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Stem Cell Therapy for Brain Injury
Background:
Every 15 seconds, throughout the world, someone suffers a brain injury. For people who suffer permanent brain injury, the average cost of lifetime care and rehabilitation is in the millions of dollars per person. According to one of the leading researchers in the field of traumatic brain injury (TBI), Dr. Tracy McIntosh of the University of Pennsylvania School of Medicine,
“Sadly, it is an epidemic that most people do not realize exists, and to date, there is no clinical treatment that can effectively treat the damage.”
Another leading researcher in the field, Dr. Ronald Hayes, director of the University of Florida Brain Institute, concurs by stating, “Currently no effective treatment exists.”
TBI affects more people than stroke or Alzheimer’s disease combined. It is the leading cause of death in Americans under the age of 45, and it is also the leading cause of long-term neurological disability in children and young adults.
According to the website of National Institute of Neurological Disorders and Stroke (NINDS), a
division of the National Institutes of Health (NIH),
“Traumatic brain injury (TBI) is a major public health problem, especially among male adolescents and young adults ages 15 to 24, and among elderly people of both sexes 75 years and older. Children aged 5 and younger are also at high risk for TBI.” (From www.ninds.nih.gov).
The Brain Injury Association of America defines TBI as follows:
“A traumatic brain injury (TBI) is defined as a blow or jolt to the head or a penetrating head injury that disrupts the function of the brain. Not all blows or jolts to the head result in a TBI. The severity of such an injury may range from ‘mild’, i.e., a brief change in mental status or consciousness, to ‘severe’, i.e., an extended period of unconsciousness or amnesia after the injury. A TBI can result in short or long-term problems with independent function.” (From www.biausa.org).
Also known as “acquired brain injury”, or simply “head injury”, TBI is a type of “neurotrauma” that has been estimated to occur in approximately 1.5 million people per year in the United States alone. Of those, approximately 1.1 million cases per year are considered mild and are treatable in hospital emergency rooms, while approximately 235,000 cases per year are considered moderate and result in extended hospitalization, and approximately 50,000 cases per year are fatal. These figures are believed to be conservative estimates, as the actual number of people who sustain TBIs but who do not seek medical treatment is unknown. According to the U.S. Centers for Disease Control and Prevention (CDC), there are currently more than 5.3 million Americans who are living with some form of long-term or lifelong injuries that were incurred from TBI. (From www.cdc.gov). Reliable global statistics for TBI do not exist, although the World Health Organization has issued the following statement on the subject:
“Neurotrauma is a critical public health problem that deserves the attention of the world’s health community. Estimates of brain and spinal cord injury occurrence indicate that these injuries cause enormous losses to individuals, families, and communities. They result in a large number of deaths and impairments leading to permanent disabilities. Research has also shown that traumatic brain injury (TBI) usually requires long-term care and therefore incurs economic cost to health systems. For this reason, many countries need to develop surveillance systems and conduct epidemiologic studies to measure the impact of neurotrauma among their people to guide the development of more effective preventive methods. A number of methods have already proven effective, such as the use of motorcycle helmets, head supports in vehicles or on sports equipment.” (From www.who.int).
Among members of the military who have been deployed to war zones, and also among reporters who are assigned to cover such wars, blasts are the leading cause of TBIs. For military medical personnel who may be involved in the triage, treatment, and transport of such combat-related injuries, a publication entitled “Guidelines for the Field Management of Combat-Related Head Trauma” is available from the Brain Trauma Foundation, at www.braintrauma.org. The guidelines were compiled by a group of civilian and military experts from the fields of neurosurgery, trauma and EMS who were assembled by the Brain Trauma Foundation for the specific purpose of formulating such guidelines that would address the particular nature of war-related head injuries. The publication was funded by the Defense and Veterans Brain Injury Center in collaboration with the Henry M. Jackson Foundation for the Advancement of Military Medicine.
Among the civilian population of the U.S., approximately half of all TBIs are caused by motor vehicle traffic accidents, and approximately half of all TBIs involve the use of alcohol. Outside of war zones, therefore, TBIs are among the most preventable of injuries. Between the ages of 15 and 24, males are nearly twice as likely as are females to sustain a TBI. For people aged 75 and older, most TBIs are the result of falls. Approximately 20% of all TBIs are due to violence, and approximately 3% are the result of sports injuries. Over 90% of TBIs that are caused by the use of firearms result in death, whereas approximately 11% of TBIs that are caused by falls result in death. As of 1995, combined direct medical expenses and indirect costs such as lost productivity from work due to TBI was estimated at $56.3 billion in the United States. (From www.ninds.nih.gov).
Symptoms:
TBIs may result in a wide range of “functional” changes, the most obvious of which often involve disorders of personality as well as problems with physical and cognitive skills. It is not uncommon for people who have suffered moderate TBI to exhibit psychological behavior that may be considered “out of character”, as they may be unusually susceptible to emotional upsets and to outbursts of temper. Difficulty with memory and computation, as well as a low tolerance for stress, are common symptoms.
In their mildest forms, problems that result from TBI are only temporary and will resolve on their own, without medical intervention. In their moderate or severe forms, however, problems resulting from TBI may include various types of long-term physical and mental incapacitation. As the statistics cited above indicate, TBI may also be fatal.
Physical problems resulting from moderate TBI may include difficulty with ambulation, coordination, balance, fine motor skills, strength and endurance. Cognitive problems may include disrupted faculties in language and communication, reasoning, information processing and analysis, memory and perception. Depending on the particular regions of the brain that have been injured, some psychological abnormalities may also become apparent over time.
Regardless of the precise area of injury to the head, many TBIs result in widespread damage to the brain when the brain “ricochets” inside the skull during an accident. Certain regions of the brain are more vulnerable to damage than are other areas, and the extent of injury to specific cerebral tissue will depend upon a number of factors. Precise symptomology and the course of progression will vary widely among individuals, depending upon the particular areas of the brain that have been damaged and the extent of that damage. According to the website of the National Institute of Neurological Disorders and Stroke (NINDS), a division of the National Institutes of Health (NIH), the symptomatic varieties of TBI are described as follows:
“Symptoms of a TBI can be mild, moderate, or severe, depending on the extent of the damage to the brain. A person with a mild TBI may remain conscious or may experience a loss of consciousness for a few seconds or minutes. Other symptoms of mild TBI include headache, confusion, lightheadedness, dizziness, blurred vision or tired eyes, ringing in the ears, bad taste in the mouth, fatigue or lethargy, a change in sleep patterns, behavioral or mood changes, and trouble with memory, concentration, attention, or thinking. A person with a moderate or severe TBI may show these same symptoms, but may also have a headache that gets worse or does not go away, repeated vomiting or nausea, convulsions or seizures, an inability to awaken from sleep, dilation of one or both pupils of the eyes, slurred speech, weakness or numbness in the extremities, loss of coordination, and increased confusion, restlessness, or agitation. (From www.ninds.nih.gov).
