A Warning about White Matter Damage

I recently gave a lecture at the North American Brain Injury Society (NABIS) speaking about what many perceive as a wide spread problem in our health care system involving TBI. The problem is that most radiologists in the United States have decided they do not want to be involved in TBI cases. Why do I say this and what does it mean? Let me explain:

1. The most common method of brain injury in the world arising from trauma is called Diffuse Axonal Injury (DAI), this occurs when the brain is subjected to rapid acceleration or deceleration though a high speed motor vehicle accident, for example. We now know that DAI can and does occur in the full spectrum of TBI – from mild to severe. However, the fact that DAI occurs in mild to moderate TBI is a fairly recent finding and many radiologist were not trained to know this.

2. Radiologist, like other physicians, are suppose to attempt to identify the illness or cause of illness, through a process known as “differential diagnosis.” This is done by ruling out different possible causes of say an abnormality shown in the brain on MRI, until a proven cause can be found.

3. The problem arises when identifying an abnormality on brain MRI known as “white matter hyperintensities” (WMH). These small white areas on an MRI are what damage due to DAI looks like, but there are numerous other non-traumatic causes for WMH. These include: the aging process (starting at 45 to 50); smoking; high blood pressure; Lymes disease; Lupus; vasculitis; migraines, headaches, some mental disorders; and MS.

4. The problem is that currently a radiologist will identify WMH on an MRI following a patient’s trauma but will describe the findings as “non-specific.” That means that there are many causes for the abnormality – not that there is no abnormality. Sometimes following this statement the radiologist will give a short list of possible causes, most commonly “demyelinating disease” (MS), migraine, or ischemic disease (vascular degeneration). But what they will generally not say is that another possibility is trauma.

5. It is therefore imperative that someone who has suffered a TBI and has ongoing symptoms for more than six months to be certain that the brain MRI is not showing an undiagnosed TBI. How do you do this? Certainly if a person is under the age of 45, and has no history of the above conditions, than trauma should be suspected. A comprehensive blood test can be ordered which can help rule in or rule out certain autoimmune diseases, Lyme disease, Lupus, and other possible causes.

6. It is also important for your treating physician to talk to you about where these WMH’s are in your MRI. Location is vitally important in determining the cause of WMH. If they are described as being located in the “deep white matter” then they are less likely to be caused by trauma than by one of the above conditions. However, if they are located at the gray-white junction, than trauma should be suspected. Brain injury occurs in this region due to the differential indensity between the gray matter (which is like the thick skin of a grapefruit) and the white matter, which are the long fibers that connect different areas of the brain together (the inside of the grapefruit). Because of this differential, when the brain is twisted or shaken the white matter often shows damage close to this area. In fact, a recent study in China of over 700 healthy 60 to 64-year olds showed zero WMH within four millimeters of the gray white junction. We can therefore infer that following a trauma, abnormalities found in this region are due to trauma. Even if 10% of the WMH are in this area, it would be consistent with trauma. Be aware that your treating radiologist and/or lawyer will not be aware of this information.

What can be done? A film can be reread by another radiologist. A better scan of the brain can be obtained. By this I mean an MRI that has a 3.0 teslor magnet instead of a 1.5. an MRI that includes Susceptibility Weighted Imaging (SWI), as well Diffuse Tensor Imaging (DTI). SWI can identify tiny microhemorrhages in the brain which not coincidently, look like WMH. Survivors of severe brain trauma can have hundreds of these microhemorrhages show up on SWI, whereas zero or only a few show up on standard MRI. DTI looks at white matter injury and a description of DTI can be found elsewhere on the website.

The single most important thing in brain injury litigation is objectification of injury. Once there is a picture of damage to the brain, the tables are turned on the insurance company. They can no longer call the victim crazy, a liar, a drug addict so easily. A picture is indeed worth a thousand words.

Sports Injury: Return to Play (RTP)

In the last ten years it has become clear that high school, and even junior high school, sports such as football, soccer and lacrosse pose a danger of acute or chronic brain injuries. The autopsies of football players as young as 16 years-old have shown evidence of CTE (Chronic Traumatic Encephalopathy).

