were administered every 2 h between 08:00 and 14:00 on travel day 0 and every 2h between 10:00 and 16:00 on post-travel days 1-6. The subjects were randomly assigned to the bright light treatment (N=25) group or the placebo (N=30) group. The study set-up for the placebo group was the same except that the bright light device was inactive. The effect of TBL on jet lag symptoms was measured after traveling eastwards. Symptoms of jet lag were measured by the Visual Analog Scale (VAS), the Karolinska Sleepiness Scale (KSS), and the Profile of Mood States (POMS). There were a significant reduction of overall jet lag symptoms, subjective sleepiness, fatigue, inertia and forgetfulness when comparing the TBL group (N=25) to the placebo group (N=30).
Summary: This study is the first to show that transcranial light has a significant effect on OPN3 expression in the mouse brain. The study also shows that because of transcranial light, dopamine and noradrenaline concentrations increased significantly in the plasma and adrenalin gland. Thirty adult male mice were used in this study. Mice were blind. Transcranial light was given via ear canals for 4 weeks, five times a week. Based on these findings, it is reasonable to hypothesize that light-activated molecules can also be stimulated transcranially, not only through the retina.
Summary: Recent fMRI findings suggested that transcranial bright light (TBL) might have physiological effects on brain functions in humans. The present study investigated if TBL treatment was able to improve psychomotor speed in professional ice hockey players in a randomized, placebo controlled design. A total of 22 pro hockey players (N=11 TBL group; N=11 placebo group; overall mean age ± SD: 25 ±5 yrs) received either 12 min of TBL or placebo every morning between 8 and noon for a period of 24 days. Psychomotor speed using a visual warning signal paradigm was tested before and after trial completion and data were analyzed for mean reaction time and mean motor time. Results showed that psychomotor speed, particular motor time, improved after 24 days of TBL treatment compared to placebo in a group of professional ice hockey players.
Summary: The present study investigated the effects of transcranial bright light (TBL) on melatonin and cortisol secretion in healthy volunteers. 8 subjects (3F, 5M; mean age ± SD: 27± 5 yrs) were exposed to TBL during the night-time in a randomized, placebo controlled study design. Subjects reported to the laboratory in the evening (21 h) and were subjected to the same light/dark rhythm in both conditions (16L:8D; lights off at 23 h, lights on at 07 h) prior to the TBL or placebo exposure form 01:10-01:34 h. Saliva and urine samples for melatonin and cortisol were collected at noon, 18, 21, 22, 23, midnight, 01, 02, 03, 06, 07, 08, and 09h. Results clearly showed that neither melatonin or cortisol secretion nor the circadian rhythm of both endocrine markers was affected by the nocturnal exposure to TBL compared to placebo. This is in line with recent findings showing no melatonin suppression due to TBL exposure in the late evening (Bromundt et al., 2013).
Summary: Resting state functional brain activity provides a method to detect an existing neurobiological substrate for various disorders, including Seasonal Affective Disorder (SAD). For this purpose, a total of 90 subjects (45 SAD patients; 45 healthy controls) underwent an fMRI to determine functional connectivity of various brain areas in the resting state. A total of 47 resting state networks (RSNs) were investigated. The results showed a clear difference in functional connectivity between SAD patients and healthy, age, gender and ethnicity-matched controls in 11 out of the 47 tested RSNs. The SAD patients showed increased functional connectivity in attentional, visual, and sensomotoric RSNs. These findings support previous findings of psychomotor, attentional, and cognitive impairments seen in SAD patients. Interestingly enough, the same brain areas showed increased activity in healthy controls when exposed to TBL.
Summary: In a 4 week trial, 89 patients suffering from SAD were randomly assigned to one of three treatment groups and received either a low (1 lumen), medium (4 lumen), or high dose (9 lumen) of daily bright light via ear canals for 12 minutes in the morning. Depressive symptoms and cognitive performance were assessed using standard psychiatric instruments such as the Beck Depression Inventory (BDI) and the Trial Making Test (TMT) at the beginning, during, and at the end of the trial. The results showed a significant, at least 50% reduction of depressive symptoms in 74-79% of the patients according to the BDI in all three treatment groups as well as a significant improvement of cognitive performance compared to baseline.
Summary: 50 healthy subjects were randomized into two groups (N=24 experimental group, N=26 control group) and either received 12 min of transcranial bright light therapy or sham, i.e. no light, while being subjected to Functional Magnetic Resonance Imaging (fMRI). The results of the fMRI showed a clear increase in neural connectivity of the visual cortex and senso-motoric areas of the cortex under the transcranial light compared to the sham group. This suggests the brain to be light perceptive. In addition, these were the same brain areas that showed increased connectivity in the studies by Abou-Elseoud et al. (2011; 2014).
Summary: In this initial pilot study, 13 SAD patients were subjected to a daily dose of 8-12 min of transcranial bright light therapy for 3 weeks. Depressive and anxiety symptoms were measured using standard questionnaires such as the 17-item Hamilton Depression Rating Scale (HAMD-17), the Beck Depression Inventory-21 (BDI), and the 14-item Hamilton Anxiety Rating Scale (HAMA) prior to the 4 week trial and afterwards. When comparing the depression and anxiety score between week zero (baseline) and week 4 (study endpoint), results showed a significant reduction in reported symptoms on all three measures. The findings suggest that transcranial bright light therapy might be an alternative to the traditional light therapy and should be explored in more depth.
Summary: The presence of light-sensitive opsins in the retina has been shown successfully in various studies. The present study investigates the expression encephalopsin (OPN3) proteins in brain and peripheral tissue of mice. Tissue samples of 10 mice were analysed using Western blotting and immunohistochemistry. Results showed the OPN3 protein expression could be shown in almost all brain areas as well as in the peripheral tissue analyzed. This suggests that OPN3 might be involved in the mechanism of transcranial bright light.
Summary: 90 subjects (45 SAD patients; 45 healthy controls) underwent a fMRI to determine functional connectivity of brain areas. Results from the fMRI scans were analyzed with different mathematical models. In addition to increased neuronal connectivity within the visual and senso-motoric cortex of the SAD patients, results showed that depending on the model order and analysis, the sensitivity towards disease detection can be significantly improved and resting state brain activity might prove to be a very useful tool to detect the underlying neurobiological substrates of diseases.
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