It is important for physicians to distinguish between primary and secondary damage in TBI since it is now known that not all brain damage occurs at the moment of injury but develops over time. Most secondary damage is the result of tissue swelling within the brain that occurs over the ensuing hours and days following an injury and which may persist for weeks. Surgery is required in approximately half of all severe cases of TBI in order to treat complications from brain swelling and to remove intracranial hematomas (blood that collects between the skull and the brain) or contusions (bruised brain tissue). In severe cases of TBI, shrinkage of neural tissue and gross atrophy of the brain result from the cumulative effects of cellular necrosis and apoptosis (programmed cell “suicide”) that are triggered by the injury, especially by the secondary damage. Since very little can be done to attenuate primary damage once it has occurred, treatment of TBI emphasizes management of secondary damage, and of the associated symptoms. In collaboration with various physicians and medical organizations, the Brain Trauma Foundation has developed a series of guidelines which may be employed to minimize secondary damage from TBI. Information on such guidelines is available at www.braintrauma.org.
War-related TBI now constitutes a distinct category, since it has recently been discovered that TBIs which result from the types of explosives used in wars are significantly different from TBIs that are caused by ordinary trauma among the civilian population. In a concussion from a motorcycle accident, for example, the brain is injured by being stretched or torn. However, according to Dr. Steven Macedo, a neurologist formerly with the U.S. Veterans Administration,
“TBIs from Iraq are different. When the sound wave moves through the brain, it seems to cause little gas bubbles to form. When they pop, it leaves a cavity. So you are littering people’s brains with these little holes.”
Even in soldiers who are not close enough to an explosion to be physically injured by shrapnel, the shock wave from the blast may be sufficient to disrupt neurological tissue, thereby causing physical damage within the brain. Corresponding disruptions in cognitive function may manifest as memory loss, confusion, anxiety, depression and short attention spans, among other symptoms. Military physicians have therefore learned to suspect a physiological etiology for what may appear to be a purely behavioral pathology in soldiers who have been subjected to the powerful and detrimental shock waves from explosions.
Diagnosis and Prognosis:
As the name implies, traumatic brain injuries are most typically associated with physical trauma. Injury to the brain is also possible, however, as a result of nonphysical, chemical trauma, such as hypoxia (insufficient oxygen), poisoning or infection. Regardless of the specific causes, however, diagnosis and treatment of damaged brain tissue are conducted according to an assessment of the same universal conditions.
The prognosis of the patient will depend upon the nature and extent of injuries, an accurate determination of which may not always be immediately possible. According to NINDS,
“Disabilities resulting from a TBI depend upon the severity of the injury, the location of the injury, and the age and general health of the individual. Some common disabilities include problems with cognition (thinking, memory, and reasoning), sensory processing (sight, hearing, touch, taste, and smell), communication (expression and understanding), and behavior or mental health (depression, anxiety, personality changes, aggression, acting out, and social inappropriateness). More serious head injuries may result in stupor, an unresponsive state, but one in which an individual can be aroused briefly by a strong stimulus, such as sharp pain; coma, a state in which an individual is totally unconscious, unresponsive, unaware, and unarousable; vegetative state, in which an individual is unconscious and unaware of his or her surroundings, but continues to have a sleep-wake cycle and periods of alertness; and a persistent vegetative state (PVS), in which an individual stays in a vegetative state for more than a month.” (From www.ninds.nih.gov).
TBI damage may be either focal (confined to one area of the brain) or diffuse (spread among more than one area), and may be classified either as a closed head injury or a penetrating head injury, depending on whether or not the skull and the brain tissue have been penetrated by an object. Some symptoms and disabilities may manifest immediately, while others may not become apparent until days or even weeks after the injury. Ongoing monitoring of the individual is therefore necessary to identify the full extent of injuries.
Recent studies have indicated that in certain individuals who may be genetically predisposed to such conditions, TBI may increase the risk of developing other neurological disorders later in life, such as Alzheimer’s disease, Parkinson’s disease and epilepsy.
Treatment:
Conventionally, very few treatment options have existed for people with TBI. In the hours and days following trauma to the brain, initial efforts are focused primarily on stabilizing the patient, after which time the therapeutic emphasis is on rehabilitation that may include both physical and occupational therapy, depending on the severity of the TBI. As explained on the website of NINDS,
“Because little can be done to reverse the initial brain damage caused by trauma, medical personnel try to stabilize an individual with TBI and focus on preventing further injury. Primary concerns include insuring proper oxygen supply to the brain and the rest of the body, maintaining adequate blood flow, and controlling blood pressure. Imaging tests help in determining the diagnosis and prognosis of a TBI patient. Patients with mild to moderate injuries may receive skull and neck X-rays to check for bone fractures or spinal instability. For moderate to severe cases, the imaging test is a computed tomography (CT) scan. Moderately to severely injured patients receive rehabilitation that involves individually tailored treatment programs in the areas of physical therapy, occupational therapy, speech/language therapy, physiatry (physical medicine), psychology/psychiatry, and social support.” (From www.ninds.nih.gov).
Whenever injury is sustained anywhere in the body, swelling is the first response of natural defense mechanisms, and in most parts of the body such defenses expedite the healing process. In the delicate white and gray matter of the central nervous system, however, which includes tissue within the spinal cord as well as the brain, such swelling often causes further, secondary damage. TBI is, in fact, identified most characteristically by the prominent secondary damage that typically results, the precise cellular mechanisms of which are not yet fully understood, but which are believed to be associated with a disruption of calcium regulation in brain cells following an injury. A proper balance of calcium levels is crucial to mitochondrial function and to proper adenosine triphosphate (ATP) synthesis and metabolism, a disruption in which will result in a series of cascading molecular events that end ultimately in necrosis and apoptosis (programmed cell “suicide”) of neuronal cells. In severe cases of TBI, neuronal shrinkage and gross brain atrophy are visible, precisely for these reasons.
