Neuroscience

Researchers at Georgetown University Medical Center (GUMC) have found what they say is evidence that veterans who suffer from “Gulf War Illness” have physical changes in their brains not seen in unaffected individuals. Brain scans of 31 veterans with the illness, compared to 20 control subjects, revealed anomalies in the bundles of nerve fibers that connect brain areas involved in the processing and perception of pain and fatigue.

The discovery, published online March 20 in PLOS ONE, could provide insight into the mysterious medical symptoms reported by more than one-fourth of the 697,000 veterans deployed to the 1990-1991 Persian Gulf War, the researchers say. These symptoms, termed Gulf War Illness, range from mild to debilitating and can include widespread pain, fatigue, and headache, as well as cognitive and gastrointestinal dysfunctions.

Although these veterans were exposed to nerve agents, pesticides and herbicides, among other toxic chemicals, no one has definitively linked any single exposure or underlying mechanism to Gulf War Illness according to the scientists.

This is the first study to show veterans, compared to unaffected subjects, have significant axonal damage. Bundles of axons, which form the brain white matter, are akin to telephone wires that carry nerve impulses between different parts of the gray matter in the brain. The researchers found that damage to the right inferior fronto-occipital fasciculus was significantly correlated with the severity of pain, fatigue, and tenderness.

“This tract of axons links cortical gray matter regions involved in fatigue, pain, emotional and reward processing.  This bundle also supports activity in the ventral attention network, which searches for unexpected signals in the surrounding environment that may be inappropriately interpreted as causing pain or being dangerous. Altered function in this tract may explain the increased vigilance and distractibility observed in veterans.” says lead author Rakib Rayhan, MS, a researcher in the lab of the study’s senior investigator, James Baraniuk, MD, a professor of medicine at GUMC.

In this Department of Defense-funded study, the research team used a form of functional magnetic resonance imaging (fMRI) called diffusion tensor imaging. This imaging method examines patterns of water diffusion in the brain to look for changes in the integrity of white matter, which is not seen on regular MRI scans. “This provides a completely new perspective on Gulf War Illness,” says Baraniuk. “While we can’t exactly tell how this tract is affected at the molecular level — the scans tell us these axons are not working in a normal fashion.”

Although preliminary, “the changes appear distinct from multiple sclerosis, major depression, Alzheimer’s disease and other neurodegenerative diseases,” says Rayhan. “These novel findings are really exciting because they provide validation for many veterans who have long said that no one believes them.”

The results must be replicated, say its authors, but for the first time a potential biomarker for Gulf War Illness may be on the horizon as well as a possible target for therapy aimed at regenerating these neurons.

“Pain and fatigue are perceptions, just like other sensory input, and Gulf War Illness could be due to extensive damage to the structures that facilitate them,” says Rayhan. “Some of the veterans we studied feel pain when doing something as simple as putting on a shirt. Now we have something to tell them about why their lives have been so greatly affected.”

Cognitive problems with memory and behavior experienced by individuals with schizophrenia are linked with changes in brain activity; however, it is difficult to test whether these changes are the underlying cause or consequence of these symptoms. By altering the brain activity in mice to mimic the decrease in activity seen in patients with schizophrenia, researchers reporting in the Cell Press journal Neuron on March 20 reveal that these changes in regional brain activity cause similar cognitive problems in otherwise normal mice. This direct demonstration of the link between changes in brain activity and the behaviors associated with schizophrenia could alter how the disease is treated.

"We artificially decreased activity of the mediodorsal thalamus region of the brain in the mouse and found that it is sufficient to lead to deficits in working memory and other schizophrenia-like cognitive deficits," says senior author Dr. Christoph Kellendonk of Columbia University in New York City. "Our findings further suggest that decreased thalamic activity interferes with cognition by disrupting communication between the thalamus and the prefrontal cortex, an area of the brain that has already been shown to be important for working memory," he added.

