Neuroscience
Month
New research from the Copenhagen Centre for Social Evolution and Yale University offers compelling support for the general evolutionary theory that birth weight and -length can partially predict the likelihood of being diagnosed with mental health disorders such as autism and schizophrenia later in life. The study analyzed medical records of 1.75 million Danish births, and subsequent hospital diagnoses for up to 30 years, and adjusted for almost all other known risk factors. The study is published today in the Proceedings of the Royal Society, London B.
The number of people diagnosed with mental health disorders is on the rise in most affluent countries, but we do not yet have a comprehensive understanding of the factors that make people vulnerable to these disorders.
A new analysis of the extensive Danish public health database suggests that part of the answer may reside in genetic imprints established at conception that influence both size at birth and mental health during childhood and early adolescence.
The study tests predictions of the evolutionary theory of genomic imprinting – the idea that during fetal development some genes inherited from the mother are expressed differently to those inherited from the father. The potential consequence of this asymmetry is that maternal and paternal genes in a fetus will not cooperate fully during this period, even though they subsequently have shared interests due to their lifetime commitment to the same body.
Opposite forces balance each other
The reason for the conflict is that some of the genes known to be expressed in the placenta and the brain carry imprints that affect resource provisioning of the unborn child. When such genes come from the father, they favor investment of more of the mother’s resources in the developing fetus, whereas the maternally-imprinted genes will normally compensate for such paternally-influenced manipulative effects to lessen the drain on maternal resources. These opposite forces balance each other in most pregnancies, with the result that most children are born with close to average length and weight and with a high likelihood of balanced mental health development.
Small deviations may well be favorable in human populations, when somewhat heavier babies are more likely to develop abstract talents and somewhat lighter babies above average social talents, for instance. However, this incurs the risk of increasing the frequency of autistic- and schizophrenic-spectrum disorders in the rare cases where imprinting imbalances are larger. The theory may explain why natural selection has not removed this portion of the burden of mental disease from our ancestors.
The new study tests these predictions and its results are remarkably consistent. They show that the change to the risk of developing mental disorders when born smaller or larger than average are relatively small, but very consistent, clearly diametrical, and part of the single continuum that the theory predicts.
“When we started this large scale analysis four years ago, we hoped to find evidence that genetic imprinting happens, but we did not expect that the results would match the predictions as consistently as we found”, explains Professor Jacobus Boomsma, Director of the Centre for Social Evolution, University of Copenhagen, who coordinated the work.
Boomsma adds: “Our study confirms that larger babies have a higher risk for incurring autism-spectrum diagnoses later in life and lower risk for schizophrenia-spectrum disorders. For example, Danish newborns are on average 52 cm long and being born at 54 cm increases the autism risk by 20%. However, these are relative risks and these disorders remain rare: in this example the absolute risk increases from 0.65% to 0.78%. Risk patterns are opposite in smaller newborns, who have higher risks for schizophrenia and lower risks for autism. Only for the smallest, prematurely-born babies does this diametric pattern disappear, because they have elevated risks for almost all disease categories”.
Evolutionary conflicts
Boomsma also underlines that focused genomic studies will be needed to find out which genes are involved and how they affect brain function: ”Our Centre’s main objective is to develop and test evolutionary theory about the ways in which gene-level conflicts can corrupt even the most sophisticated forms of naturally evolved cooperation. It is no surprise that humans are vulnerable to such deep evolutionary conflicts, as are other mammals, and it is both useful and interesting to be aware of this part of our biological heritage”, says Professor Boomsma.
New research shows that patients with fibromyalgia have hypersensitivity to non-painful events based on images of the patients’ brains, which show reduced activation in primary sensory regions and increased activation in sensory integration areas. Findings published in Arthritis & Rheumatology, a journal of the American College of Rheumatology (ACR), suggest that brain abnormalities in response to non-painful sensory stimulation may cause the increased unpleasantness that patients experience in response to daily visual, auditory and tactile stimulation.
Fibromyalgia is a chronic, musculoskeletal syndrome characterized by widespread pain, affecting roughly two percent of the world population, say experts. According to the ACR, five million people in the U.S. have fibromyalgia, which is more prevalent among women. In previous studies fibromyalgia patients report reduced tolerance to normal sensory (auditory, visual, olfactory, and tactile) stimulation in addition to greater sensitivity to pain.
For the present study, researchers used functional magnetic resonance imaging (fMRI) to assess brain response to sensory stimulation in 35 women with fibromyalgia and 25 healthy, age-matched controls. Patients had an average disease duration of 7 years and a mean age of 47.
According to the study, patients reported increased unpleasantness in response to multisensory stimulation in daily life activities. Furthermore, fMRI displayed reduced activation of both the primary and secondary visual and auditory areas of the brain, and increased activation in sensory integration regions. These brain abnormalities mediated the increased unpleasantness to visual, auditory and tactile stimulation that patients reported to experience in daily life.
Lead study author, Dr. Marina López-Solà from the Institute of Cognitive Science, University of Colorado Boulder said, “Our study provides new evidence that fibromyalgia patients display altered central processing in response to multisensory stimulation, which are linked to core fibromyalgia symptoms and may be part of the disease pathology. The finding of reduced cortical activation in the visual and auditory brain areas that were associated with patient pain complaints may offer novel targets for neurostimulation treatments in fibromyalgia patients.”
