Early morning blue light exposure therapy can aid the healing process of people impact by mild traumatic brain injury, according to new research from the University of Arizona.
“Daily exposure to blue wavelength light each morning helps to re-entrain the circadian rhythm so that people get better, more regular sleep.
This is likely true for everybody, but we recently demonstrated it in people recovering from mild traumatic brain injury, or mTBI. That improvement in sleep was translated into improvements in cognitive function, reduced daytime sleepiness and actual brain repair,” said William D. “Scott” Killgore, psychiatry professor in the College of Medicine – Tucson and lead author on a new study published in the journal Neurobiology of Disease.
Mild traumatic brain injuries, or concussions, are often the result of falls, fights, car accidents and sports participation.
Among other threats, military personnel can also experience mTBI from exposure to explosive blasts: Shockwaves strike the soft tissue of the gut and push a burst of pressure into the brain, causing microscopic damage to blood vessels and brain tissue, Killgore said.
“Your brain is about the consistency of thick Jell-O,” he said. “Imagine a bowl of Jell-O getting hit from a punch or slamming against the steering wheel in a car accident. What’s it doing? It’s absorbing that shock and bouncing around. During that impact, microscopic brain cells thinner than a strand of hair can easily stretch and tear and rip from the force.”
Those with a concussion or mTBI might can momentarily seen stars, become disoriented, or even briefly lost consciousness following the injury; however, loss of consciousness doesn’t always happen and many people who sustain a concussion are able to walk it off without realizing they have a mild brain injury, according to Killgore.
Headaches, attention problems and mental fogginess are commonly reported after head injuries and can persist for weeks or months for some people.
Few, if any, effective treatments for mTBI exist. The U.S. Army Medical Research and Development Command funded the research to find alternatives to medicinal methods of mTBI recovery.
“About 50% of people with mTBI also complain that they have sleep problems after an injury,” Killgore said.
Recent research has shown that the brain repairs itself during sleep, so Killgore and his co-authors – John Vanuk, Bradley Shane, Mareen Weber and Sahil Bajaj, all from the Department of Psychiatry – sought to determine if improved sleep led to a faster recovery.
In a randomized clinical trial, adults with mTBI used a cube-like device that shines bright blue light (with a peak wavelength of 469 nm) at participants from their desk or tables for 30 minutes early each morning for six weeks. Control groups were exposed to bright amber light.
“Blue light suppresses brain production of a chemical called melatonin,” Killgore said. “You don’t want melatonin in the morning because it makes you drowsy and prepares the brain to sleep. When you are exposed to blue light in the morning, it shifts your brain’s biological clock so that in the evening, your melatonin will kick in earlier and help you to fall asleep and stay asleep.”
People get the most restorative sleep when it aligns with their natural circadian rhythm of melatonin – the body’s sleep-wake cycle associated with night and day.
“The circadian rhythm is one of the most powerful influences on human behavior,” Killgore said. “Humans evolved on a planet for millions of years with a 24-hour light/dark cycle, and that’s deeply engrained in all our cells. If we can get you sleeping regularly, at the same time each day, that’s much better because the body and the brain can more effectively coordinate all these repair processes.”
As a result of the blue light treatment, participants fell asleep and woke an average of one hour earlier than before the trial and were less sleepy during the daytime.
Participants improved their speed and efficiency in brain processing and showed an increase in volume in the pulvinar nucleus, an area of the brain responsible for visual attention. Neural connections and communication flow between the pulvinar nucleus and other parts of the brain that drive alertness and cognition were also strengthened.
Research Technician Cami Barnes tests a blue light device. Image is credited to University of Arizona.
“We think we’re facilitating brain healing by promoting better sleep and circadian alignment, and as these systems heal, these brain areas are communicating with each other more effectively. That could be what’s translating into improvements in cognition and less daytime sleepiness,” Killgore said.
Blue light from computers, smartphones and TV screens often gives blue light a bad rap. But according to Killgore, “when it comes to light, timing is critical. Light is not necessarily good or bad in-and-of-itself. Like caffeine, it all comes down to when you use it. It can be terrible for your sleep if you’re consuming coffee at 10 o’clock at night, but it may be great for your alertness if you have it in the morning.”
