Tired all the time: Could undiagnosed sleep problems be making MS patients’ fatigue worse?

People with multiple sclerosis (MS) might assume that the fatigue they often feel just comes with the territory of their chronic neurological condition.

But a new University of Michigan study suggests that a large proportion of MS patients may have an undiagnosed sleep disorder that is also known to cause fatigue. And that disorder – obstructive sleep apnea – is a treatable condition.

In the latest issue of the Journal of Clinical Sleep Medicine, researchers from the U-M Health System’s Sleep Disorders Center report the results of a study involving 195 patients of the U-M Multiple Sclerosis Center.

In all, 56 percent of the MS patients were found to be at increased risk for obstructive sleep apnea, based on a method of screening for the condition known as the STOP-Bang questionnaire. But most had never received a formal diagnosis of sleep apnea, and less than half of those who had been told they had sleep apnea were using the standard treatment for it. 

The authors also found that patients who were more fatigued were more likely to also be at elevated risk for sleep apnea – even after taking into account other factors that might have contributed to feelings of fatigue, such as age, gender, body mass index (BMI), sleep duration, depression, and other nighttime symptoms.

The research is based on patients’ answers from a sleep questionnaire designed by the authors, and four validated instruments designed to assess daytime sleepiness, fatigue severity, insomnia severity and obstructive sleep apnea risk. Medical records also were accessed with patients’ permission, to examine clinical characteristics that may predict fatigue or obstructive sleep apnea risk.

“We were particularly surprised by the difference between the proportion of patients who carried an established diagnosis of obstructive sleep apnea – 21 percent — and the proportion at risk for obstructive sleep apnea based on their STOP-Bang scores, which was 56 percent,” says the study’s lead author, Tiffany Braley, M.D., M.S. “These findings suggest that OSA may be a highly prevalent and yet under-recognized contributor to fatigue in persons with MS.” 

Braley, an assistant professor of Neurology and multiple sclerosis specialist at the U-M Medical School, conducted the study in collaboration with professors Ronald Chervin, M.D., M.S., and Benjamin Segal, M.D.  Chervin is the Director of U-M Sleep Disorders Center, and Segal directs the U-M MS Center.

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system that causes inflammation and damage of the brain and spinal cord. In addition to neurological disability, MS patients suffer from a number of chronic symptoms, the most common of which is fatigue.  Fatigue is also one of the most disabling symptoms experienced by MS patients.

Braley cautions that the design of this new study does not allow for demonstration of cause and effect – that is, the researchers can’t prove based on survey results that the patients felt more fatigued because they had a high score on a sleep apnea risk survey.  But, she says, “the findings should prompt doctors who treat MS patients to consider sleep apnea as a possible contributor to their patients’ fatigue, and recommend appropriate testing and treatment.”

The standard treatment for obstructive sleep apnea, called continuous positive airway pressure, or CPAP, involves a machine and mask device that applies a stream of air to the upper airway to keep it open during sleep. 

The patients in the study had an average age of 47 and had lived with MS for an average of 10 years. Two-thirds were female, consistent with the prevalence of MS in the U.S., and two-thirds were taking a medication to treat their MS. Three-quarters had the relapsing-remitting form of the disease.

Brain Damage in Children—The Result of Too Many Chemicals?

A new report is sounding the alarm of a “silent epidemic” of childhood neurological disorders linked to neurotoxic compounds.

While genetics is known to play a role in neurological problems, only 30 to 40 percent of neurodevelopmental disorders can be definitively tied to family history. “There are a lot of chemicals out there that have been shown to have the capability to injure the developing brain,” says study coauthor Philip Landrigan, MD, professor and chair of the department of community and preventive medicine at Mount Sinai School of Medicine in New York City and one of the world’s foremost authorities on children’s environmental health. “And we’re very concerned that a number of chemicals in everyday products have never been properly tested to determine whether they’re toxic to the human brain.”

