Inflammation thought to cause long-term problems after traumatic brain injury

A recent study claims that inflammation causes long-term problems, such as chronic degenerative problems, after a traumatic brain injury.

A new paper by researchers at the University of Maryland School of Medicine (UM SOM) argues that there is a widespread misunderstanding about the true nature of traumatic brain injury and how it causes chronic degenerative problems.

In a perspective article published in the latest issue ofNeurotherapeutics, the two authors -- Alan Faden, MD, a neurologist and professor of anesthesiology, and David Loane, PhD, an assistant professor of anesthesiology, propose that chronic brain damage and neuropsychiatric problems after trauma are to a large degree caused by long-term inflammation in the brain. In their view, this inflammation is a key culprit behind the myriad symptoms that have been linked with traumatic brain injury and mild traumatic brain injury, including brain atrophy, depression and cognitive decline.

Dr. Faden and Dr. Loane also say that there has been too much emphasis on a specific diagnosis known as chronic traumatic encephalopathy (CTE), the set of symptoms and pathology that has been found in some former professional football players. They argue that this may deflect focus from other mechanisms, which may be more important and treatable. They say that although chronic traumatic encephalopathy is a serious problem, relatively few people have been diagnosed with this condition. Instead, they contend, researchers and journalists should focus more on the fact that even repeated concussive impacts or mild traumatic brain injury may trigger chronic brain inflammation that can persist for years and cause lasting damage.

"Brain inflammation is a key issue, and it has been under-emphasized," says Dr. Faden. "Recent brain imaging studies, including those in former professional football players, indicate that persistent brain inflammation after a single moderate head injury or repeated milder traumatic brain injury may be very common, and may contribute to cognitive problems. In addition, larger studies indicate that brain inflammation persists for many months or years in many people with traumatic brain injury."

The paper also points out that chronic brain inflammation related to traumatic brain injury may be treatable. Dr. Faden and Dr. Loane say recent research shows that some experimental drugs, as well as carefully controlled exercise programs, can block brain inflammation caused by traumatic brain injury. They maintain that these avenues should be pursued vigorously.

The paper follows two recent groundbreaking publications by Dr. Faden, which appeared several months ago. The papers, which looked at animal models of traumatic brain injury, examined the mechanisms by which even mild brain injuries can cause sustained cognitive and psychiatric problems. This work elucidated how this process occurs, and appeared in of the Journal of Neuroscience and the Journal of Cerebral Blood Flow and Metabolism.

"These studies show how repeated mild injuries can lead to the same kinds of injuries that occur after a single moderate or severe traumatic brain injury," said Dr. Faden. "The brain inflammation and loss of brain cells look remarkably similar in both cases. Now that we understand more about the mechanism behind the damage, we can develop strategies to prevent or minimize the problems."

For the paper in the Journal of Cerebral Blood Flow and Metabolism, Dr. Faden and his colleagues found that the brains of animals with mild traumatic brain injury showed substantial loss of neurons, as well as increases in microglia, a kind of inflammatory immune cell active in the brain. These changes lasted for several weeks after the injury. The researchers also found that repeated mild traumatic brain injury, and the resulting inflammation, were associated with decreased function in a part of the brain called the hippocampus, which is crucial for memory.

In the other paper, in the Journal of Neuropathology and Experimental Neurology, which included Dr. Loane as the lead author, the scientists found that traumatic brain injury triggers specific long-term molecular changes that causes increased inflammation lasting up to a year and leads to the death of brain neurons and cognitive loss. "Traumatic brain injury is a major social problem, in athletics, the military and elsewhere," said Dean E. Albert Reece, MD, PhD, MBA, who is vice president for Medical Affairs, University of Maryland, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean of the School of Medicine. "This work by Dr. Faden and his colleagues helps illuminate more about the causes of traumatic brain injury, and possible treatments."

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How sleep apnea affects hearing

This article discusses how hearing is affected by sleep apnea.

Sleep apnea may not only affect the quality of your sleep. New research suggests that the sleep disorder may be linked to hearing loss as well.

