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Research suggests that disrupted or fragmented sleep after a traumatic brain injury not only interferes with the healing process but also has long-term consequences for brain health

, and far more people worldwide, report sustaining a traumatic brain injury (TBI) each year. While detection and treatment of TBI have improved over time, this has resulted in new challenges, because survivors may face additional health problems over time as a consequence of their injuries. These problems can include cognitive impairment and even neurodegeneration, including Alzheimer’s. Considering this, there is an increased interest in what factors determine how well TBI patients recover.

Rachel Rowe, an assistant professor of integrative physiology at the �鶹ӰԺ, has investigated this question, along with a number of researchers from The Ohio State University and the University of Arizona College of Medicine, in�� linking low-quality sleep following traumatic brain injury to cognitive impairment, persistent inflammation and delayed healing.��

Rachel Rowe, a CU �鶹ӰԺ assistant professor of integrative physiology, collaborated on research linking low-quality sleep following traumatic brain injury to cognitive impairment, persistent inflammation and delayed healing.

The study used mice as a controlled experimental model to examine how sleep fragmentation interacts with traumatic brain injury, following the National Institutes of Health Guidelines for the Care and Use of Laboratory Mice, and with approval from Ohio State’s Institutional Animal Care and Use Committee.

Sleep fragmentation, inflammation and microglia

The study did not look at total sleep loss, but instead at sleep fragmentation, which happens when sleep is repeatedly interrupted. Even brief awakenings can prevent the brain from staying asleep long enough to reach the deeper, more restorative stages of sleep. When sleep is broken up many times throughout the night, people may spend less time in these restorative phases, which are important for physical recovery and brain health. Unfortunately, fragmented sleep is common and can be caused by everyday factors such as noise, hospital monitoring, discomfort or changes in temperature.

“For instance,” Rowe says, if someone is in the hospital for a moderate brain injury, “then there are a lot of people coming in, they’re checking monitors, they’re doing activities that could disrupt the sleep of a person.”��

Stress can also affect the quality of sleep. “We have got a lot of things in our society that disrupt our sleep,” Rowe says, and people do not always prioritize restful sleep after an injury. These types of disturbances may influence recovery following brain injury.

One reason for this is inflammation, which is a potential determiner of the long-term results of TBI, particularly whether it will result in neurodegeneration. Brain inflammation is an innate immune response initiated by cells called microglia. Similar to a fever, inflammation does not directly target infections, damaged cells or other threats but rather makes the body inhospitable to them. This allows for a quick response to potentially life-threatening challenges, but it can also damage the body if it goes on for too long. One reason that could happen is if the microglia are primed.

When the brain faces some kind of stress, like from an injury or from sleep fragmentation, the microglia become primed, meaning they respond more strongly to subsequent challenges.��

“There is some memory in your immune system,” Rowe explains. “That is how vaccinations work. In the case of a brain injury, if it is mixed with sleep fragmentation, it is what we call a two-hit model.” When both stressors come in short succession, “that can change what the microglia are doing,” potentially resulting in a heightened or prolonged inflammatory response in the brain.

Preparation and testing

The mice were split into four groups. Some mice were given traumatic brain injuries using lateral fluid percussion injury, a well-established experimental model used to study TBI in rodents. Other mice were not given traumatic brain injuries, but were put through the same preparation process, so the only difference was that they went uninjured.��

Additionally, some mice experienced sleep fragmentation while others did not. Ultimately, the groups were traumatic brain injury (TBI) with sleep fragmentation (SF), TBI without SF, uninjured with SF, and uninjured without SF. This design allowed the researchers to examine the independent and combined effects of injury and sleep disruption.