He and his team plan to continue their research to see if blue light improves sleep quality and how light therapy might affect emotional and psychiatric disorders. Killgore believes that most people, whether injured or healthy, could benefit from correctly timed morning blue light exposure, a theory he hopes to prove for certain in future studies.
Traumatic brain injury (TBI) is defined as a disruption in brain function due to the impact of contact forces including rapid acceleration, deceleration, or collision, manifesting as altered state of consciousness, neurological deficits, and/or amnesia.1 It is classified as mild, moderate, or severe depending on the presence and duration of the symptoms.2 TBI is a significant public health problem affecting civilians, athletes, and military personnel as a result of motor vehicle accidents, falls, contact sports, assaults, and explosions.3,4
Over the years, the rates of TBI in the US population have increased with more emergency room visits, driving the health care costs, though the rate of hospitalization and deaths has been steady.5 In fact, it is estimated that 1.5 million people in the US suffer a brain injury every year. Approximately, 80% of these injuries are classified as mild in severity.1
Mild TBI (mTBI), the most common form of TBI in high-impact sports,6 can lead to a wide array of cognitive, emotional, and somatic symptoms.7 The most frequently reported symptoms include fatigue, headaches, memory impairment, concentration deficits, and sleep-related problems.6
The majority of patients achieve complete resolution of symptoms quickly after a mTBI, but 10–20% may develop persisting symptoms.7 In fact, neuropsychological testing revealed persistent cognitive impairments in boxers following mTBI extending beyond the subjectively symptomatic period.6
Sleep disorders are underrecognized consequences of TBI despite their high prevalence. In general, around 46% of individuals have sleep disorders following TBI including sleep apnea, insomnia, post-traumatic hypersomnia, and narcolepsy.3
It is important to recognize and manage sleep disorders in TBI patients because untreated sleep disturbances translate to longer hospital stays, higher cost of rehabilitation, and more disability.8
The aim of this review is to discuss the pathophysiology of sleep disturbances after TBI, the various sleep disorders encountered, their management, and future directions.
Neurobiology of sleep
The suprachiasmatic nucleus in the hypothalamus is the master regulator of circadian rhythms. A cluster of neurons, known as the reticular activating system (RAS), expand into the hypothalamus from the tegmentum of the brainstem and play a crucial role in maintaining arousal. The network of neurons in the RAS process information from multiple projections in the brain through neurotransmitters and neuromodulations to control sleep and wakefulness.4
There are three distinct states of being: wakefulness, rapid eye movement sleep (REM) and non-rapid eye movement sleep (NREM). Monoaminergic and cholinergic system are predominantly wake-promoting systems, which also receive excitatory hypothalamic hypocretin/orexin input to promote wakefulness.
GABAergic system is the important sleep-promoting system and is present in the brainstem, lateral hypothalamus, and preoptic area. REM sleep is primarily generated in the dorsolateral pons. Cholinergic activation promotes and maintains REM sleep.9
Sleep and wakefulness is a fine interplay between the homeostatic and circadian drive. Homeostatic drive is also called sleep drive, which increases continually during wakefulness and is reduced by sleeping.
This drive is primarily regulated by adenosine through a partially understood mechanism that involves cortical neuronal nitric oxide (nNOS) neurons and neurokinin 1 receptors.10 On the other hand, the circadian rhythm is the alerting process driven by suprachiasmatic nuclei in the hypothalamus.