The study found that sleep apnea was associated with hearing impairment at both high and low frequencies. That finding held true even after the researchers adjusted the data for other possible causes of hearing loss.

These findings give further support to the idea that sleep apnea likely doesn't occur in isolation. Instead, it may be a sign of other underlying health conditions, the researchers said.

"Sleep apnea is more of a systemic and chronic disease than just something that happens when you're sleeping," said one of the study's authors, Dr. Neomi Shah, an associate director of the pulmonary sleep lab at Montefiore Medical Center in New York City.

"It probably affects multiple different organs, so I would probably urge we start thinking about sleep apnea as more like a chronic disease with vascular and inflammatory issues," Shah added.

Sleep apnea is a common disorder that affects about 18 million Americans, according to the National Sleep Foundation. Typically signaled by snoring with periodic gasping or "snorting" noises, sleep apnea interrupts sleep and can cause excessive daytime fatigue and other symptoms. The condition also has been associated with generalized inflammation, cardiovascular and endocrine problems.

What might the connection be between sleep apnea and hearing loss? It might be a combination of factors that cause inflammation and abnormal functioning in the blood vessels, according to Shah. "The ear is prone to this kind of injury," explained Shah.

The study tapped data from almost 14,000 U.S. participants in the Hispanic Community Health Study/Study of Latinos. About 53 percent were women and on average the subjects were 41 years old. All completed in-home sleep studies and audiometric (hearing) testing.

About 10 percent of the study volunteers had sleep apnea. Around 30 percent had some form of hearing impairment, according to the study.

The researchers took into account age, gender, Hispanic/Latino backgrounds and health-related issues such as high blood pressure, diabetes, fat levels in the blood, cigarette and alcohol use, history of hearing loss or snoring, and noise exposure.

People in the study were more likely to have hearing impairment if they were of Cuban and Puerto Rican backgrounds, had a higher body mass index (an indication of being overweight), were people who snored, or had been diagnosed as having sleep apnea.

The study authors found that sleep apnea was associated with a 31 percent increase in high frequency hearing impairment and a 90 percent increase in low frequency hearing impairment. Sleep apnea was also linked to a 38 percent increase in both high and low frequency hearing loss. Speech tends to fall in the low frequency range, according to Shah.

The research is slated to be presented May 20 at the American Thoracic Society annual meeting in San Diego, Calif. Because the study has not yet been published in a peer-reviewed journal, the data and conclusions should be viewed as preliminary.

Some experts urged caution in interpreting the results of the study, however.

"The number one thing I always say is, correlation is not causation; it doesn't mean if you have sleep apnea you're at risk for hearing impairment," said Rebecca Spencer, a neuroscientist and associate professor in the department of psychological and brain sciences at the University of Massachusetts, Amherst. "You wouldn't know if one comes before the other: sleep apnea appears before hearing loss, or hearing loss appears before sleep apnea and maybe they don't come together at all. They may not be related except by a third factor."

Because a possible link has been discovered between sleep apnea and hearing loss, the next step should be a smaller study that looks more closely at the question of whether sleep apnea actually causes hearing loss, said Spencer.

She also pointed out that the data drew only from people of Hispanic and Latino descent. It would be important to look at the association between hearing loss and sleep apnea among a broader ethnic and geographical group, she added.

Only one thing can be concluded from the study, Spencer said: "There is the potential that treating sleep apnea may improve hearing loss."

Shah, the research author, said people with sleep apnea should be screened for hearing impairment since it has been shown to be associated with the disorder. "Get evaluated," she urged.

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Inflammation can be caused by anti-epilepsy drugs

A report claims that anti-epilepsy drugs can cause inflammation and thus may have roots in the immune system.

Physicians at the Ruhr-Universität Bochum (RUB) have been investigating if established anti-epilepsy drugs have anti-inflammatory or pro-inflammatory properties -- an effect for which these pharmaceutical agents are not usually tested. One of the substances tested caused stronger inflammations, while another one inhibited them. As inflammatory reactions in the brain may be the underlying cause for epileptic disorders, it is vital to take the trigger for the disorder under consideration when selecting drugs for treatment, as the researchers concluded. They published their report in the journal Epilepsia.

