National Institute of Neurological Disorders and Stroke

Researchers film early concussion damage, describe brain’s response to injury.

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There is more than meets the eye following even a mild traumatic brain injury. While the brain may appear to be intact, new findings reported in Nature suggest that the brain’s protective coverings may feel the brunt of the impact.

Using a newly developed mouse trauma model, senior author Dorian McGavern, Ph.D., scientist at the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health, watched specific cells mount an  to the injury and try to prevent more widespread damage. Notably, additional findings suggest a similar immune response may occur in patients with mild head injury.

In this study, researchers also discovered that certain molecules, when applied directly to the mouse skull, can bypass the brain’s protective barriers and enter the brain. The findings suggested that, in the mouse trauma model, one of those molecules may reduce effects of .

Although concussions are common, not much is known about the effects of this type of damage. As part of this study, Lawrence Latour, Ph.D., a scientist from NINDS and the Center for Neuroscience and Regenerative Medicine, examined individuals who had recently suffered a concussion but whose initial scans did not reveal any physical damage to brain tissue. After administering a commonly used dye during MRI scans, Latour and his colleagues saw it leaking into the meninges, the outer covers of the brain, in 49 percent of 142 patients with concussion.

To determine what happens following this mild type of injury, researchers in Dr. McGavern’s lab developed a new model of brain trauma in mice.

“In our mice, there was leakage from blood vessels right underneath the skull bone at the site of injury, similar to the type of effect we saw in almost half of our patients who had mild . We are using this mouse model to look at meningeal trauma and how that spreads more deeply into the brain over time,” said Dr. McGavern.

Dr. McGavern and his colleagues also discovered that the intact skull bone was porous enough to allow small molecules to get through to the brain. They showed that smaller molecules reached the brain faster and to a greater extent than larger ones. “It was surprising to discover that all these protective barriers the brain has may not be concrete. You can get something to pass through them,” said Dr. McGavern.

The researchers found that applying glutathione (an antioxidant that is normally found in our cells) directly on the skull surface after brain injury reduced the amount of  by 67 percent. When the researchers applied glutathione three hours after injury, cell death was reduced by 51 percent. “This idea that we have a time window within which to work, potentially up to three hours, is exciting and may be clinically important,” said Dr. McGavern.

Glutathione works by decreasing levels of reactive oxygen species (ROS) molecules that damage cells. In this study, high levels of ROS were observed at the trauma site right after the physical brain injury occurred. The massive flood of ROS set up a sequence of events that led to cell death in the brain, but glutathione was able to prevent many of those effects.

In addition, using a powerful microscopic technique, the researchers filmed what was happening just beneath the skull surface within five minutes of injury. They captured never-before-seen details of how the brain responds to traumatic injury and how it mobilizes to defend itself.

Initially, they saw cell death in the meninges and at the glial limitans (a very thin barrier at the surface of the brain that is the last line of defense against dangerous molecules). Cell death in the underlying brain tissue did not occur until 9-12 hours after injury. “You have death in the lining first and then this penetrates into the brain tissue later. The goal of therapies for brain injury is to protect the ,” said Dr. McGavern.

Almost immediately after head injury, the glial limitans can break down and develop holes, providing a way for potentially harmful molecules to get into the brain. The researchers observed microglia (immune cells that act as first responders in the brain against dangerous substances) quickly moving up to the brain surface, plugging up the holes.

Findings from Dr. McGavern’s lab indicate that microglia do this in two ways. According to Dr. McGavern, “If the astrocytes, the cells that make up the glial limitans, are still there, microglia will come up to ‘caulk’ the barrier and plug up gaps between individual astrocytes. If an astrocyte dies, that results in a larger space in the glial limitans, so the microglia will change shape, expand into a fat jellyfish-like structure and try to plug up that hole. These reactions, which have never been seen before in living brains, help secure the barrier and prevent toxic substances from getting into the brain.”

Studies have suggested that immune responses in the brain can often lead to severe damage. Remarkably, the findings in this study show that the inflammatory response in a model is actually beneficial during the first 9-12 hours after injury.

Mild traumatic brain injuries are a growing public health concern. According to a report from the Centers of Disease Control and Prevention, in 2009 at least 2.4 million people suffered a traumatic injury and 75 percent of those injuries were mild. This study provides insight into the damage that occurs following head trauma and identifies potential therapeutic targets, such as antioxidants, for reducing the damaging effects.

Brain Clears Toxins During Sleep.

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Scientists have long wondered why sleep is restorative and why lack of sleep impairs brain function.

Now, new animal research suggests how the sleep state may help clear the body of potentially toxic central nervous system (CNS) metabolites.