It naturally dips in the late afternoon but is high during the day and low during the night. It is primarily regulated through the light-induced suppression and darkness-induced release of the pineal neurohormone melatonin.11The integration of the two drives also takes place in the suprachiasmatic nucleus and may involve orexin A/hypocretin 1 input.12
Other neuropeptides involved in sleep–wake regulation include pituitary hormones, cytokines interleukin-1, interleukin-6, and tumor necrosis factor alpha13 as well as melanin-concentrating hormone (MCH). MCH coexists with GABA in hypothalamic neurons involved in REM control.14
Pathophysiology of sleep disturbance after TBI
Several theories have been proposed for the pathophysiology of sleep disorders after TBI. Diffuse axonal injury (DAI) occurring within the arousal and/or sleep regulation system has been implicated as a possible cause.15,17 DAI can occur across the spectrum of TBI severity and is considered the most important factor in determining morbidity in TBI patients.16
DAI leads to impairment in axonal membrane stability and intracellular function which results in signal disruption and accumulation of proteinaceous waste products.1 Moreover, the ruptured cell membranes release glutamate which provokes a toxic metabolic cascade of cell injury leading to acidosis and edema.18
Disruption of hormonal systems involved in sleep is another implicated cause of sleep disturbance after TBI. In research studies, TBI groups were found to have decreased levels of hypocretin, histamine, and melatonin in the CSF.15 Hypocretin and histamine are wake-promoting neurotransmitters; therefore, low CSF levels of these two are associated with hypersomnia.19,20 On the other hand, reduced melatonin is associated with decreased REM sleep in TBI.20
Studies showed that 95% of patients with acute TBI had low CSF hypocretin (less than 320 pg/mL),3 and autopsies of individuals who died from severe TBI showed a 41% reduction of histaminergic neurons in the tuberomammillary nucleus of the hypothalamus.19
Insults to key brain regions involved in sleep such as the hypothalamus, brain stem, and RAS also underpin sleep disturbances in TBI patients.3,20 Damage to the retino-hypothalamic tract, which coordinates the hypothalamic circadian pacemaker with the light–dark cycle, can lead to abnormally programmed circadian rhythms.20
Post-TBI animal models also show impairment in the expression of BMAL1 and Cry 1 genes indicating disruption in the circadian rhythm.21
There are also genetic factors that come to play in the development of sleeping disorders in mTBI patients. Per3 is one of the many polymorphic genes that are involved in the regulation of the circadian rhythm. Studies showed that carriers of Per3 have a shorter duration of sleep at 6 weeks post mTBI compared to baseline, and only Per3 noncarriers showed improvement in sleep quality with time.3
In addition, some craniofacial phenotypes may be particularly vulnerable to the development or worsening of sleep disorders. In acceleration–deceleration injuries, variations in the structure of the tentorial notch may impact the level of brainstem distortion. Also, people with certain anatomical features may be more prone to injure the pineal gland, resulting in dysregulation of melatonin homeostasis.
This impairs adequate circadian activity and leads to sleep disturbances.22 Sleep-disordered breathing such as obstructive sleep apnea can also be a consequence of injury to upper respiratory muscles along with TBI. Supine sleep, weight gain, and medication – induced reduced muscle tone and respiratory depression further contribute to sleep-disordered breathing in TBI patients.3
It is important to acknowledge the contribution of secondary factors like fatigue and depression after TBI to the development of sleep disturbances.15 Generalized anxiety disorder within 3 months of TBI has been consistently correlated to onset of insomnia.23
Moreover, people with TBI tend to use more medications than the general population such as antidepressants, analgesics, and sedative-hypnotics which can add to the sleep deficits observed.3,20 Other secondary complications following TBI, such as medical comorbidities, may also play a role in sleeping difficulties.20
To conclude, taken together, the risk for sleep disturbances in a patient with TBI is the product of several internal and external influences, all acting on a genetically determined substrate.22Untreated sleep disturbances following TBI can lead to potentiation of the injury at cellular level, leading to cognitive dysfunction: Sleep is essential for the optimal functioning of the glymphatic system, which is the waste clearance pathway of the central nervous system.24
Therefore, sleep disruption may lead to reduced clearance and subsequently increased accumulation of proteinaceous waste products like p-tau and beta-amyloid. Also, in TBI patients, resulting astroglial scars and inflammation may further the damage to the glymphatic system and increase the buildup of these neurotoxins. Persistent accumulation of waste products may potentiate neurodegenerative processes like Alzheimer’s disease and chronic traumatic encephalopathy.18
Various sleep disorders encountered in TBI
Studies have shown that mild TBI is more strongly associated with sleep disturbances than moderate to severe TBI.2 This may be because individuals with mild TBI are more likely to report sleep disturbances than people with severe TBI who perceive sleep disturbances as minor compared to other cognitive sequelae.2
However, research has also proposed that the location of the lesion is more important than the severity of TBI in predicting sleep outcomes, where damage to the arousal/sleep regulation centers causes the most sleep disturbances.20
Nearly 50% of patients report sleep disturbances after injury (Table1). Actigraphy and polysomnography, which are objective measures of sleep, verify the subjective complaints reported.19 A meta-analysis reported that after a TBI, 29% of patients have insomnia, 25% have sleep apnea, 28% have hypersomnia, and 4% have narcolepsy.19
Acutely after a TBI, individuals can experience early phase symptoms like headaches, fatigue, amnesia, and sleep disruption.