In the new report, Dr. Landrigan and his coauthor identified six chemicals that have been discovered, within the past seven years, to trigger brain damage in children. In 2006, he and other researchers ID’d lead, methylmercury, arsenic, polychlorinated biphenyls (PCBs), and toluene as known contributors to rising rates of neurodevelopmental disorders like autism, attention-deficit hyperactivity disorder, and learning disabilities.

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Can a virtual brain replace lab rats?

Testing the effects of drugs on a simulated brain could lead to breakthrough treatments for neurological disorders such as Parkinson’s, Huntington’s and Alzheimer’s disease.

Researchers from the University of Waterloo in Canada hope Spaun, the world’s largest functioning model of the brain, will be used to test new drugs that lead to medical breakthroughs for brain disorders.

Terrence Stewart, a post-doctoral researcher with the Centre for Theoretical Neuroscience at Waterloo and project manager for Spaun, will tell an audience at the American Association for the Advancement of Science (AAAS) annual meeting in Chicago about the advantages of using whole-brain simulation as a tool to aid new discoveries in medicine.

“Our hope is that you could try out different possible treatments quickly to see how the brain reacts and how each one changes behaviour before testing them in people,” said Stewart. “Our brain model offers a new way to test treatments. For Alzheimer’s disease or a stroke that causes memory loss, we could see how a new drug affects the firing pattern of individual brain cells and measure how it changes brain performance on memory tests before trying it on people.”

Stewart’s team has already made progress simulating Parkinson’s and Huntington’s diseases. Their next step is to simulate Alzheimer’s disease after giving Spaun a hippocampus, the brain region involved in forming new memories.

Spaun is more like the human brain than other computer brain models because it makes mistakes and loses abilities in similar ways to people. To simulate the cognitive decline associated with aging, for example, Stewart and his team killed off neurons in the brain model and observed it gradually forgetting more numbers on a memory test. 

To reproduce movement problems associated with Huntington’s disease and damage to the cerebellum, Stewart damaged parts of the simulated brain affected by those conditions.

“We showed that errors made in reaching behaviour seen in people with those disorders correspond to the errors made by our brain model when neurons in the affected brain regions are damaged,” he said.

Spaun can see, remember, think and write using a mechanical arm. Most importantly, this virtual brain – which mimics the neuron firing patterns seen in the human brain – allows the researchers to study and understand how damage to individual cells affects the behaviour of the whole brain in different neurological diseases.

Stewart presented new research on successfully simulating the effects of aging and Huntington’s disease in Spaun at a symposium panel, “Virtual Humans: Helping Facilitate Breakthroughs in Medicine” on Friday, February 14, 2014.

Researchers find brain’s ‘sweet spot’ for love in neurological patient

A region deep inside the brain controls how quickly people make decisions about love, according to new research at the University of Chicago.

The finding, made in an examination of a 48-year-old man who suffered a stroke, provides the first causal clinical evidence that an area of the brain called the anterior insula “plays an instrumental role in love,” said UChicago neuroscientist Stephanie Cacioppo, lead author of the study.

In an earlier paper that analyzed research on the topic, Cacioppo and colleagues defined love as “an intentional state for intense [and long-term] longing for union with another” while lust, or sexual desire, is characterized by an intentional state for a short-term, pleasurable goal.

In this study, the patient made decisions normally about lust but showed slower reaction times when making decisions about love, in contrast to neurologically typical participants matched on age, gender and ethnicity. The findings are presented in a paper, “Selective Decision-Making Deficit in Love Following Damage to the Anterior Insula,” published in the journal Current Trends in Neurology.

“This distinction has been interpreted to mean that desire is a relatively concrete representation of sensory experiences, while love is a more abstract representation of those experiences,” said Cacioppo, a research associate and assistant professor in psychology. The new data suggest that the posterior insula, which affects sensation and motor control, is implicated in feelings of lust or desire, while the anterior insula has a role in the more abstract representations involved in love.

In the earlier paper, “The Common Neural Bases Between Sexual Desire and Love: A Multilevel Kernel Density fMRI Analysis,” Cacioppo and colleagues examined a number of studies of brain scans that looked at differences between love and lust.

