A gene for depression localized

Psychiatric disorders can be described on many levels, the most traditional of which are subjective descriptions of the experience of being depressed and the use of rating scales that quantify depressive symptoms. Over the past two decades, research has developed other strategies for describing the biological underpinnings of depression, including volumetric brain measurements using magnetic resonance imaging (MRI) and the patterns of gene expression in white blood cells. 

During this period, a great deal of research has attempted to characterize the genes that cause depression as reflected in rating scales of mood states, alterations in brain structure and function as measured by MRI, and gene expression patterns in post-mortem brain tissue from people who had depression. 

So what would happen if one tried to find the gene or genes that explained the "whole picture" by combining all of the different types of information that one could collect? This is exactly what was attempted by Dr. David Glahn, of Yale University and Hartford Hospital's Institute of Living, and his colleagues. 

"They have provided a very exciting strategy for uniting the various types of data that we collect in clinical research in studies attempting to identify risk genes," said Dr. John Krystal, Editor of Biological Psychiatry. 

Their work localized a gene, called RNF123, which may play a role in major depression. 

They set out with two clear goals: to describe a new method for ranking measures of brain structure and function on their genetic 'importance' for an illness, and then to localize a candidate gene for major depression. 

"We were trying to come up with a way that could generally be used to link biological measurements to (psychiatric) disease risk," said Dr. John Blangero, director of the AT&T Genomics Computing Center at the Texas Biomedical Research Institute. "And in our first application of this, in relation to major depressive disorder, we've actually come up with something quite exciting." 

While RNF123 hasn't previously been linked to depression, it has been shown to affect a part of the brain called the hippocampus, which is altered in people with major depression. 

"We assume that the biological measures are closer mechanistically to the underlying disease processes in the brain. Yet, ultimately we are interested in the subjective experiences and functional impairment associated with mental illness," added Krystal. "The approach employed in this study may help to make use of all of this information, hopefully increasing our ability to identify genes that cause depression or might be targeted for its treatment." 

Glahn said, "We still have more work before we truly believe this is a home-run gene, but we've got a really good candidate. Even that has been tough to do in depression." 

Source: Elsevier [January 04, 2012]

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Psychopathy: A misunderstood personality disorder

Psychopathic personalities are some of the most memorable characters portrayed in popular media today. These characters, like Patrick Bateman from American Psycho, Frank Abagnale Jr. from Catch Me If You Can and Alex from A Clockwork Orange, are typically depicted as charming, intriguing, dishonest, guiltless, and in some cases, downright terrifying. But scientific research suggests that psychopathy is a personality disorder that is widely misunderstood. 

"Psychopathy tends to be used as a label for people we do not like, cannot understand, or construe as evil," notes Jennifer Skeem, Professor of Psychology and Social Behavior at the University of California, Irvine. Skeem, Devon Polaschek of Victoria University of Wellington, Christopher Patrick of Florida State University, and Scott Lilienfeld of Emory University are the authors of a new monograph focused on understanding the psychopathic personality that will appear in the December issue of Psychological Science in the Public Interest, a journal of the Association for Psychological Science. 

In the course of their research, the authors reviewed many scientific findings that seemed to contradict one another. "Psychopathy has long been assumed to be a single personality disorder. However, there is increasing evidence that it is a confluence of several different personality traits," Skeem says. The authors of the monograph argue that rather than being "one thing" as often assumed, psychopathy appears to be a complex, multifaceted condition marked by blends of personality traits reflecting differing levels of disinhibition, boldness, and meanness. And scientific findings also suggest that a sizable subgroup of juvenile and adult offenders labeled as psychopathic are actually more emotionally disturbed than emotionally detached, showing signs of anxiety and dysphoria. 

According to Skeem, these important distinctions have long escaped the attention of psychologists and policy-makers. As a result, she and her co-authors set about to try to dispel some of the myths and assumptions that people often make about psychopathy. Although many people might assume that psychopaths are 'born,' not 'made,' the authors stress that psychopathy is not just a matter of genes – it appears to have multiple constitutional causes that can be shaped by environmental factors. Many psychologists also assume that psychopathy is inalterable – once a psychopath, always a psychopath. However, there is currently scant scientific evidence to support this claim. Recent empirical work suggests that youth and adults with high scores on measures of psychopathy can show reduced violent and other criminal behavior after intensive treatment. 