CTE is caused by repeated subconsussive trauma to the brain from physical contact. The repeated trauma creates tangles and plaques in the brain which are similar to those found in Alzheimer’s patients. Not everyone, of course, develops CTE. It is not yet proven but it is suspected that genetic and other traits can make individuals more or less susceptible to developing CTE.

While CTE development is a chronic condition that may or may not include an event involving a concussion, the most common danger involves an athlete being returned to play while suffering from a previous concussion. The increasingly complicated and delicate question of “Return to Play” (RTP) is an issue which is still being fully developed. It has been shown that athletes and others who suffer a second concussion while still symptomatic from an earlier concussion, can develop serious and permanent brain injury. There is also evidence that physical exertion immediately following a concussion can lead to amplification of concussion symptoms and an incomplete recovery. Fortunately, most high schools in the United States now employee trainers who have undergone specialized education in dealing with and identifying athletes with concussions and how to deal with these. Yet – problems continue for the following reasons:

1. There is an immense amount of peer pressure from teammates, friends and parents on an athlete to perform and continue to play.

2. The pressure of year round training and year round leagues, some connected with the hope of college scholarships, adds to the pressure as well as the amount of trauma received per year.

3. Athletes can be uncooperative in a school’s attempt to get a “baseline” function (see below).

4. Trainers and coaches are under their own set of pressures to win games and showcase talented individuals on the playing field.

One of the new tools used by schools is called ImPACT testing. This test of motor and cognitive skills was developed by neuropsychologist and neurologist with a great deal of experience in sports injuries. The ImPACT test is given very widely, but parents should keep in mind the following:

1. There should be a “baseline” ImPACT test before the season starts. That way, following a possible concussion, the student can be retested to see if there are deficits in cognitive or motor abilities.

2. Be aware that athletes can often attempt to “dog” the test and achieve a low baseline score, which in effect will keep them in the game even if they have a mild concussion. Review the ImPACT test with your child’s trainer or at least educate yourself on the scoring. There are indications on the testing as to whether or not full effort was given by the student. If there is any question about the validity of your child’s baseline score – ask the trainer to retest the student.

3. Sometimes it’s up to the moms. It is not uncommon for the father of an athlete to be more likely to agree to let the athlete return to play. If either parent has any questions about their child’s return to play, friends of the student as well as boyfriends or girlfriends, should be questioned. The student may be more likely to describe symptoms such as headache, dizziness or foggy thinking to friends than to parents or coaches.

4. Another precaution would be to perform the “gaze nystagmus” test on the student who might have suffered a concussion. This test is also performed by doctors and trainers when appropriate. You simply have the student follow the tip of a pencil with their eyes back and forth, looking for jerking movements of the eyeball at the left and right extremes. The more the jerking occurs, away from the extremes, the more likely there may be a problem. Be aware that some drugs and alcohol can cause this symptom as well.

Training Your Immune System

It has become well known that our brains are not a fixed and static blob of material that we are born with. To the contrary, our brains are constantly changing, a notion called plasticity. For Example, the idea of “making a lawyer out of a student” after three years of a specific type of cognitive bombardment turns out to be truer than expected. Every occupation and lifestyle results in the building of a particular type of brain, which can physically change if the environment and stimulus changes.

It was never thought that a human could, without drugs, alter in any significant way their own immune system. The immune systems change, get stronger or weaker, depending on the health and genetics of an individual. However, a Dutchman by the name of Wim Hof, also known as “The Iceman” has changed this idea completely. For years he has been known as a person who, through meditation, breathing methods and exposure, is able to withstand far lower painful temperatures than any other human. At a University in the Netherlands, his methods were put to analytical science. They found that his system of resistance involved his ability to consciously raise the level of adrenaline in his blood stream. Twelve healthy volunteers were trained in Hof’s techniques. When the blood levels of adrenaline in the trained volunteers was measured, it was significantly higher than controls. These people were also increasingly able to withstand cold temperatures like their teacher does.

Skeptics, which were almost universal, now have to come to grips with our ability to alter our own immune systems through practice, meditation, and concentration. This is an exciting breakthrough which may lead to additional non evasive, therapeutic types of training which could, for example, make patients less susceptible to the pain of a chronic disease, the distraction of pain, and increases in infectious responses during illness.