The studies showed consistently that the anterior insula was associated with love, and the posterior insula was associated with lust. However, as in all fMRI studies, the findings were correlational.

“We reasoned that if the anterior insula was the origin of the love response, we would find evidence for that in brain scans of someone whose anterior insula was damaged,” she said. 

In the study, researchers examined a 48-year-old heterosexual male in Argentina, who had suffered a stroke that damaged the function of his anterior insula. He was matched with a control group of seven Argentinian heterosexual men of the same age who had healthy anterior insula.

The patient and the control group were shown 40 photographs at random of attractive, young women dressed in appealing, short and long dresses and asked whether these women were objects of sexual desire or love. The patient with the damaged anterior insula showed a much slower response when asked if the women in the photos could be objects of love.

“The current work makes it possible to disentangle love from other biological drives,” the authors wrote. Such studies also could help researchers examine feelings of love by studying neurological activity rather than subjective questionnaires.

Understanding the basic biology of bipolar disorder

Scientists know there is a strong genetic component to bipolar disorder, but they have had an extremely difficult time identifying the genes that cause it. So, in an effort to better understand the illness’s genetic causes, researchers at UCLA tried a new approach.

Instead of only using a standard clinical interview to determine whether individuals met the criteria for a clinical diagnosis of bipolar disorder, the researchers combined the results from brain imaging, cognitive testing, and an array of temperament and behavior measures. Using the new method, UCLA investigators — working with collaborators from UC San Francisco, Colombia’s University of Antioquia and the University of Costa Rica — identified about 50 brain and behavioral measures that are both under strong genetic control and associated with bipolar disorder. Their discoveries could be a major step toward identifying the specific genes that contribute to the illness.

The results are published in the Feb. 12 edition of the journal JAMA Psychiatry.

A severe mental illness that affects about 1 to 2 percent of the population, bipolar disorder causes unusual shifts in mood and energy, and it interferes with the ability to carry out everyday tasks. Those with the disorder can experience tremendous highs and extreme lows — to the point of not wanting to get out of bed when they’re feeling down. The genetic causes of bipolar disorder are highly complex and likely involve many different genes, said Carrie Bearden, a senior author of the study and an associate professor of psychiatry and psychology at the UCLA Semel Institute for Neuroscience and Human Behavior.

"The field of psychiatric genetics has long struggled to find an effective approach to begin dissecting the genetic basis of bipolar disorder," Bearden said. "This is an innovative approach to identifying genetically influenced brain and behavioral measures that are more closely tied to the underlying biology of bipolar disorder than the clinical symptoms alone are."

The researchers assessed 738 adults, 181 of whom have severe bipolar disorder. They used high-resolution 3-D images of the brain, questionnaires evaluating temperament and personality traits of individuals diagnosed with bipolar disorder and their non-bipolar relatives, and an extensive battery of cognitive tests assessing long-term memory, attention, inhibitory control and other neurocognitive abilities.

Approximately 50 of these measures showed strong evidence of being influenced by genetics. Particularly interesting was the discovery that the thickness of the gray matter in the brain’s temporal and prefrontal regions — the structures that are critical for language and for higher-order cognitive functions like self-control and problem-solving — were the most promising candidate traits for genetic mapping, based on both their strong genetic basis and association with the disease.

"These findings are really just the first step in getting us a little closer to the roots of bipolar disorder," Bearden said. "What was really exciting about this project was that we were able to collect the most extensive set of traits associated with bipolar disorder ever assessed within any study sample. These data will be a really valuable resource for the field."

The individuals assessed in this study are members of large families living in Costa Rica’s central valley and Antioquia, Colombia. The families were founded by European and native Amerindian populations about 400 years ago and have a very high incidence of bipolar disorder. The groups were chosen because they have remained fairly isolated since their founding and their genetics are therefore simpler for scientists to study than those of general populations.

The fact that the findings aligned so closely with those of previous, smaller studies in other populations was surprising even to the scientists, given the subjects’ unique genetic background and living environments.