The researchers made their discovery by giving mice a drug that decreased activity selectively in the mediodorsal thalamus region of the brain. They then tested the animals in various cognitive tasks involving levers and mazes. The investigators found that even a subtle decrease in the activity of the mediodorsal thalamus led to altered connectivity between this brain region and the prefrontal cortex region and that the altered connectivity was associated with a variety of cognitive impairments experienced by patients with schizophrenia.

The findings likely apply to humans because patients with schizophrenia have decreased thalamic activity as well as altered connectivity between the thalamus and the prefrontal cortex. “Our work suggests that these two findings may be linked,” explains co-senior author Dr. Joshua Gordon, also of Columbia University. “One next step would be to examine this relationship in patients. For example, one could ask whether deficits in thalamic activity and connectivity between the thalamus and prefrontal cortex are correlated with each other.”

Cognitive symptoms of schizophrenia include problems with memory and behavioral flexibility, two processes that are essential for activities of daily living. These symptoms are resistant to current treatments, but this study’s findings provide new information for the design of potentially more effective therapies that target the neuronal mechanisms underlying patients’ cognitive problems.

The effects of antiepileptic drugs during pregnancy have long been a concern of clinicians and women of childbearing age whose seizures can only be controlled by medications. In 1999, a study called the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) began following the children of women who were taking a single antiepileptic agent during pregnancy. The drugs included carbamazepine, lamotrigine, phenytoin or valproate.

Recently released final data from NEAD shows that at age 6, IQ is 7-10 points lower in children exposed in utero to the anti-epileptic drug valproate (Depakote) than those exposed to the other medications. The children exposed to valproate also did poorly on measures of verbal and memory abilities, and non-verbal and executive functions. The results were reported in the January 23, 2013, Lancet Neurology publication on line.

"Data published at ages 3 and 4.5 showed similar results in cognitive impairment," says lead study author Kimford Meador, MD, professor of neurology at Emory University School of Medicine. "Age 6 IQ was our primary outcome goal because it is standardized and predictive of school performance."

The NEAD study is the largest prospective study examining the cognitive effects of fetal antiepileptic drug exposure. The researchers monitored women through pregnancy and followed their children, performing cognitive testing at ages 2,3,4.5 and finally at 6. In addition to the effect on cognitive function, earlier data from NEAD showed an increase in the risk of anatomical birth defects.

Valproate is an anticonvulsant used in the treatment of epilepsy, migraines and bipolar disorder, and is particularly effective in the treatment of primary generalized seizures.  Except for a small number of women who only respond to valproate, there are alternative medications.

"These findings consistently show a substantial loss of developmental abilities for these children," says Meador. "Women of childbearing age who have epilepsy should talk with their doctors about their options, and possibly test the safer medications prior to pregnancy to find out if they work."

In order to avoid seizures with potentially serious consequences, Meador emphasizes that women who are already pregnant and taking valproate should not stop without consulting their physicians.

"For a woman who has significant seizures, the risk from the seizure itself is worse than the risk of taking the drugs," he points out.  "The number one reason for miscarriage late in pregnancy for women with epilepsy is trauma resulting from a seizure."

Meador will co-lead a follow-up study with Page Pennell, MD, from Harvard. The new study funded by the National Institutes of Health is called Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD), and will investigate the risks of these same drugs to both the mother and the child. The study will be conducted at 19 sites, enrolling 350 women with epilepsy during pregnancy. An additional 100 women with epilepsy who are not pregnant, and 100 healthy pregnant women will serve as controls.

New research published in The Journal of Neuroscience suggests that modifying signals sent by astrocytes, our star-shaped brain cells, may help to limit the spread of damage after an ischemic brain stroke. The study in mice, by neuroscientists at Tufts University School of Medicine, determined that astrocytes play a critical role in the spread of damage following stroke.

The National Heart Foundation reports that ischemic strokes account for 87% of strokes in the United States. Ischemic strokes are caused by a blood clot that forms and travels to the brain, preventing the flow of blood and oxygen.