Using advanced computer models, neuroscience researchers at the University of Copenhagen have gained new knowledge about the complex processes that cause Parkinson’s disease. The findings have recently been published in the prestigious Journal of Neuroscience.
The defining symptoms of Parkinson’s disease are slow movements, muscular stiffness and shaking. There is currently no cure for the condition, so it is essential to conduct innovative research with the potential to shed some light on this terrible disruption to the central nervous system that affects one person in a thousand in Denmark.
Dopamine is an important neurotransmitter which affects physical and psychological functions such as motor control, learning and memory. Levels of this substance are regulated by special dopamine cells. When the level of dopamine drops, nerve cells that constitute part of the brain’s ‘stop signal’ are activated.
“This stop signal is rather like the safety lever on a motorised lawn mower: if you take your hand off the lever, the mower’s motor stops. Similarly, dopamine must always be present in the system to block the stop signal. Parkinson’s disease arises because for some reason the dopamine cells in the brain are lost, and it is known that the stop signal is being over-activated somehow or other. Many researchers have therefore considered it obvious that long-term lack of dopamine must be the cause of the distinctive symptoms that accompanies the disease. However, we can now use advanced computer simulations to challenge the existing paradigm and put forward a different theory about what actually takes place in the brain when the dopamine cells gradually die,” explains Jakob Kisbye Dreyer, Postdoc at the Department of Neuroscience and Pharmacology, University of Copenhagen.
A thorn in the side
Scanning the brain of a patient suffering from Parkinson’s disease reveals that in spite of dopamine cell death, there are no signs of a lack of dopamine – even at a comparatively late stage in the process.
“The inability to establish a lack of dopamine until advanced cases of Parkinson’s disease has been a thorn in the side of researchers for many years. On the one hand, the symptoms indicate that the stop signal is over-activated, and patients are treated accordingly with a fair degree of success. On the other hand, data prove that they are not lacking dopamine,” says Postdoc Jakob Kisbye Dreyer.
Computer models predict the progress of the disease
“Our calculations indicate that cell death only affects the level of dopamine very late in the process, but that symptoms can arise long before the level of the neurotransmitter starts to decline. The reason for this is that the fluctuations that normally make up a signal become weaker. In the computer model, the brain compensates for the shortage of signals by creating additional dopamine receptors. This has a positive effect initially, but as cell death progresses further, the correct signal may almost disappear. At this stage, the compensation becomes so overwhelming that even small variations in the level of dopamine trigger the stop signal – which can therefore cause the patient to develop the disease.”
The new research findings may pave the way for earlier diagnosis of Parkinson’s disease.
Magnetic stimulation of a brain area involved in “executive function” affects cravings for and consumption of calorie-dense snack foods, reports a study in the September issue of Psychosomatic Medicine: Journal of Biobehavioral Medicine, the official journal of the American Psychosomatic Society. The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.
After stimulation of the dorsolateral prefrontal cortex (DLPFC), young women experience increased cravings for high-calorie snacks—and eat more of those foods when given the opportunity, according to the study by researchers at University of Waterloo, Ont., Canada. “These findings shed a light on the role of the DLPFC in food cravings (specifically reward anticipation), the consumption of appealing high caloric foods, and the relation between self-control and food consumption,” the researchers write. The senior author was Peter Hall, PhD.
Brain Stimulation Affects Cravings and Consumption for ‘Appetitive’ Snacks
The study included 21 healthy young women, selected because they reported strong and frequent cravings for chocolate and potato chips. Such “appetitive,” calorie-dense snack foods are often implicated in the development of obesity.
The women were shown pictures of these foods to stimulate cravings. The researchers then applied a type of magnetic stimulation, called continuous theta-burst stimulation, to decrease activity in the DLPFC. Previous studies have suggested that DLPFC activity plays a role in regulating food cravings.
After theta-burst stimulation, the women reported stronger food cravings—specifically for “appetitive” milk chocolate and potato chips. During a subsequent “taste test,” they consumed more of these foods, rather than alternative, less-appetitive foods (dark chocolate and soda crackers).
Stimulation to weaken DLPFC activity was also associated with lower performance on a test of inhibitory control strength (the Stroop test). Decreased DLPFC activity appeared to be associated with increased “reward sensitivity”—it made the participants “more sensitive to the rewarding properties of palatable high caloric foods,” the researchers write.
Weak Executive Function May Contribute to Obesity Risk
The results highlight the role of executive function in governing “dietary self-restraint,” the researchers believe. Executive function, which involves the DLPFC, refers to a set of cognitive functions that enable “top-down” control of action, emotion, and thought.
At the “basic neurobiological level,” the study provides direct evidence that the DLPFC is involved in one specific aspect of food cravings: reward anticipation. People with weak executive function may lack the dietary self-control necessary to regulate snack food consumption in “the modern obesogenic environment.” Faced with constant cues and opportunities to consume energy-dense foods, such individuals may be more likely to become overweight or obese.