Along with challenging the assumption that psychopathy is a monolithic entity, perhaps the other most important myth that the authors hope to dispel is that psychopathy is synonymous with violence. Skeem points out that psychopathic individuals often have no history of violent behaviour or criminal convictions. "Psychopathy cannot be equated with extreme violence or serial killing. In fact, "psychopaths" do not appear different in kind from other people, or inalterably dangerous," she observes. Nor is it clear that psychopathy predicts violence much better than a past history of violent and other criminal behavior – or general antisocial traits. 

Effectively dispelling these myths is important, the authors argue, because accurate policy recommendations hinge on which personality traits – and which groups of people – associated with psychopathy one is examining. "Decisions about juvenile and adult offenders that are based on faulty assumptions about violence risk, etiology, and treatment amenability have adverse consequences, both for individual offenders and the public," Skeem says. 

In clarifying the personality traits that characterize psychopathy, scientists can contribute to prevention and treatment strategies that improve public health and safety. "In short, research on psychopathy has evolved to a level that it can greatly improve on the current, 'one size fits all' policy approach," concludes Skeem. 

Source: Association for Psychological Science [December 07, 2011]

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Psychopaths' brains show differences in structure and function

Images of prisoners' brains show important differences between those who are diagnosed as psychopaths and those who aren't, according to a new study led by University of Wisconsin-Madison researchers. 

This study found reduced connectivity between an area of prefrontal cortex (PFC, red) and the amygdala (blue). The white matter pathway connecting the two structures (the uncinate fasciculus) is shown in green [Credit: UWSMPH]

The results could help explain the callous and impulsive anti-social behavior exhibited by some psychopaths. 

The study showed that psychopaths have reduced connections between the ventromedial prefrontal cortex (vmPFC), the part of the brain responsible for sentiments such as empathy and guilt, and the amygdala, which mediates fear and anxiety. Two types of brain images were collected. Diffusion tensor images (DTI) showed reduced structural integrity in the white matter fibers connecting the two areas, while a second type of image that maps brain activity, a functional magnetic resonance image (fMRI), showed less coordinated activity between the vmPFC and the amygdala. 

"This is the first study to show both structural and functional differences in the brains of people diagnosed with psychopathy," says Michael Koenigs, assistant professor of psychiatry in the University of Wisconsin School of Medicine and Public Health. "Those two structures in the brain, which are believed to regulate emotion and social behavior, seem to not be communicating as they should." 

The study, which took place in a medium-security prison in Wisconsin, is a unique collaborative between three laboratories, 

UW-Madison psychology Professor Joseph Newman has had a long term interest in studying and diagnosing those with psychopathy and has worked extensively in the Wisconsin corrections system. Dr. Kent Kiehl, of the University of New Mexico and the MIND Research Network, has a mobile MRI scanner that he brought to the prison and used to scan the prisoners' brains. Koenigs and his graduate student, Julian Motzkin, led the analysis of the brain scans. 

The study compared the brains of 20 prisoners with a diagnosis of psychopathy with the brains of 20 other prisoners who committed similar crimes but were not diagnosed with psychopathy. 

"The combination of structural and functional abnormalities provides compelling evidence that the dysfunction observed in this crucial social-emotional circuitry is a stable characteristic of our psychopathic offenders,'' Newman says. "I am optimistic that our ongoing collaborative work will shed more light on the source of this dysfunction and strategies for treating the problem." 

Newman notes that none of this work would be possible without the extraordinary support provided by the Wisconsin Department of Corrections, which he called "the silent partner in this research." He says the DOC has demonstrated an unprecedented commitment to supporting research designed to facilitate the differential diagnosis and treatment of prisoners. 

The study, published in the most recent Journal of Neuroscience, builds on earlier work by Newman and Koenigs that showed that psychopaths' decision-making mirrors that of patients with known damage to their ventromedial prefrontal cortex (vmPFC). This bolsters evidence that problems in that part of the brain are connected to the disorder. 

"The decision-making study showed indirectly what this study shows directly – that there is a specific brain abnormality associated with criminal psychopathy,'' Koenigs adds. 