Even when blood and oxygen flow is restored, however, neurotransmitter processes in the brain continue to overcompensate for the lack of oxygen, causing brain cells to be damaged. The damage to brain cells often leads to health complications including visual impairment, memory loss, clumsiness, moodiness, and partial or total paralysis.

Research and drug trials have focused primarily on therapies affecting neurons to limit brain cell damage. Phil Haydon’s group at Tufts University School of Medicine have focused on astrocytes, a lesser known type of brain cell, as an alternative path to understanding and treating diseases affecting brain cells.

In animal models, his research team has shown that astrocytes—which outnumber neurons by ten to one—send signals to neurons that can spread the damage caused by strokes. The current study determines that decreasing astrocyte signals limits damage caused by stroke by regulating the neurotransmitter pathways after an ischemic stroke.

The research team compared two sets of mice: a control group with normal astrocyte signaling levels and a group whose signaling was weakened enough to be made protective rather than destructive. To assess the effect of astrocyte protection after ischemic strokes, motor skills, involving tasks such as walking and picking up food, were tested. In addition, tissue samples were taken from both groups and compared.

“Mice with altered astrocyte signaling had limited damage after the stroke,” said first author Dustin Hines, Ph.D., a post-doctoral fellow in the department of neuroscience at Tufts University School of Medicine. “Manipulating the astrocyte signaling demonstrates that astrocytes are critical to understanding the spread of damage following stroke.”

“Looking into ways to utilize and enhance the astrocyte’s protective properties in order to limit damage is a promising avenue in stroke research,” said senior author Phillip Haydon, Ph.D. Haydon is the Annetta and Gustav Grisard professor and chair of the department of neuroscience at Tufts University School of Medicine and a member of the neuroscience program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts.

Researchers have found new evidence that insulating cells, the cells that protect our nerves, can be made and added to the central nervous system throughout our lifetime.

Chief investigator on the paper, Menzies Research Institute Tasmania’s Dr Kaylene Young, says there is now evidence that these cells may not be the passive by-standers to brain function that we once thought.

“Previously it was thought that most insulating cells in an adult brain were born before reaching adulthood,” Dr Young said.

“This research shows that new insulating cells are made from an immature cell type found in our brains, called oligodendrocyte precursor cells (OPCs).

“In fact, new insulation is added to brain circuits every day, which changes the way the circuits function. 

“This process is likely to be very important for learning, memory, vision and co-ordination.”

“This finding may have important implications for sufferers of Alzheimer’s Disease, multiple sclerosis and other neurological disorders.

Alzheimer’s disease is the most common form of dementia. There are over 321,600 Australians living with dementia and without a medical breakthrough, the number of people with dementia is expected to be almost 900,000 by 2050. (Alzheimer’s Australia)

In Alzheimer’s Disease (AD) many nerve cells die. This causes patients with AD to progressively lose their ability to think clearly and remember things, and they can also experience problems with movement and co-ordination.

A single insulating cell in the brain supports the health and function of many nerve cells.

We know from diseases like multiple sclerosis that losing insulation makes nerve cells extremely vulnerable to damage and death.

This may also be true for AD, and there is an increasing amount of evidence that supports the idea that insulating cells are damaged before nerve cells and could contribute directly to nerve cell loss.

By studying brain scans from patients with AD, researchers previously found that the amount of insulation that is damaged matched the level of the patient’s dementia. The more damaged the insulation, the worse the person’s memory problems.

Dr Young’s research team are now investigating ways to hijack the natural ability of OPCs to make new insulating cells, and repair the insulation damage that is seen in the brains of AD patients.

“Stimulating OPCs in the brain is an appealing possibility since they are found throughout all brain regions, meaning that they are already where they need to be to make new insulating cells!

“We expect that increasing brain insulation, to re-wrap the nerve cells, will prevent more nerve cells from dying. Protecting nerve cells would prevent the rapid mental deterioration seen in people after they are diagnosed with AD,” Dr Young said.