Glial cells play a crucial role in the nervous system

Hannes Dambach from the Department for Neuroanatomy and Molecular Brain Research, together with a team of colleagues, studied how anti-epilepsy drugs affect the survival of glial cells in cultures. Glial cells are the largest cell group in the brain; they are crucial for supplying neurons with nutrients and affect immune and inflammatory responses. The question of how glial cells are affected by anti-epilepsy drugs had previously not been studied in depth. The RUB work group Clinical Neuroanatomy, headed by Prof Dr Pedro Faustmann, analysed four substances: valproic acid, gabapentin, phenytoin and carbamazepine.

Four anti-epilepsy drugs affect glial cells in different ways

Glial cells treated by the researchers with valproic adic and gabapentin had better survival chances than those treated with phenytoin and carbamazepine. However, carbamazepine had a positive effect, too: it reduced inflammatory responses. Valproic acid, on the other hand, turned out to be pro-inflammatory. In how far the anti-epilepsy drugs affected inflammations was also determined by the applied dose. Consequently, different drugs affected glial cells -- and hence indirectly the neurons -- in different ways.

Inflammatory responses should be taken under consideration in clinical studies

"Clinical studies should focus not only on the question in how far anti-epilepsy drugs affect the severity and frequency of epileptic seizures," says Pedro Faustmann. "It is also necessary to test them with regard to the role they play in inflammatory responses in the central nervous system." Thus, doctors could take the underlying inflammatory condition under consideration when selecting the right anti-epilepsy drug.

Epilepsy may have different causes

In Germany, between 0.5 and 1 percent of the population suffer from epilepsy that requires drug treatment. The disease may have many causes: genetic predisposition, disorders of the central nervous system after meningitis, traumatic brain injury and stroke. Inflammatory responses may also be caused by damage to the brain.

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New and odd ideas for treating autism symptoms.

Fasten your seatbelt - new and unusual autism treatments (???): hot baths and worm eggs, were presented at a recent meeting  to help with autism symptoms. 

I was asked what I thought of these treatments... My impression, from a medical  standpoint is..."YIKES", "OMG" and "You are kidding, right?". 

It goes without saying, but Ill say it....I DO NOT recommend these therapies.   1) There does not seem to be biologic plausibility. 2) This is not nearly convincing data. 3) There may be dangers in these treatments (the picture of the child sitting alone in the bath is intended to be alarming).  

http://www.autism-watch.org/ is still a good site. 

Hardly a nihilist on therapeutics, I look forward to more data on effective treatments.    - JR

A new study shows that two unusual treatment approaches may have beneficial effects on the symptoms of autism in children and adults with the disorder. Using a hot bath to raise body temperature and thereby mimic the effects of infection, or using worm eggs to stimulate the production of immunoregulatory factors in the gut to diminish inflammatory signals, both attenuated symptoms of autism. These findings support the idea that disruption of systems in the body that control inflammation may contribute to the disorder. The study was presented at the American College of Neuropsychopharmacology (ACNP) Annual Meeting.

Approximately 1 in 88 children are afflicted with autism spectrum disorder (ASD). A prevailing hypothesis of ASD is that a hyperactive immune system, resulting in elevated levels of inflammation, may contribute to the disorder. Consistent with this possibility, it is known that approximately one third of those with ASD show a clinical improvement in symptoms in response to a fever.

In a new study led by Eric Hollander MD, a professor at Albert Einstein College of Medicine in New York, the effects of two novel treatment approaches that modify aspects of inflammation were tested on ASD symptoms.

First, as fever may trigger the release of protective anti-inflammatory signals in the body, the effects of raising body temperature to mimic fever on ASD symptoms were assessed. It was found that children with ASD and a history of positive behavioral response to fever had improved social behaviors when bathed each day in a hot tub at 102oF compared with water at 98 oF.

Second, using a more unusual approach, adults with ASD were treated for 12 weeks with Trichuris suis ova (TSO), which are the eggs of the worm helminth trichura (whip worm). This worm is safe in humans as it does not multiply in the host, is not transmittable by contact, and is cleared spontaneously. However, the worms can inhibit immune-mediated responses and diminish inflammation.