The results suggest that interventions aimed at enhancing or preserving DLPFC function may help to prevent obesity and related diseases. In conditions such as type 2 diabetes, where healthy dietary habits are essential for effective disease control, “Interventions focused on enhancing DLPFC activity, through aerobic exercise or other means, may result in increased dietary self-control and subsequently improve disease management,” Dr Hall and coauthors add.
Breakthrough in detecting early onset of refractory epilepsy in children will lead to effective treatment using non-pharmacological therapies.
65 million people around the world today suffer from epilepsy, a condition of the brain that may trigger an uncontrollable seizure at any time, often for no known reason. A seizure is a disruption of the electrical communication between neurons, and someone is said to have epilepsy if they experience two or more unprovoked seizures separated by at least 24 hours.
Epilepsy is the most common chronic disease in pediatric neurology, with about 0.5-1% of children developing epilepsy during their lifetime. A further 30-40% of epileptic children develop refractory epilepsy, a particular type of epilepsy that cannot be managed by antiepileptic drugs (AED). Regardless of etiology, children with refractory epilepsy are invariably exposed to a variety of physical, psychological and social morbidities. Patients whose seizures are difficult to control could benefit from non-pharmacological therapies, including surgery, deep brain stimulation and ketogenic diets. Therefore, the early identification of patients whose seizures are refractory to AED would allow them to receive alternative therapies at an appropriate time.
Despite idiopathic etiology being a significant predictor of a lower risk of refractory epilepsy, a subset of patients with idiopathic epilepsy might still be refractory to medical treatment.
Using a new electroencephalography (EEG) analytical method, a team of medical doctors and scientists in Taiwan has successfully developed a tool to detect certain EEG features often present in children with idiopathic epilepsy.
The team developed an efficient, automated and quantitative approach towards the early prediction of refractory idiopathic epilepsy based on EEG classification analysis. EEG analysis is widely employed to investigate brain disorders and to study brain electrical activity. In the study, a set of artifact-free EEG segments was acquired from the EEG recordings of patients belonging to two classes of epilepsy: well-controlled and refractory. To search for significantly discriminative EEG features and to reduce computational costs, a statistical approach involving global parametric features was adopted across EEG channels as well as over time. A gain ratio-based feature selection was then performed.
The study found a significantly higher DecorrTime avg AVG and RelPowDelta avg AVG in the well-controlled group than in the refractory group. This suggests that refractory patients have a higher risk of seizure attacks than well-controlled patients.
The main contributions of this study are as follows:
Further research with more diversity (in terms of pediatric and adult participants) is encouraged to expand on the tool’s reliability and generalisation. This study was supported partly by a grant from the Kaohsiung Medical University Hospital and grants from Ministry of Science and Technology, Taiwan.
The paper can be found in the upcoming issue of the International Journal of Neural Systems (IJNS)
Cognitive neuroscience research has shown that certain brain regions are associated with specific cognitive abilities, such as language, naming, and decision-making.
How and where these specific abilities are integrated in the brain to support complex cognition is still under investigation. However, researchers at the University of Iowa and Washington University in St. Louis, Missouri, believe that several hub regions may be especially important for the brain to function as an integrated network.
In research published online Sept. 15 in the Early Edition of the Proceedings of the National Academy of Sciences, scientists studied neurological patients with focal brain damage, and found that damage to six hub locations—identified in a model developed at Washington University using resting state fMRI, functional connectivity analyses, and graph theory—produced much greater cognitive impairment than damage to other locations.
Doctors have long observed that despite having similar locations or extent of brain injury, patients often present with wide-ranging degrees of impairment and exhibit different recovery trajectories. A better understanding of brain networks and hubs may improve the understanding of outcomes of brain injuries (for example, stroke, resection, or trauma) and help inform prognosis and rehabilitation efforts.
“We were able to identify a set of brain hubs and show that damage to those locations unexpectedly causes widespread cognitive impairments,” says David Warren, cognitive neuroscientist at the University of Iowa and lead study author. “We hope that this framework will help neurologists with diagnosis and prognosis, and neurosurgeons with surgical planning.”
Two contrasting views of brain hubs exist. One view focuses on the sheer number of connections between brain regions, with those regions showing the most connections considered hubs.
Warren and his colleagues contend that the number of connections a given region makes may not reflect the importance of a region to network function because it can be strongly influenced by network size. Instead, their framework defines hubs as brain regions that show correlated activity with multiple brain systems (rather than regions). The authors predicted that because hubs should be critical for brain function and complex cognition, damage to true hubs should produce widespread cognitive impairment.
This study evaluated long-term cognitive and behavioral data in 30 patients in the Iowa Neurological Patient Registry—19 with focal damage to one of the authors’ six target hub locations and 11 with damage to two control locations that fit the alternative hub definition.
On average, patients with lesions to target hubs had significant impairment in nine major cognitive domains—orientation/attention, perception, memory, language skills, motor performance, concept formation/reasoning, executive functions, emotional functions, and adaptive functions. In contrast, the group with lesions to control hubs was significantly impaired in just three of the nine domains (executive functions, emotional functions, and adaptive functions).
Additionally, the target group had significantly greater cognitive deficits than the control group in seven of nine domains (all except perception and emotional functions), again showing the widespread cognitive effects of target hub lesions.