This work was published this month, in the international journal, Neuron and involved collaboration with researchers in the United Kingdom and Japan.

Innovative medical records software developed by geriatricians and informaticians from the Regenstrief Institute and the Indiana University Center for Aging Research will provide more personalized health care for older adult patients, a population at significant risk for mental health decline and disorders.

A new study published in eGEMs, a peer-reviewed online publication recently launched by the Electronic Data Methods Forum, unveils the enhanced Electronic Medical Record Aging Brain Care Software, an automated decision-support system that enables care coordinators to track the health of the aging brain and help meet the complex biopsychosocial needs of patients and their informal caregivers.

The eMR-ABC captures and monitors the cognitive, functional, behavioral and psychological symptoms of older adults suffering from dementia or depression. It also collects information on the burden placed on patients’ family caregivers.

Utilizing this information, the software application provides decision support to care coordinators, who, working with physicians, social workers and other members of the health care team, create a personalized care plan that includes evidence-based non-pharmacological protocols, self-management handouts and alerts of medications with potentially adverse cognitive effects. The software’s built-in engine tracks patient visits and can be used to generate population reports for specified indicators such as cognitive decline or caregiver burnout.

"The number of older adults is growing rapidly. Delivering personalized care to this population is difficult and requires the ability to track a large number of mental and physical indicators," said Regenstrief Institute investigator Malaz Boustani, M.D., MPH, associate director of the IU Center for Aging Research and associate professor of medicine at the IU School of Medicine. He is senior author of the new study. "The software we have developed will help care coordinators measure the many needs of patients and their loved ones and monitor the effectiveness of individualized care plans."

In clinical trials over the past decade, Regenstrief and the IU Center for Aging Research investigator-clinicians developed and demonstrated the efficacy of an Alzheimer’s disease collaborative care model called the Aging Brain Care Medical Home. A hallmark of the ABC-MedHome is the employment of care coordinators who help clinicians identify and manage processes and protocols for Alzheimer’s patients who receive care in local primary care physician offices. The ABC-MedHome has been shown to improve the quality of Alzheimer’s care and decrease its burden on the health care system.

Within the ABC-MedHome program, Dr. Boustani and colleagues have now developed, tested, implemented and improved software that is sensitive to the clinical needs of a multispecialty team of professionals who provide care to complex patients across a variety of settings. The new software allows tracking of individual patient health outcomes as well as the ability to follow the status of an entire patient population with key quality, health and cost metrics.

"Integration of the eMR-ABC program within Wishard-Eskenazi Health was pivotal to our receipt in 2012 of a Health Care Innovation Challenge award from the Centers for Medicare & Medicaid Services to expand from care of 250 patients to 2,000 patients plus caregivers," said Dr. Boustani, who is medical director of the Wishard Healthy Aging Brain Center and also an IU Health geriatrician. "New models of care, supported by population health management tools, are needed if we are to provide improved quality of care and encourage better health outcomes for our patients and be cost sensitive. We are using health information technology to manage high-risk populations while achieving the triple aim of better health and better care at lower cost."

Since the 1960s, psychiatrists have been hunting for substances made by the body that might accumulate in abnormally high levels to produce the symptoms associated with schizophrenia. In particular, there was a search for chemicals that might be related to the hallucinogens phencyclidine (PCP) or lysergic acid diethylamide (LSD), which could explain the emergence of psychotic symptoms in schizophrenia. This “auto-intoxication” hypothesis led investigators on a wild goose chase where substances, including the “Pink Spot” and the “Frohman Factor”, were isolated from people with schizophrenia and implicated in their illness, but these findings were later discredited.

The mysterious GRIN3A is a new version of the hunt for an intrinsic mechanism that produces schizophrenia-like symptoms. GRIN3A is a gene that codes for the GluN3A subunit of the N-methyl-D-aspartate-type (NMDA) receptor, a target for the neurotransmitter glutamate in the brain. Functional NMDA receptors usually have two GluN1 subunits and two GluN2 subunits. The ability of glutamate to activate these receptors is blocked by PCP and the anesthetic/hallucinogen, ketamine. When the GluN3A subunit is incorporated, it prevents the NMDA receptor from being activated by glutamate, almost as if the receptor had been blocked by PCP.

