The Root of Thought (21 page)

After WWI, it became obvious that soldiers would benefit from mobile surgical units, which were put in place for WWII. With doctors arriving directly on the scene of battle, they were able to save many more lives. From the Soviet Union, Alexander Luria (1902–1977) was one surgeon who studied soldiers returning from Germany with psychiatric disorders and brain injury. An amazing short book he published in 1948, entitled
Restoration of Function after Brain Injury
, described many aspects of the injury. His research wasn’t known in the West until 1963 when his book was finally translated into English. His most famous work,
The Man with a Shattered World
, was a history of an interesting case of lifelong brain injury and wasn’t translated into English until 10 years after his death.

When studying soldiers, Luria determined that a secondary injury results after the primary wound. Over the cause of the next days and weeks, subsequent degeneration of brain cells occurs. This idea has
proved to be exceedingly correct and a difficult conundrum for researchers. If they can treat the primary injury, how do they also treat the subsequent secondary degeneration, which is a completely separate event? The secondary injury might result from the inability for astrocytes to help or signal to the neurons. Encouraging astrocytes to grow might counteract secondary injury.

The advances from WWI and WWII on the treatment and outcome of brain injury went stale during the Vietnam War. No new advances occurred, and in an abstract in 1971 on 2187 open head wounds in the war, the author concluded—“the previously established principles of combat neurosurgery are confirmed and their continued use recommended.”

Trench warfare in WWI also created the advent of a better helmet. Bullets would ricochet off easier. However, with the helmet comes its own problems. The other type of injury, closed head injury or a diffuse axonal injury, occurs in patients who don’t have a fractured skull. In 1705, a prisoner in France who was sentenced to be tortured, sprinted 15 feet across the dungeon and smashed his head into the stone wall, to commit suicide, and succeeded, dying instantly. The surgeon in charge of investigating the death, Alexis Littré (1658-1726), could find nothing wrong with the skull or the brain. This study was cited for many years, and it has only recently been understood what causes such severe damage and deficits in closed head injury patients.

The skull stays closed and the swelling has nowhere to go. It is said that you cannot receive a severe injury to the brain unless you fall from a height greater than how tall you are. But with incredibly high buildings, men smashing into each other on the football field, people driving in high-speed cars, and people riding bicycles down hills at 30 mph, it behooved people to invent the helmet.

Of course, the helmet can do only so much. As Seinfeld says about skydiving, “You jump out of that plane and that chute doesn’t open, the helmet is now wearing you for protection. Later on the helmet’s talking with the other helmets going ‘It’s a good thing that he was there or I would have hit the ground directly.’” It is true even in events less extreme than skydiving. The shaking of the brain inside the skull can cause just as much damage whether someone is wearing a helmet or not wearing a helmet. In the Iraq War, the most common effect soldiers
experience is diffuse axonal injury to the brain; with all the armor they wear, they can’t help their brains from rattling around in their heads when they get tossed by an explosion.

The development of better helmet technology in football has resulted in more concussions, not less. In the early twentieth century, football was so brutal that President Teddy Roosevelt considered banning the sport. In recent years, the game has become more specialized in equipment to protect the players. However, the feelings of inhibition because of the equipment results in many more concussions than before the helmet. Severe skull fractures, though, have been minimized.

The sense of invincibility from equipment safety technology has occurred in other fields as well. In boxing, when gloves became the norm, the arm worked like an anvil slamming down a leather glove drenched in sweat that had become heavy and hard as a rock. This is the reason modern gloves are slick and waterproof.

When the brain shakes and rotates in the skull, the long axons extending out of the cortex down into the lower brain and subsequently the spinal cord are sheared and stretch. The stretching can cause some adverse impairment. Our astrocytes come to the rescue. The astrocytic response in the white matter is extensive. When someone suffers from a coma, he rarely comes back like in the soap operas. Most people are debilitated for the rest of their lives. In rare cases, they can come back and talk or maybe walk, but usually they are never the same.