Proteins linked to neurodegenerative diseases, including β-amyloid (Aβ), are present in the interstitial space surrounding cells in the brain. In a series of experiments, researchers tested the hypothesis that Aβ clearance is increased during sleep and that the sleep-wake cycle regulates the glial cell–dependent glymphatic system, which is responsible for clearing waste from the brain and spinal cord.

“Basically, we found a new function of sleep,” said study lead author Lulu Xie, PhD, Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, New York.

“When mice are awake, the brain cells continuously produce toxic waste. This waste can build up in the spaces between the brain cells and damage them. However, during sleep, the spaces between brain cells increase, which may help the brain flush out the toxic waste. Therefore, a good sleep can clear the brain.”

“Sleep changes the cellular structure of the brain. It appears to be a completely different state,” Maiken Nedergaard, MD, DMSc, codirector of the Center for Translational Neuromedicine at the University of Rochester Medical Center, who is a leader of the study, said in a statement from the National Institute of Neurological Disorders and Stroke, which supported the study.

The new research was published October 18 in Science.

Sleeping vs Awake Brain

The researchers infused fluorescent dye into the cerebrospinal fluid (CSF) of mice and observed it flow through the brain. At the same time, they monitored electrical brain activity and wakefulness with electrocorticography (EcoG) and electromyography (EMG)..

“In the sleeping brain, we found the CSF flushed into the brain very quickly and broadly,” said Dr. Xie. “After half an hour, we woke the mice up by gently touching their tails, and injected another color of dye. But what we saw is that CSF barely flowed when the same mice were awake.”

These results suggest that the awake brain may have more resistance to CSF influx, which leads to the assumption that the path of CSF flow into the brain is smaller in the awake brain, said Dr. Xie.

Next, the scientists inserted electrodes into the brain to directly measure the space between brain cells, and found that it increased by around 60% when the mice were asleep.

“Theoretically, big spaces lead to easier fluid influx,” said Dr. Xie. “So we presumed that the clearance of the toxic protein between cells will become more efficient.”

To test this assumption, they infused radio-labeled Aβ into the brain and measured how long it stayed in both the sleeping brain and the awake brain.

We found Aβ disappeared 2-fold faster in the sleeping mice brains as compared with awake mice,” noted Dr. Xie. “Based on this experiment, we can see that the sleeping brain is more capable of clearing out the toxic protein.”

Technically, it might be relatively easy to study these processes in humans, possibly using magnetic resonance imaging. However, Dr. Xie said she does not know when human trials, which involve “a lot more concerns” than animal experiments, might come about.

“These results may have broad implications for multiple neurological disorders,” said Jim Koenig, PhD, a program director at the National Institute of Neurological Disorders and Stroke (NINDS), which funded the study, in a statement. “This means the cells regulating the glymphatic system may be new targets for treating a range of disorders.”

Sleep ‘boosts brain cell numbers’

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Scientists believe they have discovered a new reason why we need to sleep – it replenishes a type of brain cell.

Sleep ramps up the production of cells that go on to make an insulating material known as myelin which protects our brain’s circuitry.

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The findings, so far in mice, could lead to insights about sleep’s role in brain repair and growth as well as the disease MS, says the Wisconsin team.

The work is in the Journal of Neuroscience.

Dr Chiara Cirelli and colleagues from the University of Wisconsin found that the production rate of the myelin making cells, immature oligodendrocytes, doubled as mice slept.

The increase was most marked during the type of sleep that is associated with dreaming – REM or rapid eye movement sleep – and was driven by genes.

In contrast, the genes involved in cell death and stress responses were turned on when the mice were forced to stay awake.

Precisely why we need to sleep has baffled scientists for centuries. It’s obvious that we need to sleep to feel rested and for our mind to function well – but the biological processes that go on as we slumber have only started to be uncovered relatively recently.

Growth and repair

Dr Cirelli said: “For a long time, sleep researchers focused on how the activity of nerve cells differs when animals are awake versus when they are asleep.

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“Now it is clear that the way other supporting cells in the nervous system operate also changes significantly depending on whether the animal is asleep or awake.”

The researchers say their findings suggest that sleep loss might aggravate some symptoms of multiple sclerosis (MS), a disease that damages myelin.

In MS, the body’s immune system attacks and destroys the myelin coating of nerves in the brain and spinal cord.

Future studies could look at whether or not sleep affects the symptoms of MS, says Dr Cirelli.

Her team is also interested in testing whether lack of sleep, especially during adolescence, may have long-term consequences for the brain.

Sleep appears necessary for our nervous systems to work properly, says the US National Institute of Neurological Disorders and Stroke (NINDS).

Deep sleep coincides with the release of growth hormone in children and young adults. Many of the body’s cells also show increased production and reduced breakdown of proteins during deep sleep.

Since proteins are the building blocks needed for cell growth and for repair of damage from factors like stress and ultraviolet rays, deep sleep may truly be “beauty sleep”, says NINDS.

Source:BBC