In a related, but very different experiment, a lungfish from Africa was taken out of its normal environment to see if that would have an effect on its biology. Lungfish can live for some time out of water and can “walk” across dry land, usually to get from lake to lake. Scientist asked the question if a lungfish spends most of its life out of water and just a small percentage in water (reversed life style) whether this would have any effect on the biology of the lungfish. They found out that the lungfish, which stayed out on land the longest, had changes in their biology that allowed them to “walk” more efficiently than other lungfish. This is yet another exciting part of the “plasticity revolution” that is going through all of the biological sciences. We can change our brains, our bodies, and our immune systems and that is very exciting.

Brain injuries no match for sPIF treatment

New Haven, Conn. — Researchers at Yale School of Medicine and their colleagues have uncovered a new pathway to help treat perinatal brain injuries. This research could also lead to treatments for traumatic brain injuries and neurodegenerative disorders such as Alzheimer’s and Parkinson’s.


The findings are published in the Sept. 8 issue of Proceedings of the National Academy of Sciences.


The microRNA let-7 is known to cause the death of neurons in the central nervous system. The research team found that a synthetic molecule derived from the embryo called PreImplantation Factor (sPIF) protects against neuronal death and brain injury by targeting let-7.


“We would never have connected the dots between PIF and let-7 without prior knowledge and experience with let-7 and H19, a developmentally regulated gene that is highly expressed in the developing embryo,” said senior author Yingqun Huang, M.D., associate professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine.


Using a rat perinatal brain injury model, Huang and the team found that sPIF rescued damaged neurons and reduced inflammation. The team performed a series of in vivo and in vitro experiments and found that sPIF helped to stop the production of let-7. “We showed that sPIF works by destabilizing the key microRNA processing protein called KH-type splicing regulatory protein,” said Huang.


Lead author Martin Mueller, who helped develop the rat perinatal brain injury model, was surprised at the consistency of the results from both the in vivo and in vitro studies. “Collectively, our findings suggest that sPIF mitigates brain damage through a novel pathway,” said Mueller. “We saw more cortical brain volume and more neurons restored in brain-damaged animals receiving sPIF.”


“For the first time, we have clear indication to pursue a new line of investigation in the treatment of perinatal brain injury, and possibly traumatic brain injury,” said co-author Michael Paidas, M.D., professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine.


Paidas, who is also vice chair of obstetrics at Yale, has helped to identify PIF’s effects with co-author Eytan R. Barnea, founder of the Society for the Investigation of Early Pregnancy (SIEP) and chief scientific officer of BioIncept, LLC. Barnea discovered and characterized the peptide and described key elements of PIF’s mode of action.


Based on this promising data, the FDA has awarded sPIF fast-track designation and allowed a phase 1 sPIF clinical trial to treat patients with autoimmune liver disease at the University of Miami.



In addition to Huang, Paidas, Mueller, and Barnea, other authors on the study include Jichun Zhou, Lihua Yang, Yuan Gao, and Fuju Wu of Yale; and Andreina Schoeberlein and Daniel Surbek of the University of Bern, Switzerland.


Citation: Proceedings of the National Academy of Sciences www.pnas.org/cgi/doi/10.1073/pnas.1411674111