The first research on closed-head injuries by French military surgeon Jean-Pierre Gama (1775-1861) involved putting jelly in a jar with wires and shaking it up to see how the wires (white matter) and jelly (grey matter) moved around. This was an early nineteenth century attempt to understand how our brain moved in our skull under fast impact. However, a jar of jelly certainly didn’t tell us about the extensive glial reaction to the wound.

Most research on brain injury is an attempt to find out how to protect the neurons. Equations to determine the amount of force and speed the brain undergoes and amount of neuronal degeneration that results are studied thoroughly. The key to understanding how to help brain injuries might be in the astrocytes and how they repair the neuron. First, protection of remaining neurons immediately after injury would be essential. Then, the only way to stop subsequent secondary degeneration of neurons would be to influence astrocytes to become more robust and beneficial by manipulating their growth and regenerative properties to repair areas of damage.

In the event of a gunshot wound to the head, astrocyte therapy might be the only avenue to regrow areas of the brain. It is known that astrocytes cause a scar to occur in the brain after an injury. Astrocyte scarring can be considered a good thing, like after injury to the muscle. The goal should be how to reconstruct the part of the brain lost to the destructive force that injured it.

In brain injury and stroke, astrocytes light up when the tissue is stained for GFAP (glial fibrillary acidic protein). Around the area affected, many spider-shaped astrocytes come to the call of duty. Since the 1970s, not long after GFAP was discovered, astrocytes have been known to proliferate when they are near an injured area. One interesting aspect of research is to look at whether two markers occur at the same time. For instance, researchers looked at GFAP to see if it was expressed in the same cells that were marked with thymidine, cells that are dividing to form new cells. This way, they could tell if astrocytes divided and compare them to neuron markers. Neurons do not divide. But researchers noticed that astrocytes proliferate in an attempt to replace the cells in this area and eventually create a scar.

However, this evidence did not satisfy researchers at the time to continue to study how to get astrocyte growth to protect the brain. At the time, in their blind lust for neurons, the researchers were not impressed and decided not to pursue that avenue, but instead looked for a way to create neurons. It is known that we can create neurons in a dish with embryonic stem cells, and researchers thought that implanting these cells in the brain would regrow neurons. This has produced little noteworthy results to date.

However, an attempt to understand why astrocytes would proliferate near destroyed brain tissue might bring us insight into how to help the brain survive and regrow. We now know that astrocytes are the adult stem cells that eventually lead to neurons in some areas and turnover to replace themselves in all areas. After injury, if it is possible to protect neurons initially, then harnessing innate astrocytic regenerative ability could lead to brain injury treatments that are effective.

It is still currently the belief that astrocyte scarring is an impediment to growth. Cajal would take cats, brutally lesion their brains, let the cat survive for a while longer, then take the brain out and analyze it. Cajal
noticed that neurons were not able to grow past a scar that the glia formed. His conclusion was not that glia are trying to save the brain, but that glia are somehow impediments to neuronal growth necessary to repair the brain. However, because his torturous slice through the cat brain was too destructive to replace, Cajal didn’t realize that glia do beneficial services.

Placing neuronal stem cells in the brain does not help it grow past an astrocyte scar either. Somehow the astrocytes cause the neuroblasts not to grow into the area of wound. However, if one thinks about scarring on our skin, the clotting material does exactly that: It repairs the wound.

If you lose the area in your brain that contributes to speech, it is a bit like having a leg amputated. For humans, attempting to regrow a large swath of brain is as challenging as trying to regrow an arm or leg. Some invertebrate animals can do it, such as the starfish, earthworm, or the leech, but we cannot.

Astrocyte turnover contributes to our ever-changing information and thoughts in our brain; as the seat of our imagination and creativity, they are the quintessential cells that are responsible for repairing the damage that occurs in the brain. This constant turnover, likely increased in areas of injury, repairs small rifts that occur in the brain over time. However, a traumatic event like a gunshot wound or railroad spike that rips through the brain like a tornado can take some time to repair.