Source: University of Wisconsin-Madison [November 22, 2011]

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Tuning out: How brains benefit from meditation

Experienced meditators seem to be able switch off areas of the brain associated with daydreaming as well as psychiatric disorders such as autism and schizophrenia, according to a new brain imaging study by Yale researchers. 

Experienced meditators seem to switch off areas of the brain associated with wandering thoughts, anxiety and some psychiatric disorders such as schizophrenia. Researchers used fMRI scans to determine how the brains of meditators differed from subjects who were not meditating. The areas shaded in blue highlight areas of decreased activity in the brains of meditators [Credit: Yale University]

Meditation's ability to help people stay focused on the moment has been associated with increased happiness levels, said Judson A. Brewer, assistant professor of psychiatry and lead author of the study published the week of Nov. 21 in the Proceedings of the National Academy of Sciences. Understanding how meditation works will aid investigation into a host of diseases, he said. 

"Meditation has been shown to help in variety of health problems, such as helping people quit smoking, cope with cancer, and even prevent psoriasis," Brewer said. 

The Yale team conducted functional magnetic resonance imaging scans on both experienced and novice meditators as they practiced three different meditation techniques. 

They found that experienced meditators had decreased activity in areas of the brain called the default mode network, which has been implicated in lapses of attention and disorders such as anxiety, attention deficit and hyperactivity disorder, and even the buildup of beta amyloid plaques in Alzheimer's disease. The decrease in activity in this network, consisting of the medial prefrontal and posterior cingulate cortex, was seen in experienced meditators regardless of the type of meditation they were doing. 

The scans also showed that when the default mode network was active, brain regions associated with self-monitoring and cognitive control were co-activated in experienced meditators but not novices. This may indicate that meditators are constantly monitoring and suppressing the emergence of "me" thoughts, or mind-wandering. In pathological forms, these states are associated with diseases such as autism and schizophrenia. 

The meditators did this both during meditation, and also when just resting — not being told to do anything in particular. This may indicate that meditators have developed a "new" default mode in which there is more present-centered awareness, and less "self"-centered, say the researchers. 

"Meditation's ability to help people stay in the moment has been part of philosophical and contemplative practices for thousands of years," Brewer said. "Conversely, the hallmarks of many forms of mental illness is a preoccupation with one's own thoughts, a condition meditation seems to affect. This gives us some nice cues as to the neural mechanisms of how it might be working clinically."  

Source: Yale University [November 21, 2011]

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Unraveling how a mutation can lead to psychiatric illness

In recent years, scientists have discovered several genetic mutations associated with greater risk of psychiatric diseases such as schizophrenia and bipolar disorder. One such mutation, known as DISC1 — an abbreviation for “Disrupted in Schizophrenia-1” — was first identified in a large Scottish family with high rates of schizophrenia, bipolar disorder and depression. 

Studies have since shown that DISC1 mutations can lead to altered brain structure and impaired cognition, but it was unknown exactly how this occurs. A new study from Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory, shows that DISC1 mutations impair a specific signaling pathway in neurons that is critical for normal brain development. 

In a genetic screen of 750 people — some of whom were healthy and some of whom had psychiatric diseases — the researchers found several common variants of the DISC1 gene. However, even though these mutations disrupted normal brain development, they were not necessarily enough to cause disease on their own. 

“A lot of the human population may carry this [genetic defect], and they probably actually have some defects in their brain development. However, it’s also pretty clear that that by itself it is not sufficient to cause psychiatric disorder,” Tsai says. “That’s very consistent with the notion that there probably has to be a combination of several different genetic variations to trigger a clinically measurable outcome.” 

The study will appear in the Nov. 17 issue of the journal Neuron. Lead author of the paper is Karun Singh, a postdoc at the Picower Institute. 

Disrupted development 

In a study published in 2009, Tsai and her colleagues showed that the DISC1 gene regulates a cell signaling pathway known as Wnt. This pathway has been found to stimulate stem cell proliferation during embryonic development. Most importantly in terms of psychiatric disease, Wnt signaling promotes the proliferation of neuroprogenitor cells, immature cells that eventually become neurons. 

“What we found is that DISC1 actually maintains the integrity of Wnt signaling,” Tsai says. “So if DISC1, for whatever reason, is lost, then Wnt signaling is impaired. This also resulted in impaired neuroprogenitor proliferation and brain development.” 