It is unclear why the brain needs this mechanism for normal brain development and function, hence the mystery surrounding GRIN3A. One piece of evidence supporting a link between GluN3A and schizophrenia is the finding that GluN3A levels are elevated in the post-mortem brain tissue from people who had been diagnosed with schizophrenia.

In this issue of Biological Psychiatry, Japanese researchers led by Dr. Takeo Yoshikawa provide new support for this hypothesis by implicating variation in GRIN3A in the heritable risk for schizophrenia.

Schizophrenia is thought to have a substantial genetic background which is, to some extent, population-specific. Genome-wide searches have revealed many common genomic variants with weak effects, but the remaining “missing heritability” is largely unknown. Scientists theorize that it may be partly explained by rare variants with large effect.

To identify genetic variants with larger effect sizes, Yoshikawa and his colleagues examined genetic data from several Asian populations. They identified a rare variant in GRIN3A with study-wide significance.

"This discovery is important, because the ‘NMDA receptor hypothesis’ for schizophrenia is a common disease model," said Yoshikawa. "We propose a novel point of therapeutic intervention in the NMDA receptor signaling system for schizophrenia."

Dr. John Krystal, Editor of Biological Psychiatry, commented, “The notion that a genetic trait that acts like PCP in the brain produces schizophrenia is a very attractive but over-simplistic hypothesis. It is that the biology of schizophrenia is much more complicated than this single factor. Nonetheless, perhaps this study of GRIN3A brings us another step closer to understanding glutamate abnormalities in schizophrenia.”

Researchers in the UK have taken an important step towards understanding how the human brain ‘decodes’ letters on a page to read a word. The work, funded by the Economic and Social Research Council (ESRC), will help psychologists unravel the subtle thinking mechanisms involved in reading, and could provide solutions for helping people who find it difficult to read, for example in conditions such as dyslexia.

In order to read successfully, readers need not only to identify the letters in words, but also to accurately code the positions of those letters, so that they can distinguish words like CAT and ACT. At the same time, however, it’s clear that raeders can dael wtih wodrs in wihch not all teh leettrs aer in thier corerct psotiions.

"How the brain can make sense of some jumbled sequences of letters but not others is a key question that psychologists need to answer to understand the code that the brain uses when reading," says Professor Colin Davis of Royal Holloway, University of London, who led the research.

For many years researchers have used a standard psychological test to try to work out which sequences of letters in a word are important cues that the brain uses, where jumbled words are flashed momentarily on a screen to see if they help the brain to recognise the properly spelt word.

But, this technique had limitations that made it impossible to probe more extreme rearrangements of sequences of letters. Professor Davis’s team used computer simulations to work out that a simple modification to the test would allow it to question these more complex changes to words. This increases the test’s sensitivity significantly and makes it far more valuable for comparing different coding theories.

"For example, if we take the word VACATION and change it to AVACITNO, previously the test would not tell us if the brain recognises it as VACATION because other words such as AVOCADO or AVIATION might start popping into the person’s head,” says Professor Davis. "With our modification we can show that indeed the brain does relate AVACITNO to VACATION, and this starts to give us much more of an insight into the nature of the code that the brain is using – something that was not possible with the existing test."

The modified test should allow researchers not only to crack the code that the brain uses to make sense of strings of letters, but also to examine differences between individuals – how a ‘good’ reader decodes letter sequences compared with someone who finds reading difficult.

"These kinds of methods can be very sensitive to individual differences in reading ability and we are starting to get a better idea of some of the issues that underpin people’s difficulty in reading," says Professor Davis. Ultimately, this could lead to new approaches to helping people to overcome reading problems.