“With a grant from the McDonnell Foundation, we’re planning to follow up by exploring the effects of damage to additional brain hubs, examining how damage to hubs alters brain activation, and studying neurosurgery patients prospectively before and after their surgeries,” says senior study author Daniel Tranel, professor of neurology in the UI Carver College of Medicine and psychology in the College of Liberal Arts and Sciences. “We think that this work could have a tremendous influence on clinical practice.”
UC San Francisco researchers have used brain scans to predict how young children learn to read, giving clinicians a possible tool to spot children with dyslexia and other reading difficulties before they experience reading challenges.
In the United States, children usually learn to read for the first time in kindergarten and become proficient readers by third grade, according to the authors. In the study, researchers examined brain scans of 38 kindergarteners as they were learning to read formally at school and tracked their white matter development until third grade. The brain’s white matter is essential for perceiving, thinking and learning.
The researchers found that the developmental course of the children’s white matter volume predicted the kindergarteners’ abilities to read.
“We show that white matter development during a critical period in a child’s life, when they start school and learn to read for the very first time, predicts how well the child ends up reading,” said Fumiko Hoeft, MD, PhD, senior author and an associate professor of child and adolescent psychiatry at UCSF, and member of the UCSF Dyslexia Center.
The research is published online in Psychological Science.
Doctors commonly use behavioral measures of reading readiness for assessments of ability. Other measures such as cognitive (i.e. IQ) ability, early linguistic skills, measures of the environment such as socio-economic status, and whether there is a family member with reading problems or dyslexia are all common early factors used to assess risk of developing reading difficulties.
“What was intriguing in this study was that brain development in regions important to reading predicted above and beyond all of these measures,” said Hoeft.
The researchers removed the effects of these commonly used assessments when doing the statistical analyses in order to assess how the white matter directly predicted future reading ability. They found that left hemisphere white matter in the temporo-parietal region just behind and above the left ear — thought to be important for language, reading and speech — was highly predictive of reading acquisition beyond effects of genetic predisposition, cognitive abilities, and environment at the outset of kindergarten. Brain scans improved prediction accuracy by 60 percent better at predicting reading difficulties than the compared to traditional assessments alone.
“Early identification and interventions are extremely important in children with dyslexia as well as most neurodevelopmental disorders,” said Hoeft. “Accumulation of research evidence such as ours may one day help us identify kids who might be at risk for dyslexia, rather than waiting for children to become poor readers and experience failure.”
According to the National Institute of Child and Human Development, as many as 15 percent of Americans have major trouble reading.
“Examining developmental changes in the brain over a critical period of reading appears to be a unique sensitive measure of variation and may add insight to our understanding of reading development in ways that brain data from one time point, and behavioral and environmental measures, cannot,” said Chelsea Myers, BS, lead author and lab manager in UCSF’s Laboratory for Educational NeuroScience. “The hope is that understanding each child’s neurocognitive profiles will help educators provide targeted and personalized education and intervention, particularly in those with special needs.”
New research shows that schizophrenia isn’t a single disease but a group of eight genetically distinct disorders, each with its own set of symptoms. The finding could be a first step toward improved diagnosis and treatment for the debilitating psychiatric illness.
The research at Washington University School of Medicine in St. Louis is reported online Sept. 15 in The American Journal of Psychiatry.
About 80 percent of the risk for schizophrenia is known to be inherited, but scientists have struggled to identify specific genes for the condition. Now, in a novel approach analyzing genetic influences on more than 4,000 people with schizophrenia, the research team has identified distinct gene clusters that contribute to eight different classes of schizophrenia.
“Genes don’t operate by themselves,” said C. Robert Cloninger, MD, PhD, one of the study’s senior investigators. “They function in concert much like an orchestra, and to understand how they’re working, you have to know not just who the members of the orchestra are but how they interact.”
Cloninger, the Wallace Renard Professor of Psychiatry and Genetics, and his colleagues matched precise DNA variations in people with and without schizophrenia to symptoms in individual patients. In all, the researchers analyzed nearly 700,000 sites within the genome where a single unit of DNA is changed, often referred to as a single nucleotide polymorphism (SNP). They looked at SNPs in 4,200 people with schizophrenia and 3,800 healthy controls, learning how individual genetic variations interacted with each other to produce the illness.
In some patients with hallucinations or delusions, for example, the researchers matched distinct genetic features to patients’ symptoms, demonstrating that specific genetic variations interacted to create a 95 percent certainty of schizophrenia. In another group, they found that disorganized speech and behavior were specifically associated with a set of DNA variations that carried a 100 percent risk of schizophrenia.
“What we’ve done here, after a decade of frustration in the field of psychiatric genetics, is identify the way genes interact with each other, how the ‘orchestra’ is either harmonious and leads to health, or disorganized in ways that lead to distinct classes of schizophrenia,” Cloninger said.
Although individual genes have only weak and inconsistent associations with schizophrenia, groups of interacting gene clusters create an extremely high and consistent risk of illness, on the order of 70 to 100 percent. That makes it almost impossible for people with those genetic variations to avoid the condition. In all, the researchers identified 42 clusters of genetic variations that dramatically increased the risk of schizophrenia.