Advances in Sleep Science

A study published this year opens up some profound doors in explaining the relationship between sleep and the brain. Until now, the actual physiological reason for sleep in humans was not known. People assumed it was to rest the body or to rest the mind. Research showed both of these to be incorrect. Yet we know that humans can die if kept awake for more than a week without sleep. Why?
The recent study showed that during sleep the cerebral spinal fluid that surrounds the brain and spinal cord is cleaned. This cleansing and rejuvenation of this very important fluid does not occur if sleep is prevented or is profoundly disrupted. This will open up whole new worlds of speculation in research – do sleep problems cause psychiatric problems because of this mechanism? What are the ramifications of failure to fully cleanse the fluid because of disrupted sleep.
Sleep research has been hindered through the years by a couple of things. First, when a human subject is asleep there is no obvious method of communication. Also, the reliability of reporting on what is happening during sleep by the sleeper himself is froth with problems. Secondly, the early research on the stages of sleep as recorded by brain EEG (Alpha, beta, REM sleep, etc) has been ingrained in physicians and researchers. Problems or difficulties which occur outside of these known parameters were dismissed as psychiatric. For example, a small group of person that suffer from a sleep disorder whereby they feel as if they have not sleep at all, but in sleep labs all of the known tests show that they are “sleeping like a baby.” By going beyond the standard tests, the scientists finally determined that these individuals have unusually high alpha waves firing during sleep. Alpha waves are those which occur primarily during active waking hours. Now they can try to solve the problem, instead of ignoring it.
Persons that suffer from TBI very commonly have disruptive sleep and other sleep problems. It is highly recommended for TBI victims to go to a sleep lab and see if there is something there that could be corrected, if the problem is known. The problem with a TBI victim living with a sleep disorder, is that the sleep disorder will give rise to worsening of cognitive and psychiatric problems, already at hand, because of the initial brain injury. We know that sleep disruption causes a decrease in the neurogenesis of new memory brain cells in the hippocampus. We now, see above, know that disruptive sleep results in the incomplete cleaning of the cerebral spinal fluid. Sleep apnea has shown to shorten the human life span and cause cognitive deficits. If you have any questions about sleep affecting your present condition, by all means go get it checked out.


In 1970, a Japanese robotics expert, Masahiro Mori, coined the term “The Uncanny Valley.” What he was describing was how humans interacted with and felt about robots. When robots looked very little like a real human being, the viewers emotional response was increasingly positive as they moved toward humans. However, when a robot looked, say 80% human, the negative emotional response poured in and viewers felt that these “near human” robots were creepy and scary. The chart that describe Mori’s term is often used to describe why we find zombies so horrifying.
Unfortunately, some of the negative aspects of the “Uncanny Valley” can occur in the context of TBI. Consider, for example, the difference between our response to a person in a wheelchair and a person who is walking with an extreme limp. Mori, and others who have researched this phenomenon, suggest that persons who appear human, but are physically or neurologically impaired in some way, trigger a response in the viewer which says “that person is pathological or sick.” This also may account for the negative feelings that arise when a TBI victim is 70% or 80% of the pre-accident person, but has frontal lobe injuries that have changed the personality and cognitive functioning. The most common description, in my experience with TBI, from a spouse of a TBI victim is “that’s not the person I married.”
Studies using functional MRI have verified these emotional responses in the human brain – whereby as what is being viewed becomes more and more human, the emotions fall off the cliff at a certain point near fully human. Hopefully, our future research can find ways around this ingrained human response so that TBI victims do not have to deal with it. In the meantime, it needs to be taken into account as one of the problems to be faced on a daily basis by victims of TBI.

Big Brain Project

Researchers in Germany and Canada have produced a new map of the human brain which is considered to be fifty (50) times as detailed as the best previous effort. A human brain was sliced into 7400 sections and photographed at the microscopic level.

This is not the same as the brain initiative from the Obama administration, which seeks to show the connectivity of the brain and the expression of genes. However, this massive new exemplar of the brain will be significant in the following ways:

• It will give researchers additional information as to where to look in smaller regions of the brain for specific deficits, especially those found in TBI.
• New relationships between different parts of the brain inner-connectivity will be established.
• These anatomical breakthroughs will be able to be matched up with functional information (which parts of the brain light up during different activities on functional MRI).
• New structures can be found.

The increasingly minute looks we can now have at the human brain are getting us ever closer to seeing the often “invisible” cellular damage suffered after so called “mild TBI.”

Pre Implantation Factor (PIF) and Neurogenesis

A possibly astounding discovery has been made by Dr. Eytan Barnea, an OB/GYN researcher and professor at Rutgers. For decades there has been a desire to scientifically explain why the foreign genetic material (the father’s) in a fertilized human egg is not rejected by the mother’s immune system upon attaching itself to the uterus. Researchers have tried mightily to figure out how the mother accomplishes this miraculous task. However, Dr. Barnea cleverly decided to look at what the human embryo could be doing to possible make that happen. There, he discovered the first molecule secreted by a human (or any other mammalian) embryo – a peptide protein molecule he has named Pre-Implantation Factor (PIF).