Sleep fragmentation was achieved through disturbances that happened automatically every two minutes for five hoursper day during the early light phase, when mice normally obtain most of their sleep. All mice experienced a simulated light/dark cycle where each half lasted 12 hours. Sleep fragmentation began an hour before the end of the dark period and ended four hours after the beginning of the light period.��

“Mice are nocturnal,” Rowe says, “so the study was designed to fragment their sleep right at the beginning of the light period, which is when mice normally get most of their sleep. In many ways, it’s similar to repeatedly waking a person just as they are trying to fall asleep at night.”��

The mice’s sleep, including both when they were asleep and how long they stayed asleep, was measured using specialized piezoelectric sensors. This technology has been popularized recently through its use to generate electricity from people walking on piezoelectric tiles in places with heavy foot traffic in Japan. The sensors from the study work according to the same principle, transforming pressure from the mice’s movements into electrical signals.��

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“Sleep is a time when the brain can heal, and if that is disrupted, the healing process can be disrupted too,” says CU �鶹ӰԺ scientist Rachel Rowe. (Photo: Mart Production/Pexels)

“When a mouse drops into sleep,” Rowe explains, “their breathing gets really rhythmic at 3 hertz.” The frequency of pressure created by that breathing was distinguished from the way mice breathe when they are resting using an algorithm.

Sleep fragmentation continued for 14 days following injury. After this period, mice were allowed to recover with normal sleep conditions, and researchers evaluated behavioral and molecular outcomes. One of the behavioral assessments used was the Morris Water Maze, a common test of spatial learning and memory in rodents. In this task, mice learn to locate a hidden platform in a pool using spatial cues in the environment. Their ability to remember and efficiently navigate to the platform reflects spatial memory performance.

How good sleep improves outcomes

When tested in the Morris water maze, mice with TBIs who also experienced sleep fragmentation used random search strategies, indicating that they did not learn the cues or that they did not remember them. This means that sleep fragmentation after this type of injury could impair spatial learning and memory.��

“If there are cognitive deficits, then the mouse is looking at those cues, but it does not know which one is near the platform. It is just searching randomly because it does not know what it is supposed to be doing,” Rowe says.

Researchers also looked at what was happening inside the brains of the mice. They found that when brain injury was combined with disrupted sleep, the brain showed stronger signs of inflammation and less activity in the genes involved in repairing and rebuilding connections between brain cells. These connections, called synapses, allow brain cells to communicate with each other and are important for recovery after injury. In other words, poor sleep after a brain injury appeared to increase inflammation while slowing some of the brain’s natural repair processes. In contrast, mice that had a brain injury but were able to sleep normally showed stronger signs of these repair pathways being activated.

There were 14 days for the mice to recover from sleep fragmentation before these results were measured, and they had 30 days to recover from the injury itself. This indicates that the consequences were long-term or chronic.

��“When we are looking at rodents,” Rowe says, “their lifespan is much shorter than humans’.” In mouse studies, researchers often consider about one month after injury to represent a chronic time point. “So, when we see effects at 30 days in a mouse, it suggests that the biological changes are lasting well beyond the immediate injury period.”��

While animal models cannot directly predict human timelines, these findings indicate that sleep disruption shortly after a brain injury may have long-term consequences for recovery.��

“The chronic time period is when you start thinking about longer-term consequences of brain injury,” Rowe says. If inflammation persists beyond the initial injury phase, even at lower levels, it can create an environment that interferes with normal brain recovery. “You can start to see sustained inflammatory signaling, stress on neurons and changes that may contribute to neurodegenerative diseases over time.”��

In summary, when combined with sleep fragmentation, TBI can weaken spatial learning and memory, cause persistent inflammation and prevent proper healing. If this inflammation continues for long enough, it can cause serious, permanent damage to the brain, potentially resulting in long-term neurological consequences or pathology associated with neurodegenerative diseases like Alzheimer’s.

“Sleep is a time when the brain can heal,” Rowe says, “and if that is disrupted, the healing process can be disrupted too.” Ultimately, the study shows that “if you are not protecting sleep after a concussion or brain injury, there are some long-term consequences through inflammatory pathways, and that can delay your healing process.”

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