“In the past, scientists had been looking for associations between individual genes and schizophrenia,” explained Dragan Svrakic, PhD, MD, a co-investigator and a professor of psychiatry at Washington University. “When one study would identify an association, no one else could replicate it. What was missing was the idea that these genes don’t act independently. They work in concert to disrupt the brain’s structure and function, and that results in the illness.”
Svrakic said it was only when the research team was able to organize the genetic variations and the patients’ symptoms into groups that they could see that particular clusters of DNA variations acted together to cause specific types of symptoms.
Then they divided patients according to the type and severity of their symptoms, such as different types of hallucinations or delusions, and other symptoms, such as lack of initiative, problems organizing thoughts or a lack of connection between emotions and thoughts. The results indicated that those symptom profiles describe eight qualitatively distinct disorders based on underlying genetic conditions.
The investigators also replicated their findings in two additional DNA databases of people with schizophrenia, an indicator that identifying the gene variations that are working together is a valid avenue to explore for improving diagnosis and treatment.
By identifying groups of genetic variations and matching them to symptoms in individual patients, it soon may be possible to target treatments to specific pathways that cause problems, according to co-investigator Igor Zwir, PhD, research associate in psychiatry at Washington University and associate professor in the Department of Computer Science and Artificial Intelligence at the University of Granada, Spain.
And Cloninger added it may be possible to use the same approach to better understand how genes work together to cause other common but complex disorders.
“People have been looking at genes to get a better handle on heart disease, hypertension and diabetes, and it’s been a real disappointment,” he said. “Most of the variability in the severity of disease has not been explained, but we were able to find that different sets of genetic variations were leading to distinct clinical syndromes. So I think this really could change the way people approach understanding the causes of complex diseases.”
Living cells are like miniature factories, responsible for the production of more than 25,000 different proteins with very specific 3-D shapes. And just as an overwhelmed assembly line can begin making mistakes, a stressed cell can end up producing misshapen proteins that are unfolded or misfolded.
(Image caption: A color-enhanced electron micrograph shows the nucleus of a cell (blue) adjacent to the rough endoplasmic reticulum (green), where proteins are manufactured from mRNA templates produced by the nucleus. Credit: University of Edinburgh, via the Wellcome TrustAdd)
Now Duke University researchers in North Carolina and Singapore have shown that the cell recognizes the buildup of these misfolded proteins and responds by reshuffling its workload, much like a stressed out employee might temporarily move papers from an overflowing inbox into a junk drawer.
The study, which appears Sept. 11, 2014 in Cell, could lend insight into diseases that result from misfolded proteins piling up, such as Alzheimer’s disease, ALS, Huntington’s disease, Parkinson’s disease, and type 2 diabetes.
“We have identified an entirely new mechanism for how the cell responds to stress,” said Christopher V. Nicchitta, Ph.D., a professor of cell biology at Duke University School of Medicine. “Essentially, the cell remodels the organization of its protein production machinery in order to compartmentalize the tasks at hand.”
The general architecture and workflow of these cellular factories has been understood for decades. First, DNA’s master blueprint, which is locked tightly in the nucleus of each cell, is transcribed into messenger RNA or mRNA. Then this working copy travels to the ribosomes standing on the surface of a larger accordion-shaped structure called the endoplasmic reticulum (ER). The ribosomes on the ER are tiny assembly lines that translate the mRNAs into proteins.
When a cell gets stressed, either by overheating or starvation, its proteins no longer fold properly. These unfolded proteins can set off an alarm — called the unfolded protein response or UPR – to slow down the assembly line and clean up the improperly folded products. Nicchitta wondered if the stress response might also employ other tactics to deal with the problem.
In this study, Nicchitta and his colleagues treated tissue culture cells with a stress-inducing agent called thapsigargin. They then separated the cells into two groups — those containing mRNAs associated with ribosomes on the endoplasmic reticulum, and those containing mRNAs associated with free-floating ribosomes in the neighboring fluid-filled space known as the cytosol.
The researchers found that when the cells were stressed, they quickly moved mRNAs from the endoplasmic reticulum to the cytosol. Once the stress was resolved, the mRNAs went back to their spots on the production floor of the endoplasmic reticulum.
“You can slow down protein production, but sometimes slowing down the workflow is not enough,” Nicchitta said. “You can activate genes to help chew up the misfolded proteins, but sometimes they are accumulating too quickly. Here we have discovered a mechanism that does one better — it effectively puts everything on hold. Once things get back to normal, the mRNAs are released from the holding pattern.”
Interestingly, the researchers found that shuttling ribosomes between the ER and the cytoplasm during stress only affected the subset of mRNAs that would give rise to secreted proteins like hormones or membrane proteins like growth factor receptors — the types of proteins that set off the stress response if they’re misfolded. They aren’t sure yet what this means.
Nicchitta is currently searching for the factors that ultimately determine which mechanisms cells employ during the stress response. He has already pinpointed one promising candidate, and is looking to see how cells respond to stress when that factor is manipulated.
In what may be the largest study of sleep problems among individuals with multiple sclerosis (MS), researchers at UC Davis have found that widely undiagnosed sleep disorders may be at the root of the most common and disabling symptom of the disease: fatigue.
Conducted in over 2,300 individuals in Northern California with multiple sclerosis, the large, population-based study found that, overall, more than 70 percent of participants screened positive for one or more sleep disorders.