Neurophysiologically, these cellular events are very similar in people who incur moderate to severe TBI and people who suffer from certain other types of neurological maladies. For example, the “ischemic cascade” which occurs after a stroke, and the inflammatory immunological response following spinal cord injury, are both similar in nature to the swelling that may occur after a TBI, depending upon the severity of the particular TBI. Various cellular and molecular mechanisms that characterize any one of these disorders may therefore be relevant to the others.
The problem of cellular excitotoxicity is one such example, during which an excessive release of excitatory neurotransmitters such as glutamate triggers a series of chemical and cellular processes that cause secondary damage to tissue by overexcitement of the nerve cells. In abnormally high amounts, glutamate disrupts calcium metabolism and related enzymatic activity of the proteases, which in turn disrupts mitochondrial oxidation, thereby damaging glial cells via a number of direct and indirect mechanisms. This phenomenon remains an area of widespread research focus in the treatment of various pathologies involving central nervous system tissue, including not only TBI but also stroke, spinal cord injuries and various neurodegenerative diseases.
In TBI, such cascading cellular events may exacerbate hypoxic and ischemic injury and may require urgent neurosurgical intervention to relieve subdural, extradural or intracerebral hemorrhage. Pathologies of this nature do not always manifest immediately but may develop within days or even weeks following a TBI, and therefore many secondary injuries are not detectable on the same day of injury. Cerebral contusions, for example, are not usually identifiable by CT scan until at least the second or third day following an injury. As already described, continued monitoring of the individual is therefore a crucial aspect of TBI treatment.
Focal injuries in the frontal and temporal lobes are most commonly identifiable, due primarily to the shape of the inner surface of the skull along these regions. While intracranial hematomas may be surgically accessed relatively easily, deep intracerebral hemorrhages, by contrast, which may be caused by arterial damage resulting either from focal or diffuse injury, are virtually inaccessible. In general, diffuse brain injury, known technically as diffuse axonal injury or DAI, is visible on CT scans only in 5 to 10% of the most severe cases, and when it is visible at all it is most commonly recognizable either as intraventricular hemorrhage or as multiple punctate subcortical lesions in and around the corpus callosum and the deep white matter. Symptomatically, DAI manifests as altered states of consciousness, although most DAI patients will not yield any supporting evidence of such damage on CT scans. In the event of coma, the depth and duration of the coma will reflect the extent of the injury, while other clinical markers in the absence of coma may include prolonged retrograde and anterograde amnesia. Certain aspects of an injury increase the risk of DAI, such as a high speed of impact.
Unlike stroke patients, people with DAI that was incurred through TBI seem to maintain more active neural repair mechanisms, and therefore often receive a prognosis that may include some improvement and recovery during the first 5 years following their injury. Such recovery is often the result not merely of natural repair mechanisms but also of various built-in compensatory strategies of neuroplasticity.
Medications that are administered to TBI patients include primarily those that are efficacious in reducing inflammation. To counteract the phenomenon of calcium excitotoxicity described above, calcium channel blockers (CCBs), also known as calcium antagonists, are often employed to help reduce the risk of further injury to damaged nerve cells. CCBs are also routinely prescribed in the treatment of high blood pressure, angina and congestive heart failure and therefore may be contraindicated in certain individuals. Intravenous diuretics are also often prescribed for TBI patients to help reduce brain swelling.
CCBs that have been approved for use in the U.S. include nisoldipine (Sular), nifedipine (Adalat, Procardia), nicardipine (Cardene), bepridil (Vascor), isradipine (Dynacirc), nimodipine (Nimotop), felodipine (Plendil), amlodipine (Norvasc), diltiazem (Cardizem), and verapamil (Calan, Isoptin). Side effects of CCBs most commonly include low blood pressure and other expected consequences of dilated arteries, such as flushing, edema of the lower extremities, increased heart rate and increased palpitations. CCBs are contraindicated in people already diagnosed with heart failure since CCBs reduce the ability of the heart to pump blood. Additional side effects may include flu-like symptoms, fever, nausea, vomiting, headaches, dizziness, nervousness, depression, insomnia, impotence, blurred vision and difficulty breathing. Bepridil in particular slows the ability of cardiac muscle to recover electrically and to prepare for the next contraction, and may therefore cause arrhythmias (abnormal heart rhythm) and should not be taken with other drugs that have similar mechanisms of action, such as quinidine (Quinaglute, Duraquin, Quinidex), procainamide (Procan-SR, Pronestyl), disopyramide (Norpace), flecainide (Tambocor), and tricyclic antidepressants such as amitriptyline (Elavil). Bepridil also increases levels of digoxin (Lanoxin) in the blood and may increase the risk of digoxin toxicity. Bepridil is secreted into breast milk and is also known to cross the placenta and therefore should not be taken by women who are pregnant or nursing. Patients with low serum concentrations of potassium or magnesium, and patients with the electrocardiographic abnormality known as QT prolongation, are at the greatest risk of developing serious arrhythmias from bepridil. Diltiazem has been known to cause elevated liver enzymes.
Recent research has suggested that the drug rivastigmine may improve memory loss in some patients suffering with TBI, according to studies conducted at the New York School of Medicine. Rather than being a calcium channel blocker, rivastigmine falls into the category of medications known as cholinesterase inhibitors, and as such is frequently prescribed for the treatment of Alzheimer’s disease. In clinical trials led by Jonathan Silver, M.D., researchers at the New York School of Medicine have discovered that rivastigmine helps patients who have suffered moderate to severe memory loss from TBI, although the drug does not appear to improve memory in people who have suffered mild TBI. The beneficial effects of this medication are believed to become apparent only when relevant brain regions have incurred a significant depletion of cholinergic activity, which results in the functional impairment of memory and attention that is often seen both in Alzheimer’s disease and in certain types of TBI. Rivastigmine is generally well tolerated with relatively few side effects, as approximately half of all patients who receive the drug complain of nausea, one-third complain of vomiting, and 10% complain of dizziness. Upper respiratory tract infection and headache are also occasionally seen, and approximately 15% of patients choose to discontinue rivastigmine due to such side effects.