The subjects for this study were 10 high functioning ASD patients who were able to give informed consent and who had a history of allergies or a family history of immune-inflammatory illness. Patients were treated for 12 weeks with the worm eggs (2500 eggs every two weeks) but were also subjected to a 12 week placebo phase in a randomized order. It was found that adults with ASD had improvement in repetitive and ritualistic behaviors in response to treatment with the worm eggs.

This is not the first time that worm eggs have been used successfully to treat diseases, particularly immune-related diseases, in humans such as Crohn's Disease. As noted by Dr. Hollander, "TSO has been shown to improve various immune inflammatory illness by shifting the ratio of T regulator/T helper cells and their respective cytokines.."

The findings support the idea that inflammation may contribute to the symptoms of autism, at least in some individuals, and highlight novel treatment approaches. However, as noted by Dr. Hollander, the small sample size and unusual treatment approach means that caution should be exercised when interpreting the studies:

"Future studies in autism spectrum disorders are needed to replicate and expand these findings, and to study younger subjects with more severe irritability."

Nevertheless, the findings raise the intriguing possibility that approaches designed to module immune responses in ASD patients may be future treatment approaches for the disorder.

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Study: Concussion can mean depression years later

A study done in mice shows that concussions can lead to the development of depression later in life.

A head injury can lead immune-system brain cells to go on "high alert" and overreact to later immune challenges by becoming excessively inflammatory -- a condition linked with depressive complications, a new animal study suggests.

The findings could help explain some of the midlife mental-health issues suffered by individuals who experience multiple concussions as young adults, researchers say. And these depressive symptoms are likely inflammation-related, which means they may not respond to common antidepressants.

An added complication is that aging already increases brain inflammation. So on top of normal aging concerns, people who have had a traumatic brain injury (TBI) experience added inflammation caused by magnified immune responses to so-called "secondary challenges," such as a second head injury, infections or other stressors.

In mice, these high-alert cells in the brain -- called microglia -- had an exaggerated response to an immune challenge one month after a moderate brain injury. This increased brain inflammation corresponded with the development of depressive behaviors that were not observed in uninjured mice.

"If we had waited three, six or nine months, the symptoms probably would have gotten even worse," said lead author Jonathan Godbout, associate professor of neuroscience at The Ohio State University and a researcher in the Institute for Behavioral Medicine Research.

"A lot of people with a history of head injury don't develop mental-health problems until they're in their 40s, 50s or 60s. That suggests there are other factors involved, and that's why we're looking at this two-hit idea -- the brain injury being the first and then an immune challenge. It's as if one plus one plus one equals 15. There can be a multiplier effect."

The research is published online in the journal Biological Psychiatry.

This work applies to concussive brain injuries that result in a diffuse -- or spread out -- trauma to the brain. These are also concussive injuries from which people and animals recover fairly quickly, typically showing no problems with thinking or moving about a week after the injury to the brain.

In the study, researchers compared uninjured mice with mice that had experienced a moderate TBI. Injured mice showed some initial coordination problems, but those resolved within a week.

The injured mice also showed signs of depressive symptoms that improved within one month. Godbout and colleagues attributed those symptoms to the expected neuroinflammation that occurs after a traumatic brain injury. In these mice, most of the inflammation had cleared within seven days.

Thirty days after injury, researchers examined the brains of the injured mice to determine whether immune cells had remained on high alert since the injury. As expected, the injured brains contained microglia that had stayed in a "primed" state -- meaning they were on standby to respond to a challenge to the immune system. The cells in the brains of uninjured mice did not have the same characteristics.

Under normal circumstances, microglia are the first line of defense and help protect the brain after injury or infection by making proteins and other chemicals that generate just enough inflammation to repair the problem. When they are primed, however, these cells are in a higher state of alert and when they are activated, they generate an amplified immune response that lasts longer than necessary. When these systems are activated with nothing to fight, the circulating chemicals and proteins generate excessive inflammation.

"The young adult mice that have a diffuse head injury basically recover to normal, but not everything is normal. The brain still has a more inflammatory makeup that is permissive to hyperactivation of an immune response," Godbout said.