The research highlights the importance of diagnosing the root causes of fatigue among individuals with MS, as sleep disorders may affect the course of the disease as well as the overall health and well-being of sufferers, the authors said.
The study “The Underdiagnosis of Sleep Disorders in Patients with Multiple Sclerosis,” is published online today in the Journal of Clinical Sleep Medicine.
“A large percentage of MS subjects in our study are sleep deprived and screened positive for one or more sleep disorders,” said Steven Brass, associate clinical professor and director of the Neurology Sleep Clinical Program and co-medical director of the UC Davis Sleep Medicine Laboratory.
“The vast majority of these sleep disorders are potentially undiagnosed and untreated,” he said. “This work suggests that patients with MS may have sleep disorders requiring independent diagnosis and management.”
Fatigue is the hallmark of multiple sclerosis, an inflammatory disease affecting the white matter and spinal cord of sufferers. MS symptoms include loss of vision, vertigo, weakness and numbness. Patients also may experience psychiatric symptoms. Disease onset generally is between the ages of 20 and 50 years. The cause of MS is not known, although it is believed to be an autoimmune condition.
Sleep disorders are known to occur more frequently among patients with MS. To gauge the extent of sleep disorders, such as obstructive sleep apnea and insomnia, Brass and his colleagues surveyed members of the Northern California Chapter of the National MS Society. Subjects were recruited in 2011.
More than 11,000 surveys were mailed to prospective participants. Of those, 2,375 met criteria and were included in the study. Consistent with the reported epidemiology of multiple sclerosis, the majority (81 percent) were female and Caucasian (88 percent). The mean age of the participants was 54.
Participants were asked to complete a 10-page survey, which included a detailed sleep history and questions assessing obstructive sleep apnea, daytime sleepiness, insomnia and restless legs syndrome.
Most of the participants - nearly 52 percent - said it took them more than one half hour to fall asleep at night, and nearly 11 percent reported taking a medication to fall asleep. Close to 38 percent of participants screened positive for obstructive sleep apnea. Nearly 32 percent had moderate to severe insomnia and nearly 37 percent had restless legs syndrome.
However, most of the participants had not been diagnosed with a sleep disorder by a physician. While nearly 38 percent reported having obstructive sleep apnea, only a little more than 4 percent reported being diagnosed by a physician with the condition. Similar statistics were seen for other sleep disorders.
“This study shows that sleep disorder frequency, sleep patterns and complaints of excessive daytime sleepiness suggest that sleep problems may be a hidden epidemic in the MS population, separate from MS fatigue,” Brass said.
There is a link between our brain structure and our tolerance of risk, new research suggests.
Dr Agnieszka Tymula, an economist at the University of Sydney, is one of the lead authors of a new study that identifies what might be considered the first stable ‘biomarker’ for financial risk-attitudes.
Using a whole-brain analysis, Dr Tymula and international collaborators found that the grey matter volume of a region in the right posterior parietal cortex was significantly predictive of individual risk attitudes. Men and women with higher grey matter volume in this region exhibited less risk aversion.
"Individual risk attitudes are correlated with the grey matter volume in the posterior parietal cortex suggesting existence of an anatomical biomarker for financial risk-attitude," said Dr Tymula.
This means tolerance of risk “could potentially be measured in billions of existing medical brain scans.”
But she has cautioned against making a causal link between brain structure and behaviour. More research will be needed to establish whether structural changes in the brain lead to changes in risk attitude or whether that individual’s risky choices alter his or her brain structure - or both.
"The findings fit nicely with our previous findings on risk attitude and ageing. In our Proceedings of the National Academy of Sciences 2013 paper we found that as people age they become more risk averse,” she said.
"From other work we know that cortex thins substantially as we age. It is possible that changes in risk attitude over lifespan are caused by thinning of the cortex."
The findings are published in the September 10 issue of The Journal of Neuroscience.
One of the greatest casualties of war is its lasting effect on the minds of soldiers. This presents a daunting public health problem: More than 20 percent of veterans returning from the wars in Iraq and Afghanistan have post-traumatic stress disorder, according to a 2012 report by RAND Corp.
A new study from the Center for Investigating Healthy Minds at the Waisman Center of the University of Wisconsin-Madison offers hope for those suffering from the disorder. Researchers there have shown that a breathing-based meditation practice called Sudarshan Kriya Yoga can be an effective treatment for PTSD.
Individuals with PTSD suffer from intrusive memories, heightened anxiety, and personality changes. The hallmark of the disorder is hyperarousal, which can be defined as overreacting to innocuous stimuli, and is often described as feeling “jumpy,” or easily startled and constantly on guard.
Hyperarousal is one aspect of the autonomic nervous system, the system that controls the beating of the heart and other body functions, and governs one’s ability to respond to his or her environment. Scientists believe hyperarousal is at the core of PTSD and the driving force behind some of its symptoms.
Standard treatment interventions for PTSD offer mixed results. Some individuals are prescribed antidepressants and do well while others do not; others are treated with psychotherapy and still experience residual affects of the disorder.
Sudarshan Kriya Yoga is a practice of controlled breathing that directly affects the autonomic nervous system. While the practice has proven effective in balancing the autonomic nervous system and reducing symptoms of PTSD in tsunami survivors, it has not been well studied until now.