It should be noted, however, that anyone who has incurred injury to the brain is unusually vulnerable to adverse effects from medication, as pointed out on the website of the National Institute of Neurological Disorders and Stroke (NINDS), a division of the National Institutes of Health (NIH):
“Great care must be taken in prescribing medications because TBI patients are more susceptible to side effects and may react adversely to some pharmacological agents.” (From www.ninds.nih.gov).
Whenever brain swelling is too severe to be treated by medication alone, various types of surgery may be warranted. In the absence of hematomas or contusions, a section of the parietal bone on top of the skull may be temporarily removed in order to allow the brain to swell without increasing the risk of further neurological damage from increased intracranial pressure. Neurologists performed this procedure on the ABC News anchor, Bob Woodruff, when he incurred severe TBI from the blast of an IED (improvised explosive device) while reporting from Baghdad in 2006.
Research:
Much of what is known today about the normal, healthy brain is the result of people who incurred TBI and who consequently exhibited dramatic changes in behavior and ability as a result of their injuries. The website of NINDS describes one such historic case:
“Perhaps the most famous TBI patient in the history of medicine was Phineas Gage. In 1848, Gage was a 25-year-old railway construction foreman working on the Rutland and Burlington Railroad in Vermont. In the 19th century, little was understood about the brain and even less was known about how to treat injury to it. Most serious injuries to the brain resulted in death due to bleeding or infection. Gage was working with explosive powder and a packing rod, called a tamping iron, when a spark caused an explosion that propelled the 3-foot long, pointed rod through his head. It penetrated his skull at the top of his head, passed through his brain, and exited the skull by his temple. Amazingly, he survived the accident with the help of physician John Harlow who treated Gage for 73 days. Before the accident Gage was a quiet, mild-mannered man; after his injuries he became an obscene, obstinate, self-absorbed man. He continued to suffer personality and behavioral problems until his death in 1861. Today, we understand a great deal more about the healthy brain and its response to trauma, although science still has much to learn about how to reverse damage resulting from head injuries.” (From www.ninds.nih.gov).
In addition to being 3 feet in length, the rod was also measured at 1.25 inches in diameter and it had a weight of 13 pounds. One can only imagine the speed at which such a rod must have been propelled, and the force that it must have carried, in order to enter and exit the human skull. Immediately after the accident, awake and alert, sitting upright in a chair, Phineas Gage is reported to have greeted his physician with the words, “Doctor, here is business enough for you.” The personality disorders which developed shortly thereafter would plague him for the remainder of his life, and shortly before his death at the age of 37 in 1860 (not 1861, as often reported), Phineas Gage also suffered from epileptic seizures.
The frontal lobes, which were damaged in the case of Phineas Gage, are now commonly recognized as being associated with aspects of personality and social interaction, although such a fact was not known prior to his famous accident. Many neurologists have since written extensively on the topic of Gage’s injuries, and Gage is now acknowledged to have played an important role in the history of neuroscience. Dr. Antonio Damasio, among others, has stated that Gage’s accident marked “the historical beginnings of the study of the biological basis of behavior.” Indeed, Phineas Gage sparked a “paradigm shift” in medicine, radically changing the ways in which the brain was understood at that time, as his behavior offered the first tangible evidence of the compartmentalization of the brain, of the neuroanatomical basis of personality, and of neuroanatomical specificity of function. Without such an understanding of the relationship between behavior and anatomy, the modern medical field of neuroscience could not exist. Gage’s skull, and the rod that brought him to public attention by penetrating it, are now part of the permanent exhibition of the Warren Anatomical Museum at Harvard Medical School in Boston, Massachusetts.
Today it is understood that the cerebral cortex in general and the frontal lobes in particular are richly supplied with dopamine-sensitive neurons. Dopamine plays a fundamental role in those cognitive skills known as “executive functions”, such as the ability to recognize causality, and the ability to anticipate future consequences of one’s behavior. The frontal lobes are also involved in long-term memory, planning, motivation, and the perception of pleasure. The dysregulation of pathways within the dopamine system is known to be associated with a variety of psychological disorders, most typically with schizophrenia. The frontal lobes of all vertebrates share certain similarities, but in the human brain these regions are known to play an especially important role in judgement, in the control of spontaneity and impulse, and in sexual behavior. Damage to the frontal lobes therefore often results in a dysfunction of these corresponding cognitive and behavioral processes. For example, researchers have discovered a neuroanatomical correlate for cognitive maturity, which may be identified by increased myelination in the frontal lobes, and which typically occurs at some time in the late teenage years, marking the transition to early adulthood. A number of disorders have been associated with poor myelination in the frontal lobes, which disrupts communication with the rest of the brain, particularly in those connections responsible for the selective processing of sensory information that arrives from the thalamus. In modern TBIs, the frontal lobes are among the most commonly injured areas of the brain, especially in automobile accidents, and abnormal behavior resulting from a disruption of the activity in these neurological regions is therefore common in mild to moderate TBI. Before Phineas Gage entered the medical literature, however, such associations between neurological processes and neuroanatomical sites had not yet been made. As a “case study”, Phineas Gage shed light not only on the nature of physical injuries to the brain but also on a number of psychological and psychiatric disorders.
Similarly, the neurological functions associated with “Wernicke’s area” and “Broca’s area” were discovered as the result of damage to these regions of the brain, which results in a loss of the corresponding cognitive skills. Both regions are associated with language processing and are connected to each other by the neural pathway known as the arcuate fasciculus. Wernicke’s area, which is part of the cortex of the brain in the posterior region of the left hemisphere of the superior temporal lobe, plays an important role in the comprehension of speech. Damage to this area causes a type of aphasia known as Wernicke’s aphasia or receptive aphasia, in which individuals maintain the ability to speak but the meaning of their speech is nonsensical. The region is named after Karl Wernicke, a 19th century German neurologist and psychiatrist who discovered the associated aphasia in 1874. Broca’s area is closer to the front of the brain, in the inferior frontal gyrus of the frontal lobe of the cortex, and is named after the 19th century French physician Pierre Paul Broca, who discovered that damage to this area of the brain results in the dysfunction of language processing and speech comprehension, a malady which today is known as Broca’s aphasia, expressive aphasia, motor aphasia and nonfluent aphasia.