One of the things known about glial cells is that they respond to almost any insult, as shown in brains of alcoholics. Someone who drinks alcohol heavily, when their brain is autopsied, will have many GFAP-expressing cells. Eventually, like in Parkinson’s disease and Alzheimer’s disease, degeneration of the brain will occur in the brain of someone who abuses alcohol over many years in immense amounts. However, the glial reaction might be astrocytes trying to replace sacrificed members of their families in the war against the alcohol invasion.

After the astrocytes are disrupted, cognitive problems happen, and then the neuronal roads have nothing to maintain them and they will start to deteriorate. Alcohol attacks an area in the brain called the mammillary bodies, which are aptly named because of their resemblance to two breasts sitting on top of the brain stem. They seem to control function related to vision and cortical integration of information. When many of the cells have died off, severe alcoholics develop Korsakoff’s syndrome, in which patients exhibit behaviors similar to Alzheimer’s patients.

The same might happen with a brain injury; the astrocyte that reacts in areas that are injured could try to replace fellow astrocytes that have been destroyed because it is true that if astrocytes are healthy, neurons are healthy.

In a stroke, a clot in a blood vessel in the brain causes the lack of oxygen to get to cells surrounding the area of the clot. Astrocytes in the area die and other astrocytes outside the zone of oxygen depletion react trying to replace astrocytes in that area. But even in a stroke, where this is a known event, much of the research and response work centers around neuronal replacement stem cell therapy. Obviously, in the case of stroke or brain injury, it is helpful to protect the neurons as well. But for regrowth and replacement of cells that are more able to contribute to the overall recovery from injury or stroke, the focus should most definitely be on astrocytes.

One of the main tenants of injury research is Wallerian degeneration—as axons are stretched and destroyed, the far end of each axon degenerates away and the end nearest to the cell body sits there in a stump. The nerves that extend from the spinal cord out toward the muscles grow back at a snail’s pace and will eventually extend back out after damage.

In the brain, the axons do not regrow. When axons are cut or sheared in diffuse axonal injury, they degenerate and the cell dies. Proteins that comprise the bulk of the machinery in the cell can accumulate in the stump closest to the brain cell. One of the main proteins that builds up is APP. APP, when cut in two, creates Amyloid Beta, the protein implicated in Alzheimer’s Disease. This protein occurs in such massive amounts that if it isn’t taken up by the glia, it forms plaques in the cell and is one of the main components transported down the axon in a healthy cell.

Brain injury has been linked to degenerative disease. The prevailing theory is that the insult or injury to the neurons somehow starts a process that over time evolves into Alzheimer’s or Parkinson’s. This is thought to be because brain injury causes reactive oxygen to be released and oxidative stress. Reactive oxygen is destructive to the cell. Also, extracellular calcium can enter the neuron and destroy the cell.

We know that brain injury causes oxidative stress, and astrocytes are the cells that counteract this stress. We also know that dead astrocytes leave a calcium mark afterwards. Reactive oxygen species float out of cells with nowhere to go, and calcium slithers around without any
purpose. This can be the result of dying astrocytes as well. Neurons have no way to cope with the reactive oxygen species and excess calcium if astrocytes are not present, and they subsequently die. Neurons die because astrocytes die.

If astrocytes cannot replace themselves fast enough and some die, then the reactive oxygen species will kill all the neurons in the area. Therefore, brain injury leading to neurodegenerative disease can be prevented if astrocytes are replenished. However, almost all the research on oxidative stress focuses entirely on neurons and how to save neurons from this process. Without astrocytes, the neurons are doomed. They have no reason to function. Similar to a broken conveyer belt at the factory assembly line after everyone has been laid off (you might be able to get the conveyor belt magically working), no one will be there to run it.

That is the difficulty with most studies on injury, stroke, and disease in the field at the moment. So much evidence has mounted for the importance and possible dominance of the astrocyte, but every study is undertaken with the idea that neurons should be the focus. It’s like standing on your head to take a drink of water.