The CIHM team was interested in Sudarshan Yoga because of its focus on manipulating the breath, and how that in turn may have consequences for the autonomic nervous system and specifically, hyperarousal. Theirs is the first randomized, controlled, longitudinal study to show that the practice of controlled breathing can benefit people with PTSD.
"This was a preliminary attempt to begin to gather some information on whether this practice of yogic breathing actually reduces symptoms of PTSD," says Richard J. Davidson, founder of CIHM and one of the authors of the study. "Secondly, we wanted to find out whether the reduction in symptoms was associated with biological measures that may be important in hyperarousal."
These tests included measuring eye-blink startle magnitude and respiration rates in response to stimuli such as a noise burst in the laboratory. Respiration is one of the functions controlled by the autonomic nervous system; the eye-blink startle rate is an involuntary response that can be used to measure one component of hyperarousal. These two measurements reflect aspects of mental health because they affect how an individual regulates emotion.
The CIHM study included 21 soldiers: an active group of 11 and a control group of 10. Those who received the one-week training in yogic breathing showed lower anxiety, reduced respiration rates and fewer PTSD symptoms.
Davidson would like to further the research by including more participants, with the end goal of enabling physicians to prescribe treatment based on the cognitive and emotional style of the individual patient.
"A clinician could use a ‘tool box’ of psychological assessments to determine the cognitive and emotional style of the patient, and thereby determine a treatment that would be most effective for that individual," he says. "Right now, a large fraction of individuals who are given any one type of therapy are not improving on that therapy. The only way we can improve that is if we determine which kinds of people will benefit most from different types of treatments."
That assessment is critical. At least 22 veterans take their own lives every day, according to the U.S. Department of Veterans Affairs. Because Sudarshan Kriya Yoga has already been shown to increase optimism in college students, and reduce stress and anxiety in people suffering from depression, it may be an effective way to decrease suffering and, quite possibly, the incidence of suicide among veterans.
The study, published in the Journal of Traumatic Stress, was funded by a grant from the Disabled Veterans of America Charitable Service Trust and individual donors.
A deficiency of a single vitamin, B1 (thiamine), can cause a potentially fatal brain disorder called Wernicke encephalopathy.
(Image: iStock)
Symptoms can include confusion, hallucinations, coma, loss of muscle coordination and vision problems such as double vision and involuntary eye movements. Untreated, the condition can lead to irreversible brain damage and death, according to neurologists at Loyola University Medical Center.
In the developed world, Wernicke encephalopathy typically occurs in people who have disorders such as alcoholism and anorexia that lead to malnourishment.
Wernicke encephalopathy is an example of the wide range of brain diseases, called encephalopathies, that are caused by metabolic disorders and toxic substances, according to a report by Loyola neurologists Matthew McCoyd, MD, Sean Ruland, DO, and José Biller, MD, in the journal Scientific American Medicine.
Acute encephalopathy has a rapid onset of between hours and days. It is commonly due to toxic and metabolic factors.
“Toxic and metabolic encephalopathies may range in severity from the acute confusional state to frank coma,” McCoyd, Ruland and Biller write. “As permanent injury may occur, an organized approach is needed to make an accurate and rapid diagnosis.”
The hallmark of toxic and metabolic encephalopathies is altered sensorium. This can range from mild attention impairment, such as difficulty spelling a word backwards, to coma.
Toxic encephalopathy can be caused by illegal drugs, environmental toxins and reactions to prescription drugs.
Thiamine deficiency is among the nutritional deficiencies that can cause brain diseases such as Wernicke encephalopathy. The condition likely is underdiagnosed. Although clinical studies find a rate of 0.13 percent or less, autopsy studies show a prevalence as high as 2.8 percent.
“Particularly in those who suffer from alcoholism or AIDS, the diagnosis is missed on clinical examination in 75 to 80 percent of cases,” the Loyola neurologists write.
Untreated, Wernicke encephalopathy can lead to Korsakoff syndrome (KS), characterized by profound memory loss and inability to form memories; patients often can’t remember events within the past 30 minutes. Other KS symptoms can include apathy, anxiety and confabulation (fabricating imaginary experiences to compensate for memory loss).
About 80 percent of Wernicke encephalopathy patients develop KS, and once this occurs, only about 20 percent of patients recover.
Pollution in many cities threatens the brain development in children.
Findings by University of Montana Professor Dr. Lilian Calderón-Garcidueñas, MA, MD, Ph.D., and her team of researchers reveal that children living in megacities are at increased risk for brain inflammation and neurodegenerative changes, including Alzheimer’s or Parkinson’s disease.
Calderón-Garcidueñas’ findings are detailed in a paper titled “Air pollution and children: Neural and tight junction antibodies and combustion metals, the role of barrier breakdown and brain immunity in neurodegeneration,” which can be found online at http://iospress.metapress.com/content/xx6582688105j48h/.
The study found when air particulate matter and their components such as metals are inhaled or swallowed, they pass through damaged barriers, including respiratory, gastrointestinal and the blood-brain barriers and can result in long-lasting harmful effects.