Currently in the United States, most research on neurological disorders in general, and on TBI in particular, is funded by the National Institute of Neurological Disorders and Stroke (NINDS), a division of the National Institutes of Health (NIH). Such funding supports TBI research through grants to medical institutions throughout the country, as well as TBI research that is conducted within the laboratories of NIH itself. TBI research emphasizes the development of new pharmacological strategies and interventions that may limit both primary and secondary brain damage. The development of novel chemical and molecular therapies that will improve the long-term recovery of motor and cognitive function is also an area of research focus. As pointed out above by the World Health Organization, however, the best, easiest, least expensive and most effective measures would be preventative rather than palliative. Nevertheless, research progresses in the further elucidation of the neurological mechanisms that regulate various states of health and disease, some of which are described herein.
Neuroscientists at UCLA have identified lactate as a possible “replacement fuel” for glucose in the brain in the immediate hours following TBI. The brain is not normally able to utilize glucose under such conditions for reasons which still remain unknown yet which are believed to be related either to local dysfunction or to the diversion of glucose to other metabolic pathways for alternate uses. Although lactate is considered to be an undesirable byproduct of metabolism, previous studies have indicated a strong uptake of lactate by the brain after an injury, according to Drs. Neil Martin, professor and chief of neurosurgery at the David Geffen School of Medicine at UCLA, and Thomas Glenn, a UCLA adjunct assistant professor in the department of neurosurgery. Their studies have revealed that, especially during the first 12 to 48 hours following traumatic injury, the brain consumes more lactate than at any other time. The UCLA team of researchers labeled lactate with C13, a non-radioactive and stable isotope, which they then mixed with an intravenous solution that was administered to patients following TBI. Blood levels of lactate labeled with this marker were then measured in the blood flowing into and out of the brain. Unexpectedly high levels of carbon dioxide were found, indicating that the lactate had indeed been consumed, since carbon dioxide is a natural metabolic byproduct of lactate. As Dr. Glenn announced,
“Our preliminary tracer-based studies demonstrated the novel and unexpected finding of both lactate uptake and its utilization as fuel in traumatic brain injury. These results have led us to challenge the current conventional wisdom concerning the type of fuel the brain uses after injury to generate the energy for recovery.”
As Dr. Glenn also points out, glucose requires more than 10 enzymatic steps before it generates energy, while lactate requires much fewer steps, making it a faster and more efficient source of fuel under the particular circumstances that exist following TBI. The research was supported by the National Institute for Neurological Diseases and Stroke (NINDS), a division of the National Institutes of Health (NIH), in collaboration with Dr. George Brooks of the department of integrative biology at the University of California at Berkeley.
Researchers at the University of Florida Brain Institute have established a human brain tissue bank to support studies of traumatic brain injury. The bank, under the direction of Dr. Thomas Eskin, professor of pathology, will store samples of brain tissue from victims of brain injury and will serve as a state and national resource for the development of medical and rehabilitative therapies for patients. The bank is the first of its kind and is uniquely dedicated to traumatic brain injuries. It uses a magnetic imaging system which incorporates an 11.7-tesla imaging magnet for the analysis of tissue. According to Dr. Ronald Hayes, professor of neuroscience and neurosurgery, and director of the UF’s Center for Traumatic Brain Injury Studies,
“Because so little is understood about the mechanisms by which brain cells are damaged or killed after head injury, there are no standard FDA-approved treatments. When an injured person seeks medical care, there is no assurance that the treatment given at one hospital will remotely resemble what would be done at another hospital. Having a bank of tissue from people with brain injuries will greatly aid our efforts to gain information that can be applied in patient care, which is our real goal. Recent findings, through post-mortem analysis of brain tissue from patients with brain injuries, indicate many of them have the same kinds of brain lesions such as the amyloid plaques found in patients with Alzheimer’s. Therefore, just as banks of tissue from Alzheimer’s patients have led to greater understanding of this disease, our new tissue bank will help scientists learn more about traumatic brain injury.”
According to Dr. William Luttge, executive director of UF's Brain Institute, the new brain bank is “indispensable” to an understanding of the cellular, molecular and genetic processes that are involved in TBI. As Dr. Luttge describes,
“To speed the process of getting this information, we plan to share the bank and to share what we learn with other scientists, health-care professionals and consumers. We’re widening the scope of our work through cooperation with the UF Genetics Institute, the Brain Injury Association of Florida, the state’s Brain and Spinal Cord Injury Program, the national Brain Injury Association, the North Florida/South Georgia Veterans Affairs Health System, including a VA-funded Brain Rehabilitation Center in Gainesville, and the Brooks Center for Rehabilitative Studies, which has clinical research programs under way in Gainesville and Jacksonville.”
The researchers have designed methods for tracking the sequence by which specific genes are activated during and after TBI. Animal models are also being studied for the role of novel drugs that mimic estrogen and which have been shown to offer some protection against neuronal degeneration.
Also at the University of Florida Brain Institute, Dr. Hayes and his researchers have discovered that the “biochemical storm” that follows TBI lasts much longer than previously believed and may constitute a necessary and important stage of the healing process. Animal models have indicated that TBI triggers a flood of enzymes which consume important structural proteins in the brain for as long as one month after the injury is sustained. As Dr. Hayes explains,
“Emergency room medical personnel often talk about a golden hour, that if you don’t get a person into treatment within the first hour or so after an injury, a lot of damage has been done to the patient. With traumatic brain injury, the thought has been that treatment within the first two days is critical.”
But recent data challenge such beliefs. Dr. Hayes adds,
“In our studies, we’ve found that a biochemical storm that is initiated with an injury continues for at least a month. The implication is that we may need to treat these patients over a much longer period than anyone had ever imagined. The widely varying types of physical and mental impairments associated with such injuries make it tougher to design treatments that will boost chances for recovery.”
The calpain enzymes are already known to play a particularly important role in this “biochemical storm”, and this research investigates the mechanisms by which excessive calcium triggers the activation of calpains. Extensive atrophy and shrinkage of the brain are visible after severe TBI, which results from the death of neuronal cells, and which is caused to a large degree by the action of the calpains. Now, however, this action is believed to be a necessary part of the “resculpting” mechanisms that are involved in the healing process. According to Dr. Kevin Wang, a senior research associate at Parke-Davis Pharmaceutical Research who is conducting laboratory experiments on blocking the action of calpains,
“This is one of very few research efforts that open up a potential window for treatment in which we might be able to suppress the harmful activity of calpains while allowing repair to occur.”