For the first time, scientists have transplanted neural cells derived from a monkey’s skin into its brain and watched the cells develop into several types of mature brain cells, according to the authors of a new study in Cell Reports. After six months, the cells looked entirely normal, and were only detectable because they initially were tagged with a fluorescent protein.

Because the cells were derived from adult cells in each monkey’s skin, the experiment is a proof-of-principle for the concept of personalized medicine, where treatments are designed for each individual.

And since the skin cells were not “foreign” tissue, there were no signs of immune rejection — potentially a major problem with cell transplants. “When you look at the brain, you cannot tell that it is a graft,” says senior author Su-Chun Zhang, a professor of neuroscience at the University of Wisconsin-Madison. “Structurally the host brain looks like a normal brain; the graft can only be seen under the fluorescent microscope.”

Marina Emborg, an associate professor of medical physics at UW-Madison and the lead co-author of the study, says, “This is the first time I saw, in a nonhuman primate, that the transplanted cells were so well integrated, with such a minimal reaction. And after six months, to see no scar, that was the best part.”

The cells were implanted in the monkeys “using a state-of-the-art surgical procedure” guided by an MRI image, says Emborg. The three rhesus monkeys used in the study at the Wisconsin National Primate Research Center had a lesion in a brain region that causes the movement disorder Parkinson’s disease, which afflicts up to 1 million Americans. Parkinson’s is caused by the death of a small number of neurons that make dopamine, a signaling chemical used in the brain.

The transplanted cells came from induced pluripotent stem cells (iPS cells), which can, like embryonic stem cells, develop into virtually any cell in the body. iPS cells, however, derive from adult cells rather than embryos.

In the lab, the iPS cells were converted into neural progenitor cells. These intermediate-stage cells can further specialize into the neurons that carry nerve signals, and the glial cells that perform many support and nutritional functions. This final stage of maturation occurred inside the monkey.

Zhang, who was the first in the world to derive neural cells from embryonic stem cells and then iPS cells, says one key to success was precise control over the development process. “We differentiate the stem cells only into neural cells. It would not work to transplant a cell population contaminated by non-neural cells.”

Another positive sign was the absence of any signs of cancer, says Zhang — a worrisome potential outcome of stem cell transplants. “Their appearance is normal, and we also used antibodies that mark cells that are dividing rapidly, as cancer cells are, and we do not see that. And when you look at what the cells have become, they become neurons with long axons [conducting fibers], as we’d expect. They also produce oligodendrocytes that are helping build insulating myelin sheaths for neurons, as they should. That means they have matured correctly, and are not cancerous.”

The experiment was designed as a proof of principle, says Zhang, who leads a group pioneering the use of iPS cells at the Waisman Center on the UW-Madison campus. The researchers did not transplant enough neurons to replace the dopamine-making cells in the brain, and the animal’s behavior did not improve.

Although promising, the transplant technique is a long way from the clinic, Zhang adds. “Unfortunately, this technique cannot be used to help patients until a number of questions are answered: Can this transplant improve the symptoms? Is it safe? Six months is not long enough… And what are the side effects? You may improve some symptoms, but if that leads to something else, then you have not solved the problem.”

Nonetheless, the new study represents a real step forward that may benefit human patients suffering from several diseases, says Emborg. “By taking cells from the animal and returning them in a new form to the same animal, this is a first step toward personalized medicine.”

The need for treatment is incessant, says Emborg, noting that each year, Parkinson’s is diagnosed in 60,000 patients. “I’m gratified that the Parkinson’s Disease Foundation took a risk as the primary funder for this small study. Now we want to move ahead and see if this leads to a real treatment for this awful disease.”

"It’s really the first-ever transplant of iPS cells from a non-human primate back into the same animal, not just in the brain," says Zhang. "I have not seen anybody transplanting reprogrammed iPS cells into the blood, the pancreas or anywhere else, into the same primate. This proof-of-principle study in primates presents hopes for personalized regenerative medicine."