At 30 days after TBI, the mice were injected with lipopolysaccharide (LPS) -- the dead, outer cell wall of bacteria that stimulates an immune reaction in animals. Tests showed that over the course of 24 hours after the injection, TBI mice were much less social than uninjured mice -- one type of depressive symptom in these animals. The brains of the TBI mice also had dramatically higher levels of two inflammation-related proteins than did brains from normal mice.

Seventy-two hours after the LPS challenge, injured mice showed additional depressive symptoms, including minimal interest in sugar water -- a sign that they avoided what is typically a pleasurable activity. They also showed increased resignation, or a sign of "giving up."

Uninjured mice behaved normally and the levels of inflammatory proteins in their brains had returned to baseline over the same time period.

"These results tell us the TBI mice are having an amplified and prolonged activation of microglia, and that was associated with development of depressive symptoms in the mice," Godbout said.

His lab is now investigating potential treatments that could either prevent the priming of microglia immediately after injury or later reverse the high-alert characteristics of these cells.

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Poor sleep worsens heart issues in women

The progression of heart disease in women seems to be worsened by poor sleep. This effect was not seen in men.

Poor sleep appears to contribute to the progression of heart disease in women by raising their inflammation levels, but this effect was not seen in men, researchers say.

"Inflammation is a well-known predictor of cardiovascular health," lead author Aric Prather, a clinical health psychologist and assistant professor of psychiatry at the University of California, San Francisco, said in a university news release.

"Now we have evidence that poor sleep appears to play a bigger role than we had previously thought in driving long-term increases in inflammation levels and may contribute to the negative consequences often associated with poor sleep," Prather added.

Previous research has shown that sleeping fewer than six hours per night may raise the risk of chronic health problems, including heart disease, and is associated with higher levels of inflammation.

This new study included nearly 700 men (average age 66) and women (average age 64) with coronary heart disease. Among the women, poor sleep quality was significantly associated with increases in markers of inflammation over five years. However, this was not the case among men.

Most of the women in the study were postmenopausal and their lower levels of estrogen could help explain the link between poor sleep and higher levels of inflammation, the study authors suggested.

"It is possible that testosterone, which is at higher levels in men, served to buffer the effects of poor subjective sleep quality," Prather's team wrote in the study published online June 5 in the Journal of Psychiatric Research.

The researchers said their findings reveal potentially important gender differences and provide evidence that increased inflammation may be a major way that poor sleep contributes to the progression of heart disease in women.

Although the study found an association between self-reported poor sleep quality and increased signs of inflammation among older women with heart disease, it did not prove a cause-and-effect relationship.

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Higher rates of migraine headaches in people with celiac disease and inflammatory bowel disease

A new study claims that migraine headaches are more prevalent in people who have celiac disease or inflammatory bowel disease.

People with celiac disease or inflammatory boweldisease have higher rates of migraine headaches than their counterparts without those conditions, according to a new study.

The research team included Alexandra K. Dimitrova MD, Ryan C. Ungaro MD, Benjamin Lebwohl MD, Suzanne K. Lewis MD, Christina A. Tennyson MD, Mark W. Green MD, Mark W. Babyatsky MD, and Peter H. Green MD.

A team of researchers recently set out to assess the rates of migraine headaches in clinic and support group patients with celiac disease and inflammatory bowel disease (IBD) and to compare those with a sample group of healthy control subjects.

A number of European studies have shown higher rates of migraine headaches in patients with celiac disease and IBD compared with control subjects.

For the study, participants all answered a self-administered survey containing clinical, demographic, and dietary data, as well as questions about headache type and frequency.

They also used both the ID-Migraine screening tool and the Headache Impact Test (HIT-6).

The research team analyzed five hundred and two subjects who met exclusion criteria. Of these, 188 had celiac disease, 111 had IBD, 25 had gluten sensitivity (GS), and 178 healthy subjects served as controls.

Thirty percent of celiac patients, 56% of gluten-sensitive patients, 23% of IBD patients, and 14% of control subjects reported chronic headaches (P < .0001).