As Dr. Hayes explains,
“In the past several years, there have been a large number of clinical trials testing treatments for brain injury that have shown no effect. Researchers thought they had an effective therapy, but when they tried it, the people didn’t get better. One reason may be that they didn’t treat the patient long enough because the biochemical storm lasted longer than two days. We may have to completely redefine our approach to therapy, because if you try to get in there too early and for too brief a time with a treatment, you might not block the damage that lies ahead. But if you give a treatment for too long, you might block some of the self-repair that will make the patient better. Understanding these relationships is critical, and our research is a necessary first step in this effort.”
The study was conducted in collaboration with the University of Texas School of Medicine.
Scientists at Melbourne’s Howard Florey Institute have discovered that the BP5 protein increases in brain cells after TBI, and may prevent cellular neuronal death. As Dr. Seong-Seng Tan explains,
“BP5’s pattern of expression indicates that it allows neurons to survive in a stressed environment. We have tested this hypothesis in mice by expressing BP5 in stressed neurons and this proof-of-principle experiment showed that BP5 can prevent neurons from undergoing cell death. BP5 works by using the cell’s waste disposal system to flush away toxic and damaged proteins produced after injury, which appears to tip the balance toward nerve cell survival, instead of death.”
Prof Tan and colleagues are studying the mechanisms by which this protein may be controlled to prevent brain cells from dying. As Dr. Tan explains, their ultimate goal is the development of a drug with similar properties:
“Now our challenge is to understand how BP5 performs its neuron-saving function and develop drugs that can do the same thing. Ultimately, we want to deliver the drug to patients suffering brain injury from stroke or trauma, to save as many neurons as possible. Such a drug would limit damage to the brain after the injury, as well as in the subsequent few days when injured nerves release ‘suicide factors’ that cause surrounding, healthy neurons to die en masse. This treatment to prevent brain damage has wide applications and could be given to car accident and assault victims, people undergoing radiotherapy for brain tumors, premature babies that need to be induced, and stroke patients. While we still have a long way to go before such a drug will be available, this research is a promising step forward in the development of an effective treatment for traumatic brain injury.”
Their findings were published in the Journal of Neuroscience.
Along with many other countries, Australia has formally recognized that “finding an effective treatment for brain injury is urgent” and the Victorian State Government has committed $63 million to boost research in the treatment of brain and spinal cord injuries. Additional funding for this study was provided by the Myer Family Foundation, the Victorian Trauma Foundation, and the Australian National Health and Medical Research Council in collaboration with the Alfred Trauma Research Centre, La Trobe University, the Walter and Eliza Hall Research Institute of Medical Research and The Hanson Centre in Adelaide.
Researchers at the University of Kentucky have been studying the ability of creatine to protect the brain against traumatic injury. The studies were led by Dr. Stephen Scheff, a professor at the University of Kentucky Sanders-Brown Center on Aging and the UK College of Medicine Department of Anatomy and Neurobiology. One of the amino acids, creatine is produced naturally in the body in the liver, kidney and pancreas and is used by the body for storing energy. Creatine is also popular as a dietary supplement among athletes for increasing muscle mass, strength, and the recovery time of muscles between bursts of activity. Athletes are unusually prone to TBI, especially those participating in contact sports that routinely involve blows to the head, such as football, hockey, wrestling and boxing, which have the highest rates of TBIs, most of which are concussions that often result in subdural hematomas (bleeding under a membrane surrounding the brain). Dr. Scheff has demonstrated that brain damage in mice was reduced 21% and 36% when creatine was administered three and five days prior to the TBI, respectively. When the rats were fed a diet supplemented with creatine for four weeks before TBI, brain damage was reduced by 50%. Creatine which is administered after the injury, however, is not beneficial. According to Dr. Scheff,
“Our data show that creatine supplementation protects against secondary damage associated with TBI by inhibiting the calcium-induced activation of a protein in the mitochondrial membrane, which preserves proper function of the mitochondria. The damage also is reduced because creatine acts to maintain appropriate amounts of ATP in brain cells. This strongly suggests that athletes may be gaining a neuroprotective benefit inadvertently by chronically supplementing their diet with creatine.
The results were published in the Annals of Neurology.
Stem Cells:
As already described, conventional medical therapies for TBI emphasize the pharmacological management of symptoms in combination with rehabilitation. Stem cell therapy, however, falls into the new category of regenerative medicine, which offers a promising and novel treatment for TBI. In fact, animal models and human clinical trials have already shown very positive results in the treatment of TBI by adult stem cells.
TBI patients are prime candidates for stem cell therapy, due to the characteristics of neurological tissue and its innate potential for regeneration after trauma. It is now commonly known that specialized neural stem cells exist throughout life in adult neural tissue where they continually develop, as needed, into different types of cells within the nervous system. Such differentiation includes neurotransmitter-producing neurons, dopamine-producing cells and oligodendrocytes, which are responsible for the formation of myelin within the central nervous system. Numerous studies have demonstrated methods by which these neural stem cells may be stimulated to regenerate tissue that has been damaged from TBI. Additional studies with animal models have shown that stem cells derived from bone marrow are also capable of developing into neurons, and such transplanted stem cells have shown the capacity to migrate extensively through the blood-brain barrier into the region of the cerebral cortex, the olfactory bulb, the hippocampus and the cerebellum following TBI. Stem cells derived from bone marrow were also found to grow long fibers while producing a protein that is indicative of cellular activity, indicating that stem cells derived from bone marrow are fully capable of responding to the specialized neurological environment, and to adapting accordingly.
At the University of Texas Medical School at Houston, in collaboration with the Memorial Hermann Children’s Hospital, researchers are designing a clinical trial for the treatment of children suffering from TBI. The children will be treated with stem cells derived from their own bone marrow, which offers a promising form of treatment. According to Dr. Charles Cox, professor of pediatric surgery and trauma,
“Currently there is no reparative treatment for traumatic brain injury. All we can do now is try to prevent secondary damage by relieving pressure on the brain caused by the initial injury.”