Tsai and her colleagues showed that DISC1 regulates Wnt signaling by shutting off an enzyme known as Gsk3-beta. (Notably, Gsk3-beta is also the target of lithium, a common treatment for bipolar disease.) “We proposed in that paper that DISC1 is basically endogenous lithium, to maintain the integrity of Wnt signaling,” Tsai says. 

In the new Neuron paper, Tsai’s lab investigated the impact of DISC1 mutations in the human population. Together with researchers from the Stanley Center for Psychiatric Research at the Broad Institute, they sequenced the DISC1 gene in more than 700 people — about half of them had schizophrenia or bipolar disorder, the rest were healthy — and identified several variants of the DISC1 gene. 

However, none of those single mutations were significantly more common in the diseased population than the healthy population. “That suggests that DISC1 variants in humans, by themselves, do not cause disease,” Tsai says. 

The researchers picked out four of the most common DISC1 mutations and tested their effects in mice, zebrafish and human cells. It turned out that three of those variants do lead to impaired Wnt signaling. However, some of those mutations were found in healthy people, so they are not enough to cause disease on their own. 

The fourth variant did not affect Wnt signaling but did impair neurons’ ability to move to the proper location during brain development and form circuits with other cells. 

Albert Wong, an associate professor of pharmacology at the University of Toronto, says the findings represent “an important step forward” in understanding how DISC1 mutations can lead to abnormal brain structure and function. “This paper by Tsai's lab makes the crucial link between disease-associated human DISC1 variants and Wnt/Gsk3-beta signaling and brain development,” says Wong, who was not involved in this research. 

‘A remarkable organ’ 

Tsai says it is not surprising that even though the genetic defects clearly cause some malfunctions at the cellular level, they do not always lead to disease. “The brain is really a remarkable organ. It’s just so plastic and has this enormous capacity to compensate for any kinds of defects,” she says. 

She expects that future studies will reveal other genetic mutations that are also necessary to produce schizophrenia and other psychiatric disorders. 

In the Neuron paper, the researchers also examined Wnt signaling levels in people with bipolar disease and found that they were much lower than in healthy people, suggesting that bipolar disease and schizophrenia may share some of the same origins. “A lot of genes implicated in schizophrenia are also implicated in bipolar. Now, biochemically, it seems to be the case as well,” Tsai says. 

Author: Anne Trafton | Source: Massachusetts Institute of Technology [November 17, 2011]

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New MRI technique to diagnose or rule out Alzheimer's disease

On the quest for safe, reliable and accessible tools to accurately diagnose Alzheimer's disease, researchers from the Perelman School of Medicine at the University of Pennsylvania found a new way of diagnosing and tracking Alzheimer's disease, using an innovative magnetic resonance imaging (MRI) technique called Arterial spin labeling (ASL) to measure changes in brain function. 

The team determined that the ASL-MRI test is a promising alternative to the current standard, a specific PET scan that requires exposure to small amounts of a radioactive glucose analog and costs approximately four-times more than an ASL-MRI. Two studies now appear in Alzheimer's and Dementia: The Journal of the Alzheimer's Association and Neurology®, the medical journal of the American Academy of Neurology.. 

ASL-MRI can be used to measure neurodegenerative changes in a similar way that fluorodeoxyglucose Positron emission tomography (FDG-PET) scans are currently being used to measure glucose metabolism in the brain. Both tests correlate with cognitive decline in patients with Alzheimer's disease. 

"In brain tissue, regional blood flow is tightly coupled to regional glucose consumption, which is the fuel the brain uses to function. Increases or decreases in brain function are accompanied by changes in both blood flow and glucose metabolism," explained John A. Detre, MD, professor of Neurology and Radiology at Penn, senior author on the papers, who has worked on ASL-MRI for the past 20 years. "We designed ASL-MRI to allow cerebral blood flow to be imaged noninvasively and quantitatively using a routine MRI scanner." 

When Alzheimer's disease is suspected, patients typically receive an MRI initially to look for structural changes that could indicate other medical causes, such as a stroke or brain tumor. Adding about 10-20 minutes to the test time, ASL can be incorporated into the routine MRI and capture functional measures to detect Alzheimer's disease upfront, turning a routine clinical test (structural MRI) into both a structural and functional test. 