This molecule, research has shown, goes to over 100 genes in the mother’s body and “synchs” the immune system of the mother and the embryo. This discovery has tremendous potential in the field of reproduction – up to 20% of infertility might be explained by a lack of secreted PIF, in which case no one can ever get pregnant. However, there is more.


PIF has terrific anti-inflammatory properties without general suppression of the immune system. More extraordinary, PIF, being one of the first molecules generated by a tiny embryo, has the property of possible control over adult stem cells. In peer review studies, tissue damaged by inflamation has been healed and repaired by the administration of PIF (in arthritis, MS, and juvenile diabetes).


The good news, for victims of TBI, is that PIF has exhibited properties of neuro-regeneration. In a peer reviewed study, the administration of PIF in mice with spinal cord injury from MS, allowed a large percentage of mice with rear leg paralysis to walk. We know that PIF works in humans, as the beneficial effects during the pregnancy of autoimmune patients is well documented. Human trials are planned to start before the end of 2013. Hopefully, within two to three years, the FDA will approve the use of PIF for at least some purposes, and a great deal of good can be done. (See peer review studies by going to www.pubmed.org and look up the discovery of PIF, Barnea, R. T.)

VA Acknowledges Dementia and Parkinson’s After TBI

A new proposed rule by the Veterans Affairs Department issued in late 2012, changes the service connection of illnesses after service related TBI. A recent report from the National Academy of Sciences entitled “Gulf War and Health,” Volume 7: Long-term Consequences of Traumatic Brain Injury Showed the Association Between TBI and Five Diagnosable Illnesses. Parkinson’s, Pre-senile dementia of the Alzheimer’s type, and post traumatic dementia. They noted “reported cases showed that individuals with TBI often are diagnosed with dementia at ages younger than their early 50’s and within fifteen years of their injuries.”

Therefore the changes are to make it easier for Veterans to obtain medical benefits and disability following a moderate to severe TBI in the following instances:

1. Parkinsonism following moderate or severe TBI.
2. Unprovoked seizures following moderate or severe TBI.
3. Dementia within fifteen years of moderate or severe TBI.
4. Depression if manifest within three years of moderate or within twelve months of mild TBI.
5. Diseases of hormone deficiencies that result from changes within twelve months of moderate or severe TBI.

This goes to show that medical sciences now establishing that TBI is a chronic disease and not a static injury. Societal changes regarding this fact will take time but will represent an important shift in the way our society views this prevalent injury.

Brain Injury and Fatigue

It is a very common complaint of victims of traumatic brain injury that since the injury they experience extreme bouts of fatigue. Symptoms of “fatigue” are often ignored or downplayed by doctors because  it is considered a “vague” symptom.  It is also a symptom that has not been specifically linked to any known mechanism or area of damage in of the brain.
Like many other aspects of brain injury, this symptom of fatigue is now being studied and explained in much greater detail than done before.  This is once again thanks to the sacrifice our soldiers have made in Iraq and Afghanistan and the Army researchers trying to help them.
The first thing we know about the creation of fatigue is that in functional MRI testing, TBI victims with frontal lobe injury, when asked to perform spelling or math problems, have a much higher rate of “brain recruitment”.  Brain recruitment means what part of the brain and how much of the brain is activated by doing a given task. By these recent studies we know that the person with the injured brain is forced to recruit a larger percentage of their brain to complete a certain task, whereas an uninjured person would be activating a much lower percentage of their brain.  The brain burns up about 30% of the bodies energy on a given day.  Thus, over-recruitment of the brain because of injury is literally fatiguing, since it is costing a much higher rate of energy to do things that previously cost the body much less energy.  It would be the same of putting 5 lb weights on each hand throughout the day.  It explains nicely why there is such widespread and debilitating fatigue with TBI survivors.
In another recent study (Vanzuiden M et al., 2012) soldiers were tested before and after deployment regarding reports of severe fatigue.  It was found that severe fatigue was associated with higher reactivity to IL-1 beta and it was found in higher levels in those with severe fatigue. TBI also plays a part in increasing what is known as pro-inflammatory cytokines in the blood for many months or years after injury.  This can explain the very high level of severe fatigue found in TBI survivors.  If a way can be found to decrease the reactivity to the immune system of the IL-1 beta, treatment can be found.