TBI is the main cause of death and disability among children, as studies have shown that 15 to 25% of all children who suffer severe TBI die, and survivors of even moderate TBI often suffer lifelong disability. Approved by the U.S. Food and Drug Administration (FDA) and the university’s Committee for the Protection of Human Subjects, the clinical trial is an extension of previous laboratory and animal research which has indicated that bone-marrow-derived stem cells automatically migrate to an injured area of the brain where they differentiate into new neurons and supporting cells that induce the repair and regeneration of damaged tissue. According to Dr. James Baumgartner, associate professor of pediatric neurosurgery and co-principal investigator of the trial,
“This would be an absolutely novel treatment, the first ever with potential to repair a traumatically damaged brain.”
During Phase I of the clinical trial, bone marrow extracted from each child’s hip will be processed into two types of progenitor stem cells, namely, mesenchymal stem cells and hematopoietic stem cells, which will then be transplanted back into each patient within 48 hours of injury. Mesenchymal stem cells differentiate into bone, cartilage, fat cells and neurons, while hematopoietic stem cells develop into the cells that are necessary for the formation of blood.
The project is funded by the Memorial Hermann Foundation, internal research funds from The Office of the President at The University of Texas Health Science Center at Houston, the National Institute of Child Health and Development and the National Heart, Lung, and Blood Institute, the latter of which are both divisions within the National Institutes of Health.
The University of Pennsylvania houses the nation’s first hospital (built in 1751), the first medical school (established in 1765), and the first university teaching hospital (1874). Now scientists at the University of Pennsylvania School of Medicine are leading the field of neural stem cell research in the treatment of TBI. Led by Dr. Tracy McIntosh, professor of neurosurgery at the University of Pennsylvania, researchers have demonstrated in animal models that neural stem cells which are cultured in the laboratory and then transplanted into injured brains will proliferate and improve brain function. According to Dr. McIntosh,
“Transplantation of neural stem cells in mice three days after brain injury promotes the improvement of specific components of motor function. More importantly, these stem cells respond to signals and create replacement cells: both neurons, which transmit nerve signals, and glial cells, which serve many essential supportive roles in the nervous system.”
Neural stem cells require signals from the nervous system to trigger their differentiation into neural tissue. Dr. McIntosh and his colleagues used cells that were cloned from mouse progenitor cells and grown in culture. As Dr. McIntosh explains,
“If you put these cells into normal newborn mice, they would behave exactly like normal cells. They create different neural cell types and they don’t reproduce tumorigenically. In humans, the use of similar neural stem cells would avoid the ethical dilemmas posed by fetal stem cells and the limitations seen in cultures of cloned neurons.”
The transplantation of autologous neural stem cells offers an effective therapeutic intervention in the treatment of several central nervous system diseases such as Parkinson’s and Huntington’s diseases, as well as ischemic brain injury and spinal cord injury. The research was performed in collaboration with Harvard Medical School and the University of Cologne in Germany. The findings were published in the journal Neurosurgery.
In a separate study conducted by Dr. McIntosh, in collaboration with researchers in Sweden and Spain, animal models revealed new information about the role of the enzyme known as “nerve growth factor” (NGF) in the regeneration of neural tissue. Dr. McIntosh used two different types of cultures of the same progenitor cells, one of which had not been altered (known as “naive” cells), while the other had been transfected with a gene to produce NGF. Although both types of cells demonstrated a strong capacity for regenerating brain tissue and function, those cells that had been transfected to produced the NGF were also found to protect against further damage throughout the brain. Such findings would seem to indicate that NGF induces brain cells to produce more antioxidant enzymes which scavenge the free radicals that are involved in triggering apoptosis, which causes much of the secondary damage that results from TBI in the days and weeks following the injury.
At the University of Minnesota Medical School, researchers have discovered a new population of primitive stem cells in human umbilical cord blood, which is already known to contain a rich supply of the hematopoietic stem cells that differentiate into blood cells. The newly discovered primitive stem cells, however, show properties of greater pluripotency and were successful in improving neurological function after traumatic injury in animal models. Not only did the stem cells regenerate damaged neurons, but they also induced the reorganization of the neurons, thereby contributing to the restoration of function. According to Dr. Walter Low, professor of neurosurgery at the Stem Cell Institute at the University of Minnesota,
“We are excited by this discovery because it provides additional insight into how stem cells can restore function in the brain after injury.”
Findings were published in the journal Stem Cells and Development.
In a similar study, researchers at the Henry Ford Health Sciences Center in Detroit, Michigan, in collaboration with researchers at the University of South Florida in Tampa, have discovered that intravenous injections of cells from human umbilical cord blood improve the neurological and motor function of rats recovering from severe TBI. Their findings were reported in a special issue of the journal Cell Transplantation which is focused on new techniques in neural transplantation and brain repair, featuring several articles that explore the unique therapeutic features of human umbilical cord blood (HUCB) cells as an alternative to embryonic stem cells. The current emphasis of such research is on therapeutic applications to neurological disorders such as Parkinson’s disease, stroke, spinal cord injury, and TBI. Among the advantageous characteristics of umbilical cord blood is the fact that it is rich in trophic factors and cytokines, both of which are known to play integral roles in the regeneration of damaged tissue. Cytokines are a group of signaling protein and peptide compounds which bind to specific cell-surface receptors and which regulate the communication between cells as well as the expression of genes and transcription factors. The chemical signals of cytokines are similar to those of hormones and neurotransmitters, and cytokines play a vital role in numerous physiological processes, especially in immunological responses. Trophic factors are also necessary for the efficacy of stem cells, and in some cases it has been found that stem cells alone do not regenerate damaged tissue, but instead must be combined with the proper amounts of the right types of trophic factors. There is increasing evidence to indicate that umbilical cord blood is highly effective at regeneration, precisely because it already contains the necessary trophic factors, cytokines and other supporting cells that work together with the stem cells. These studies were led by Dr. Paul Sanberg, director of the Center for Aging and Brain Repair at the University of South Florida, and Dr. Juan Sanchez-Ramos, professor of neurology and director of stem cell research at the USF Center for Aging and Brain Repair. As Dr. Sanchez-Ramos explains,
“The results certainly raise some interesting questions about the mechanisms of recovery. It appears that the trophic factors and cytokines from cord blood help promote the brain’s self-generated repair of damaged tissue.”