"This suggests that even if the specific genetic variants we identify may be unique to this population, the biological pathways they disrupt are likely to also influence disease risk in other populations," Bearden said.

The researchers’ next step is to use the genomic data they collected from the families — including full genome sequences and gene expression data— to begin identifying the specific genes that contribute to risk for bipolar disorder. The researchers also plan to extend their investigation into the children and teens in these families. They hypothesize that many of the bipolar-related brain and behavioral differences found in adults with bipolar disorder had their origins in adolescent neurodevelopment.

Scientists discover a new pathway for fear deep within the brain

Fear is primal. In the wild, it serves as a protective mechanism, allowing animals to avoid predators or other perceived threats. For humans, fear is much more complex. A normal amount keeps us safe from danger. But in extreme cases, like post-traumatic stress disorder (PTSD), too much fear can prevent people from living healthy, productive lives. Researchers are actively working to understand how the brain translates fear into action. Today, scientists at Cold Spring Harbor Laboratory (CSHL) announce the discovery of a new neural circuit in the brain that directly links the site of fear memory with an area of the brainstem that controls behavior.

How does the brain convert an emotion into a behavioral response? For years, researchers have known that fear memories are learned and stored in a small structure in the brain known as the amygdala. Any disturbing event activates neurons in the lateral and then central portions of the amygdala. The signals are then communicated internally, passing from one group of neurons to the next. From there, they reach neurons in the brainstem, the action center for fear responses.

Last year, CSHL Associate Professor Bo Li and his colleagues were able to use new genetic techniques to determine the precise neurons in the central amygdala that control fear memory. His current research exploits new methods to understand how the central amygdala communicates fear memories to the areas of the brain that are responsible for action.

In work published today in The Journal of Neuroscience, Li and his team identify a group of long-range neurons that extend from the central amygdala. These neurons project to an area of the brainstem, known as the midbrain periaqueductal gray (PAG), that controls the fear response.

Li and his colleagues explored how these long-range neurons participate in fear conditioning. They trained animals to associate a particular sound with a shock, conditioning the animals to fear the sound. In these animals, the activity of the long-range projection neurons in the central amygdala became enhanced.

“This study not only establishes a novel pathway for fear learning, but also identifies neurons that actively participate in fear conditioning,” says Li. “This new pathway can mediate the effect of the central amygdala directly, rather than signaling through other neurons, as traditionally thought.”

The next step for these researchers is to apply this knowledge to models of PTSD. “We are working to find out how these circuits behave in anxiety disorders, so that we can hopefully learn to control fear in diseases such as PTSD,” says Li.

Filling me softly

Surgical implants are widely used in modern medicine but their effectiveness is often compromised by how our bodies react to them. Now, scientists at the University of Cambridge have discovered that implant stiffness is a major cause of this so-called foreign body reaction.

This is the first time that stiffness of implant materials has been shown to be involved in foreign body reactions. The findings – published in the journal Biomaterials – could lead to major improvements in surgical implants and the quality of life of patients whose lives depend on them.

Foreign bodies often trigger a process that begins with inflammation and ends with the foreign body being encapsulated with scar tissue. When this happens after an accident or injury, the process is usually vital to healing, but when the same occurs around, for example, electrodes implanted in the brain to alleviate tremor in Parkinson’s disease, it may be problematic.

Despite decades of research, the process remains poorly understood as neither the materials from which these implants are made, nor their electrical properties, can explain what triggers inflammation.

Instead of looking for classical biological causes, a group of Cambridge physicists, engineers, chemists, clinical scientists and biologists decided to take a different tack and examine the impact of an implant’s stiffness on the inflammatory process.

According to Dr Kristian Franze, one of the authors of the study: “Electrodes that are implanted in the brain, for example, should be chemically inert, and these foreign body reactions occur whether or not these electrodes are switched on, so it’s not the electrical signalling.

“We thought that an obvious difference between electrodes and brain tissue is stiffness. Brain tissue is as soft as cream cheese, it is one of the softest tissues in the body, and electrodes are orders of magnitude stiffer.”