Calderón-Garcidueñas and her team compared 58 serum and cerebrospinal fluid samples from a control group living in a low-pollution city and matched them by age, gender, socioeconomic status, education and education levels achieved by their parents to 81 children living in Mexico City.
The results found that the children living in Mexico City had significantly higher serum and cerebrospinal fluid levels of autoantibodies against key tight-junction and neural proteins, as well as combustion-related metals.
“We asked why a clinically healthy kid is making autoantibodies against their own brain components,” Calderón-Garcidueñas said. “That is indicative of damage to barriers that keep antigens and neurotoxins away from the brain. Brain autoantibodies are one of the features in the brains of people who have neuroinflammatory diseases like multiple sclerosis.”
The issue is important and relevant for one reason, she explained. The breakdown of the blood-brain barrier and the presence of autoantibodies to important brain proteins will contribute to the neuroinflammation observed in urban children and raises the question of what role air pollution plays in a 400 percent increase of MS cases in Mexico City, making it one of the main diagnoses for neurology referrals.
Calderón-Garcidueñas points out that there is a need for a longitudinal follow-up study to determine if there is a relationship between the cognition deficits and brain MRI alterations previously reported in Mexico City children, and their autoimmune responses. But what is clear is that the kids are suffering from immune dysregulation.
Once there is a breakdown in the blood-brain barrier, not only will particulate matter enter the body but it also opens the door to harmful neurotoxins, bacteria and viruses.
“The barriers are there for a reason,” she explains. “They are there to protect you, but once they are broken the expected results are not good.”
The results of constant exposure to air pollution and the constant damage to all barriers eventually result in significant consequences later in life. She explains that the autoimmune responses are potentially contributing to the neuroinflammatory and Alzheimer’s and Parkinson’s pathology they are observing in young urban children.
While the study focused on children living in Mexico City, others living in cities where there are alarming levels of air pollution such as Los Angeles, Philadelphia-Wilmington, New York City, Salt Lake City, Chicago, Tokyo, Mumbai, New Delhi or Shanghai, among others, also face major health risks. In the U.S. alone, 200 million people live in areas where pollutants such as ozone and fine particulate matter exceed the standards.
“Investing in defining the central nervous system pathology associated with exposure to air pollutants in children is of pressing importance for public health,” Calderón-Garcidueñas said.
The full article is scheduled to be published in Volume 43, Issue 3 of the Journal of Alzheimer’s Disease and will appear online at http://www.j-alz.com in December with a 2015 copyright.
Employing a measure rarely used in sleep apnea studies, researchers at the UCLA School of Nursing have uncovered evidence of what may be damaging the brain in people with the sleep disorder — weaker brain blood flow.
(Image caption: This brain scan shows that the brain blood flow in a subject with obstructive sleep apnea (left) is markedly lower compared to a subject without the sleep disorder. Credit: UCLA)
In the study, published Aug. 28 in the peer-reviewed journal PLOS ONE, researchers measured blood flow in the brain using a non-invasive MRI procedure: the global blood volume and oxygen dependent (BOLD) signal. This method is usually used to observe brain activity. Because previous research showed that poor regulation of blood in the brain might be a problem for people with sleep apnea, the researchers used the whole-brain BOLD signal to look at blood flow in individuals with and without obstructive sleep apnea (OSA).
“We know there is injury to the brain from sleep apnea, and we also know that the heart has problems pumping blood to the body, and potentially also to the brain,” said Paul Macey, associate dean for Information Technology and Innovations at the UCLA School of Nursing and lead researcher for the study. “By using this method, we were able to show changes in the amount of oxygenated blood across the whole brain, which could be one cause of the damage we see in people with sleep apnea.”
Obstructive sleep apnea is a serious disorder that occurs when a person’s breathing is repeatedly interrupted during sleep, hundreds of times a night. Each time breathing stops, the oxygen level in the blood drops, which damages many cells in the body. If left untreated, it can lead to high blood pressure, stroke, heart failure, diabetes, depression and other serious health problems. Approximately 10 percent of adults struggle with obstructive sleep apnea, which is accompanied by symptoms of brain dysfunction, including extreme daytime sleepiness, depression and anxiety, and memory problems.
In this study, men and women — both with and without obstructive sleep apnea had their BOLD signals measured during three physical tasks while they were awake:
“When we looked at the results, we didn’t see much difference between the participants with and without OSA in the Valsalva maneuver,” said Macey. “But for the hand-grip and cold-pressor challenges, people with OSA saw a much weaker brain blood flow response.”
The researchers believe that the reason there were differences in the sleep apnea patients during the hand-grip and cold pressor challenge was because the signals from the nerves in the arms and legs had to be processed through the high brain areas controlling sensation and muscle movement, which was slower due to the brain injury. On the other hand, the changes from the Valsalva are mainly driven by blood pressure signaling in the chest, and do not need the sensory or muscle-controlling parts of the brain.
“This study brings us closer to understanding what causes the problems in the brain of people with sleep apnea,” concluded Macey.
The study also found the problem is greater in women with sleep apnea, which may explain the worse apnea-related outcomes in females than males. Studies recently published by the UCLA School of Nursing have shown that brain injury from sleep apnea is much worse in women than men.
The researchers are now looking at whether treatment for obstructive sleep apnea can reverse the damaging effects.