According to Dr. Michael Chopp, a neuroscientist at HFHSC,
“These findings were consistent with the therapeutic benefit we obtained using cord blood to treat stroke in rats. Cord blood is readily available, noncontroversial and produces therapeutic benefit by stimulating endogenous restorative responses in the injured brain.”
Migrating to the regions of brain injury, some of the cord blood cells were found to differentiate into immature neurons and astrocytes, while other cells were integrated into the brain’s blood vessels. Results of the study were published in the journal Stroke.
In a separate study conducted by Dr. Tanja Zigova, a neuroscientist at the University of South Florida, researchers found that some undifferentiated HUCB cells that were transplanted into the developing brains of neonatal rats do in fact form nerve cells which express certain proteins that are found only in neurons and glial cells. The findings suggest that some of the transplanted HUCB cells differentiate into neural cells in response to genetic cues from the developing brain. Findings of the study were reported in the journal Cell Transplantation.
Various studies with animal models have corroborated the growing body of evidence indicating that stem cells which are already present in the adult brain may be stimulated by growth factors to develop into nerve cells, thereby replacing damaged tissue, without the need for the transplantation of stem cells from an external source. Such a therapy is particularly applicable to patients suffering from central nervous system damage which includes TBI, spinal cord injuries, stroke, and diseases such as Parkinson’s and Alzheimer’s, all of which are marked by the degeneration of nerve cells.
In a study led by Dr. James Fallon, professor of anatomy and neurobiology at the University of California at Irvine, in collaboration with Stem Cell Pharmaceuticals, researchers found that the injection of the human protein known as transforming growth factor-alpha (TGF-alpha, also known as GFA-50) into damaged areas of the brain stimulates the multiplication of stem cells that are already present in the brain. The stem cells were then shown to migrate and differentiate as needed into normal, fully developed nerves which restored motor function in rats. According to Dr. Falon,
“This study is the first to show that stem cells can be induced naturally in large enough numbers and drawn to specific sites of damage, restoring function and replacing damaged cells in the brain. The stem cells are already in the brain and other organs in small numbers. They can be stimulated in the brain to develop by a growth factor without the need for transplanting stem cells, embryonic tissue or altered cells from outside. Instead, we've just stimulated cells that are already there.”
The findings indicate that the process of stem-cell stimulation is a naturally occurring, ongoing event that replaces old or damaged cells in the brain whenever and wherever necessary. Large brain injuries, however, such as those commonly incurred by TBI or a stroke or a degenerative disease such as Alzheimer’s, require more regeneration than that which is possible by natural repair mechanisms. Natural growth factors such as TGF-alpha offer the added stimulation that is needed. As Dr. Fallon explains,
“This finding shows that it is possible to stimulate and control the growth, movement and development of large numbers of stem cells to repair brain injury. We know that there are receptors for TGF-alpha in nervous system stem cells. When damaged, enough growth factor can stimulate these cells to reproduce and draw them to damaged areas, resulting in new nerve tissue. While a simple administration of TGF-alpha worked significantly with rats, we still need to find out if other interacting factors, like injury signals in the nervous system, regulate the growth of stem cells and can be used to help restore function.”
The research was supported by the American Parkinson’s Disease Foundation, the American Foundation for Aging Research, and the College of Medicine Research Associates at the University of California at Irvine.
Scientists at the University of Texas Southwestern Medical Center in Dallas are also studying the cellular mechanisms by which the brain remodels itself after traumatic injury. It is already known that adult neural stem cells, which are specialized precursor cells, develop into neurons and astrocytes which are then utilized in the remodeling of neurological tissue. Studies with animal models have now revealed that the proliferation of these stem cells in the brain continues at a rapid pace and for a much longer period of time than previously expected, not only at the site of injury but also in distant regions. The study was led by Dr. Steven G. Kernie, assistant professor of pediatrics, in collaboration with Dr. Luis F. Parada, director of the Center for Developmental Biology and the Kent Waldrep Foundation Center for Basic Research on Nerve Growth and Regeneration. The ability to manipulate the expression of stem cell regulators could therefore accelerate or prolong the regeneration of neurons. As Dr. Kernie describes,
“We wanted to answer some basic questions about the persistence of neural stem cells proliferating into adulthood. Our study of traumatic brain injuries in adult mice found that nature’s own restorative powers are more extensive than previously thought. Perhaps even more exciting, we found that the regenerative powers are widespread, not just in the immediate area of the injury. Though using mice, our study raises the possibility that similar brain-remodeling processes may occur in humans. As one might expect, the neural repairs or remodeling were most prominent in and near the injury for the short term, but the study also showed long-term remodeling for injured mice at a rate five times greater than expected in the distant injury-affected areas.”
The study was funded by the Christopher Reeve Paralysis Foundation Consortium on Spinal Cord Injury, the Kent Waldrep Foundation Center for Basic Research on Nerve Growth and Regeneration, and the National Institutes of Health.
Adult stem cells offer the same pluripotency of embryonic stem cells, but without the danger of forming teratomas (tumors), which remains a serious risk from embryonic stem cells. It is neither necessary nor desirable to use embryonic stem cells in the treatment of traumatic brain injuries or other disorders, since a growing number of studies are showing increasing success with adult stem cells. In fact, the only stem cell studies that have ever shown success in the treatment of any human disease have involved adult stem cells, since no study has ever been conducted in which a disease was successfully treated with human embryonic stem cells, although this fact is not generally reported by the media. Ever since researchers first isolated human embryonic stem cells in 1998, there has never been a successful treatment for any human disease in a human being by embryonic stem cells. Embryonic stem cells have in fact proven to be very problematic, whereas bone marrow and cord blood stem cells, by contrast, have been safely used by doctors for over 40 years. Human umbilical cord blood in particular is now known to be a rich source of growth factors and cytokines, both of which are necessary for the regeneration of tissue, and stem cells that are derived from human umbilical cord blood have been shown to be more effective at tissue regeneration than are other types of stem cells that lack such additional factors. Ethics and politics aside, adult stem cells are highly preferable to embryonic stem cells purely for scientific reasons. (Please see the section entitled “Stem Cell Primer” for an explanation of the different properties of the different types of stem cells).
Adult stem cell therapy offers a safe and potentially effective treatment of a very severe type of injury which previously has been considered irreversible.
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