Blue-Light Therapy following Mild Traumatic Brain Injury: Effects on White Matter Water Diffusion in the Brain

Would this help stroke patients? I don't think they are referring to the blue light of your smartphones or iPads. Anything would have been helpful to counteract the massive fatigue I had post-stroke.  Or you can ask your doctor about the effectiveness of near-infrared light since it is only two years old and your doctor and stroke hospital are so efficient they already have incorporated infrared into their stroke protocols. (sarcasm)

New Study Discovers Near-Infrared Light Therapy (NILT) Effectively Treats Traumatic Brain Injury (TBI) Patients  Aug. 2015

Blue-Light Therapy following Mild Traumatic Brain Injury: Effects on White Matter Water Diffusion in the Brain

Sahil Bajaj, John R. Vanuk, Ryan Smith, Natalie S. Dailey and William D. S. Killgore*

• Social, Cognitive and Affective Neuroscience Laboratory (SCAN Lab), Department of Psychiatry, College of Medicine, University of Arizona, Tucson, AZ, United States

Mild traumatic brain injury (mTBI) is a common and often inconspicuous wound that is frequently associated with chronic low-grade symptoms and cognitive dysfunction. Previous evidence suggests that daily blue wavelength light therapy may be effective at reducing fatigue and improving sleep in patients recovering from mTBI. However, the effects of light therapy on recovering brain structure remain unexplored. In this study, we analyzed white matter diffusion properties, including generalized fractional anisotropy, and the quantity of water diffusion in isotropic (i.e., isotropic diffusion) and anisotropic fashion (i.e., quantitative anisotropy, QA) for fibers crossing 11 brain areas known to be significantly affected following mTBI. Specifically, we investigated how 6 weeks of daily morning blue light exposure therapy (compared to an amber-light placebo condition) impacted changes in white matter diffusion in individuals with mTBI. We observed a significant impact of the blue light treatment (relative to the placebo) on the amount of water diffusion (QA) for multiple brain areas, including the corpus callosum, anterior corona radiata, and thalamus. Moreover, many of these changes were associated with improvements in sleep latency and delayed memory. These findings suggest that blue wavelength light exposure may serve as one of the potential non-pharmacological treatments for facilitating structural and functional recovery following mTBI; they also support the use of QA as a reliable neuro-biomarker for mTBI therapies.

Introduction

Mild traumatic brain injury (mTBI) is a common and often unobtrusive wound that occurs when kinetic energy is transferred to the brain through some form of traumatic event, such as a fall, blow to the head, or blast wave. While there are typically no exceptionally conspicuous physical or neuroimaging signs of mTBI, the mechanical trauma to the brain leads to a mild temporary disruption of consciousness or other alteration of ongoing cognition. Also commonly known as “concussion,” mTBI can further lead to persistent alterations in neuropsychological functions, including changes in mood (e.g., depression), poor attention and concentration, and memory problems (1, 2). Importantly, sleep deprivation is also known to produce many of these same symptoms (3, 4). It is therefore possible that sleep disturbances following mTBI may cause, or at least exacerbate, ongoing post-concussion symptoms. However, the nature of these complaints and their contribution to the experience of daytime sleepiness is not well understood (5). An objective measure of daytime sleepiness is the multiple sleep latency test (MSLT), which is used to determine the time it takes an individual to fall asleep (sleep onset latency) when given the opportunity to take a nap. Following a head trauma, symptoms are believed to result from neuronal damage in the form of diffuse axonal injury (6, 7), leading to the release of specific proteins that in turn promote maladaptive functional and structural changes within the brain (8). Identifying neuro-markers of these changes remains an important challenge in ongoing attempts to understand and treat mTBI and post-concussive symptoms.

A very limited number of treatment options for mTBI have been proposed and experimentally validated. Available treatments include cognitive behavior therapy (9), neuropsychological rehabilitation (10), educational intervention (11), and pharmacological intervention (12). Although the effects are small, some intervention studies report reliable reductions in post-concussion symptoms, including sleep problems, following successful treatment (13). Considering a range of post-concussion symptoms can also occur as the result of sleep loss, it is likely that improving sleep quality in particular would also lead to improvements of other post-concussion symptoms, such as attention, concentration, memory, and mood disturbances. While improving sleep makes sense, this is often easier said than done. A natural and potentially powerful method for regulating the sleep–wake cycle is through targeted exposure to bright light in the morning hours. Exposure to short wavelength light (~430–475 nm; blue wavelength light) has been demonstrated as an alternative to pharmacological treatment methods that focus on improving alertness, concentration, daytime sleepiness, as well as sleep quality (14, 15). Intrinsically photosensitive retinal ganglion cells are particularly responsive to light within the short wavelengths. These cells transmit signals to hypothalamic nuclei, which in turn regulate the production of melatonin (16, 17). Morning exposure to blue wavelength light leads to a suppression of melatonin production, which contributes to a phase delay and stabilization of the circadian rhythm (18), increases daytime alertness and vigilance, and earlier onset of evening sleep (19, 20). Interestingly, a recent clinical trial showed that 4 weeks of 45 min of morning blue-light therapy (BLT) in comparison to longer wavelength placebo light was effective at reducing self-rated fatigue and daytime sleepiness among individuals recovering from TBI (21). However, the extent to which these behavioral changes correspond to structural changes within the brain has not been explored.