These symptoms resolve over a few weeks in the majority of people. However, 10–15% develop prolonged symptoms that affect the quality of life.1 Studies have shown that individuals with TBI have longer sleep onset latencies, shorter total duration of sleep, and more nighttime awakenings than controls.
Also, TBI patients were found to spend less time in REM sleep. They report poor sleep quality, more daytime dysfunction, and the use of more sleep medication. This was corroborated by objective sleep measures like the Epworth Sleepiness Scale and PSQI.20
The type of sleep disturbance might vary according to the number of TBIs. Following a first TBI, the most commonly reported complaint is onset insomnia. Following an additional TBI, maintenance insomnia intensifies.2
In military personnel, the number of lifetime TBIs was found to be a significant predictor of insomnia severity even when controlling for depression, PTSD, and severity of concussion symptoms.2
In fact, insomnia is one of the most commonly reported symptoms among patients with TBI, and it is the second most documented sleep disturbance in people with TBI, after snoring.22 Prevalence rates of insomnia, which are estimated to range from 6% to 10% of the general population, reach 25–29% in patients with TBI.2
In a prospective study, TBI patients were recruited from rehabilitation facilities and underwent sleep studies at least 3 months post-injury. 6% of the TBI patients met the diagnostic criteria for narcolepsy, which is significantly higher than the prevalence of the diseases in the general population (0.056%).3
The prevalence of sleep-disordered breathing in TBI patients was found to be 23% which is also significantly higher than the general population. In rehabilitation centers, parasomnias – most commonly REM sleep behavior disorder – were the presenting complaint in 25% of patients with brain trauma.3
Increased sleep need after mTBI, also known as post-traumatic hypersomnia, affects around 20% of individuals after brain injury. It manifests as fatigue, longer sleep durations, or excessive daytime sleepiness. Several notions have been proposed as causative factors. The first hypothesis is that persistent pain is an important cause for both the development and maintenance of excessive sleep need.25
Decreased quality of life due to pain was significantly associated with sleep need exceeding eight hours per day as well as increased number of naps.25 This is because patients with pain were found to have increased ß power frequency – brain waves associated with active thinking and concentration – in the prefrontal and frontal cortices during NREM and REM sleep compared to mTBI patients with no pain, which could cause a relative state of “arousal” even when asleep.
This impedes the restorative function of sleep leading to increased sleep need to compensate. Another hypothesis implicated the hypocretin system in the development of increased sleep need after brain injury. As mentioned previously, low levels of hypocretin have been found in the CSF of most TBI patients, which can explain increased sleepiness.25
Untreated sleep disorders impact sleep architecture. Moderate to severe TBI is characterized by increased slow wave sleep (SWS) and reduced stage 2 sleep, reflecting cortical reorganization and restructuring after injury. These alterations in sleep architecture have not been observed in mild TBI.1,19 Both obstructive sleep apnea and insomnia patients have reduced REM and slow wave sleep, but these tend to normalize with effective treatment.1,19
Impact on quality of life
Sleep disorders significantly impact quality of life and contribute to disability. Inadequate sleep can negatively affect rehabilitation and optimal recovery in inpatients with TBI, leading to poorer outcomes and cognitive dysfunction.26 Moreover, insomnia has been associated with increased disability and delayed recovery from brain injury in workers independent of age, gender, and other psychiatric co-morbidities. This was determined using the Sheehan disability scale (SDS), which measures items pertaining to impairment in work, social life, and family responsibilities.4 This emphasizes the importance of identifying and treating sleep disorders to improve quality of life and work-related outcomes.4
It is important to start by ruling out modifiable causes of sleep disturbances like pain, bowel/bladder issues, and mood disturbances.8
Adequate management starts with accurate diagnosis. Subjective sleep symptoms in TBI patients can be unreliable; therefore, objective testing with polysomnography and MSLT are essential to diagnose sleep disorders like sleep apnea, narcolepsy, and post-traumatic hypersomnia.3 Actigraphy and sleep logs at home over several nights are also good ways of assessing sleep after TBI.3,15The sleep lab can create a new and confounding environment for the individual, which makes actigraphy a useful alternative since it assesses sleep at home over several nights.3,15
University of Arizona