Using multivariate logistic regression, the team found that all subjects with celiac disease (odds ratio [OR] 3.79, 95% confidence interval [CI] 1.78-8.10), GS (OR 9.53, 95% CI 3.24-28.09), and IBD (OR 2.66, 95%CI 1.08-6.54) had significantly higher rates of migraine headaches than did control subjects.

Migraine rates were influenced by female sex (P = .01), depression, and anxiety (P = .0059) were independent predictors of migraine headaches, whereas age >65 was protective (P = .0345).

When it came to grading their migraines, seventy-two percent of celiac disease subjects reported having migraine that were severe in impact, compared with 30% of IBD, 60% of GS, and 50% of C subjects (P = .0919).

The number of years on gluten-free diet had no influence on the severity of migraines.

Migraine headaches were more common in people with celiac disease and IBD patients than in control subjects.

The team points out that future studies should screen migraine patients for celiac disease and assess the effects of gluten-free diet on celiac disease patients with migraines.

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Prenatal Inflammation Related to Autism Development

A new study claims that prenatal inflammation may be related to the development of autism.

Maternal inflammation during early pregnancy may be related to an increased risk of autism in children, according to new findings supported by the National Institute of Environmental Health Sciences (NIEHS), part of the National Institutes of Health. Researchers found this in children of mothers with elevated C-reactive protein (CRP), a well-established marker of systemic inflammation.

The risk of autism among children in the study was increased by 43 percent among mothers with CRP levels in the top 20th percentile, and by 80 percent for maternal CRP in the top 10th percentile. The findings appear in the journal Molecular Psychiatry and add to mounting evidence that an overactive immune response can alter the development of the central nervous system in the fetus.

"Elevated CRP is a signal that the body is undergoing a response to inflammation from, for example, a viral or bacterial infection," said lead scientist on the study, Alan Brown, M.D., professor of clinical psychiatry and epidemiology at Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, and Mailman School of Public Health. "The higher the level of CRP in the mother, the greater the risk of autism in the child."

Brown cautioned that the results should be viewed in perspective since the prevalence of inflammation during pregnancy is substantially higher than the prevalence of autism.

"The vast majority of mothers with increased CRP levels will not give birth to children with autism," Brown said. "We don't know enough yet to suggest routine testing of pregnant mothers for CRP for this reason alone; however, exercising precautionary measures to prevent infections during pregnancy may be of considerable value."

"The brain develops rapidly throughout pregnancy," said Linda Birnbaum, Ph.D., director of NIEHS, which funds a broad portfolio of autism and neurodevelopmental-related research. "This has important implications for understanding how the environment and our genes interact to cause autism and other neurodevelopmental disorders."

The study capitalized on a unique national birth cohort known as the Finnish Maternity Cohort (FMC), which contains an archive of samples collected from pregnant women in Finland, where a component of whole blood, referred to as serum, is systematically collected during the early part of pregnancy. The FMC consists of 1.6 million specimens from about 810,000 women, archived in a single, centralized biorepository. Finland also maintains diagnoses of virtually all childhood autism cases from national registries of both hospital admissions and outpatient treatment.

From this large national sample, the researchers analyzed CRP in archived maternal serum corresponding to 677 childhood autism cases and an equal number of matched controls. The findings were not explained by maternal age, paternal age, gender, previous births, socioeconomic status, preterm birth, or birth weight. The work was conducted in collaboration with investigators in Finland, including the University of Turku and the National Institute for Health and Welfare in Oulu and Helsinki.

"Studying autism can be challenging, because symptoms may not be apparent in children until certain brain functions, such as language, come on line," said Cindy Lawler, Ph.D., head of the NIEHS Cellular, Organ, and Systems Pathobiology Branch and program lead for the Institute's extramural portfolio of autism research. "This study is remarkable, because it uses biomarker data to give us a glimpse back to a critical time in early pregnancy."

This work is expected to stimulate further research on autism, which is complex and challenging to identify causes. Future studies may help define how infections, other inflammatory insults, and the body's immune response interact with genes to elevate the risk for autism and other neurodevelopmental disorders. Preventative approaches addressing environmental causes of autism may also benefit from additional research.

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