When considering the potential influences of BLT on mTBI, it is important to consider that mTBI is associated with microscopic changes in brain structure, particularly within the white matter axonal tracts. Abnormalities in fractional anisotropy (FA) in the brain following an mTBI have been studied extensively using diffusion tensor imaging (DTI), a method that allows high-resolution imaging of the directional movement of water molecules along axonal fiber tracts (i.e., how fast water molecules move along fiber tracts). Abnormalities in FA in individuals with an mTBI are reported in areas such as uncinate fasciculus (UF) (22), superior longitudinal fasciculus (SLF) (23), anterior corona radiata (ACR) (22), corpus callosum (CC) (24), and thalamus (25). Alterations in FA within (a) UF are reported to be associated with changes in Mini-Mental State Examination (MMSE) scores (cognitive function) and specifically, memory performance (22, 26); (b) SLF and CC are reported to be associated with executive function (attention and memory) (27); (c) ACR changes are correlated with changes in attention (22); and (d) anterior thalamic nucleus changes are also linked to changes in executive function, memory, and attention (25). In addition, studies have found that individuals with mTBI show alterations in white matter within the frontal lobe (frontal cortex/dorsolateral prefrontal cortex, DLPFC), and that these alterations are correlated with lower executive control and related cognitive functions (28). Also, compared to healthy controls (HCs), there are multiple studies that have reported abnormally high FA values in individuals with mTBI within several areas, including the genu and splenium of CC, ACR (bilaterally), lUF, and internal capsule (IC; bilaterally) (29, 30). Recently, new diffusion measures—quantitative anisotropy (QA), isotropic diffusion (ISO), and generalized fractional anisotropy (GFA)—were introduced to the field of DTI for the analysis of diffusion properties of white matter (31). QA and ISO represent how much water diffuses (i.e., density) in a specific/restricted direction and in an isotropic fashion (i.e., total isotropic component), respectively. In contrast, GFA, which is calculated from an orientation distribution function, is a measure of how fast water diffuses (i.e., diffusivity) in an anisotropic fashion, i.e., it represents degree to which diffusion is anisotropic (31, 32). Highly significant correlations between FA and GFA were reported in the past (33). In addition, the difference between QA and GFA pertains to the fact that QA is a measure of water diffusion along each fiber orientation, whereas GFA/FA is defined for each voxel. Compared to GFA/FA, QA is also reported to have lower susceptibility to partial volume effects of crossing-fibers, free-water diffusion in ventricles, and non-diffusive particles (31). Moreover, normalization of QA helps to stabilize the spin-density measurement across subjects. In this study, we investigated multiple diffusion measures (i.e., diffusivity as well as density measures) simultaneously to better characterize the white matter properties; therefore, in conjunction with GFA, we also estimated normalized QA (NQA) and ISO measures. To the best of our knowledge, no study to date has used these metrics simultaneously to examine the effect of light exposure treatment on the brain following mTBI.

In individuals with mTBI, how changes in post-concussion symptoms following an exposure to BLT may correspond to structural changes within the brain has not yet been explored. Recent evidence suggests that sleep is important for clearing the neurotoxins that build up throughout the day (34) and increases the production of oligodendrocyte progenitor cells that contribute to myelin formation (35), which could conceivably facilitate repair of axonal damage. Based on this, we hypothesized that 6 weeks of daily morning BLT, compared to a placebo condition with an amber-light therapy (ALT) device, would improve sleep and, consequently, lead to changes in white matter water diffusion, improvements in cognitive abilities such as attention and memory, and daytime sleepiness. To this end, we investigated whether individuals in the BLT and ALT groups showed significant changes in diffusion (i.e., GFA, NQA, and ISO), cognitive, and sleep measures. Furthermore, we examined the correlations between changes in diffusion measures from pre- to post-treatment and changes in neuropsychological performance and sleep onset latency.