To test their hypothesis that mechanical signals trigger inflammation, the team cultured brain cells on two different substrates. The substrates were chemically identical but one was as soft as brain tissue and the other two orders of magnitude stiffer, akin to the stiffness of muscle tissue.

When they examined the cells, they found major differences in their shape. “The cells grown on the stiffer substrate were very flat, whereas those grown on the soft substrate looked much more like cells you find in the brain,” he explained.

To confirm the findings they did genetic and other tests, which revealed that many of the inflammatory genes and proteins known to be involved in foreign body reactions had been upregulated on stiff surfaces.

The team then implanted a tiny foreign body into rats’ brains. The implant was made of a single material but one side was as soft as brain tissue and the other as stiff as muscle. They found much greater foreign body reaction around the stiff part of the implant.

“This strongly indicates that stiffness of a material may trigger foreign body reactions. It does not mean there aren’t other triggers, but stiffness definitely contributes and this is something new that hasn’t been known before,” he said.

The findings could have major implications for the design of implants used in the brain and other parts of the body.

“While it may eventually be possible to make implants out of new, much softer materials, our results suggest that in the short term, simply coating existing implants with materials that match the stiffness of the tissue they are being implanted into will help reduce foreign body reactions,” said Dr Franze.

Mathematical beauty activates same brain region as great art or music

People who appreciate the beauty of mathematics activate the same part of their brain when they look at aesthetically pleasing formula as others do when appreciating art or music, suggesting that there is a neurobiological basis to beauty.

There are many different sources of beauty - a beautiful face, a picturesque landscape, a great symphony are all examples of beauty derived from sensory experiences. But there are other, highly intellectual sources of beauty. Mathematicians often describe mathematical formulae in emotive terms and the experience of mathematical beauty has often been compared by them to the experience of beauty derived from the greatest art.

In a new paper published in the open-access journal Frontiers in Human Neuroscience, researchers used functional magnetic resonance imaging (fMRI) to image the brain activity of 15 mathematicians when they viewed mathematical formulae that they had previously rated as beautiful, neutral or ugly. 

The results showed that the experience of mathematical beauty correlates with activity in the same part of the emotional brain – namely the medial orbito-frontal cortex – as the experience of beauty derived from art or music.

Professor Semir Zeki, lead author of the paper from the Wellcome Laboratory of Neurobiology at UCL, said: “To many of us mathematical formulae appear dry and inaccessible but to a mathematician an equation can embody the quintescence of beauty. The beauty of a formula may result from simplicity, symmetry, elegance or the expression of an immutable truth. For Plato, the abstract quality of mathematics expressed the ultimate pinnacle of beauty.”

“This makes it interesting to learn whether the experience of beauty derived from such as highly intellectual and abstract source as mathematics correlates with activity in the same part of the emotional brain as that derived from more sensory, perceptually based, sources.”

In the study, each subject was given 60 mathematical formulae to review at leisure and rate on a scale of -5 (ugly) to +5 (beautiful) according to how beautiful they experienced them to be. Two weeks later they were asked to re-rate them while in an fMRI scanner.

The formulae most consistently rated as beautiful (both before and during the scans) were Leonhard Euler’s identity, the Pythagorean identity and the Cauchy-Riemann equations. Leonhard Euler’s identity links five fundamental mathematical constants with three basic arithmetic operations each occurring once and the beauty of this equation has been likened to that of the soliloquy in Hamlet.

Mathematicians judged Srinivasa Ramanujan’s infinite series and Riemann’s functional equation as the ugliest.

Professor Zeki said: “We have found that activity in the brain is strongly related to how intense people declare their experience of beauty to – even in this example where the source of beauty is extremely abstract. This answers a critical question in the study of aesthetics, namely whether aesthetic experiences can be quantified.”

Professor Zeki added: “We have found that, as with the experience of visual or musical beauty, the activity in the brain is strongly related to how intense people declare their experience of beauty to be – even in this example where the source of beauty is extremely abstract. This answers a critical question in the study of aesthetics, one which has been debated since classical times, namely whether aesthetic experiences can be quantified.”