"If ASL-MRI were included in the initial diagnostic work-up routinely, it would save the time for obtaining an additional PET scan, which we often will order when there is diagnostic uncertainty, and would potentially speed up diagnosis," said David Wolk, MD, Assistant Professor of Neurology and Assistant Director of the Penn Memory Center, and a collaborator on this research. 

The studies being reported this week show a comparison of ASL-MRI and FDG-PET in a group of Alzhiemer's patients and age-matched controls. Cerebral blood flow and glucose metabolism were measured simultaneously by injecting the PET tracer during the MRI study. The data were then analyzed two different ways. 

In the first study, now online in Alzheimer's and Dementia, ASL-MRI and FDG-PET images from 13 patients diagnosed with Alzheimer's and 18 age-matched controls were analyzed by visual inspection. Independent, blinded review of the two tests by expert nuclear medicine physicians demonstrated similar abilities to rule out (sensitivity) and diagnose (specificity) Alzheimer's. Neither ASL-MRI nor FDG-PET showed a clear advantage from quantitative testing. 

In the second study, published in Neurology, the ASL-MRI and FDG-PET images were compared statistically at each location in the brain by computerized analysis. Data from 15 AD patients were compared to 19 age-matched healthy adults. The patterns of reduction in cerebral blood flow were nearly identical to the patterns of reduced glucose metabolism by FDG-PET, both of which differed from the patterns of reduction in gray matter seen in AD. 

"Given that ASL-MRI is entirely non-invasive, has no radiation exposure, is widely available and easily incorporated into standard MRI routines, it is potentially more suitable for screening and longitudinal disease tracking than FDG-PET," said the Neurology study authors. 

Additional studies will focus on larger sample sizes including patients with mild cognitive impairment and other kinds of neurodegenerative conditions.  

Source: University of Pennsylvania School of Medicine [November 16, 2011]

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Mental Illness: Probing the causes of schizophrenia, depression and anxiety

New research identifies the brain chemicals and circuits involved in mental illnesses like schizophrenia, depression, and anxiety, giving potential new directions to their treatment. In addition, research with children shows that early-life depression and anxiety changes the structure of the developing brain. The findings were presented at Neuroscience 2011, the Society for Neuroscience’s annual meeting and the world’s largest source of emerging news about brain science and health. 

One in 17 Americans suffer from a serious mental illness, such as schizophrenia, major depression, or bipolar disorder, making it one of the leading causes of disability. Yet science is only beginning to understand the underlying physical causes of these diseases. 

Today’s new findings show: 

• Childhood anxiety and depression alter the way the amygdala connects to other regions of the brain. This finding may help explain how early life stress can lead to future emotional and behavioral issues (Shaozheng Qin, PhD, abstract 927.06, see attached summary). 

• In animal studies, a link between two factors associated with schizophrenia, prenatal infection and impaired function of a molecule important in memory (Melissa Burt, abstract 763.11, see attached summary). 

• Researchers have identified a brain chemical important to antidepressant response in mice. The findings may help in the design of therapies for major depression (Maha Elsayed, abstract 904.10, see attached summary). 

• The connections between two specific areas of the brain — the prefrontal cortex and the dorsal raphe nucleus — may contribute to depression. Stimulating these circuits in rats had an antidepressant effect (Melissa Warden, PhD, abstract 306.15, see attached summary). 

• An enzyme called STEP is elevated in the brains of people with schizophrenia. Mice lacking this chemical did not develop schizophrenia-like behaviors (Nikisha Carty, PhD, abstract 238.03, see attached summary). 

"If we can fully understand the roots of mental illness in brain circuitry and systems, we may be able to develop better treatment targets for the millions suffering from these diseases," said press conference moderator Carol Tamminga, MD, of the University of Texas Southwestern, who is an expert on schizophrenia. 

This research was supported by national funding agencies, such as the National Institutes of Health, as well as private and philanthropic organizations. 

Source: Society for Neuroscience [November 15, 2011]

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People with Parkinson's disease more likely to have leg restlessness than restless leg syndrome

People with Parkinson's disease may be more likely to have a movement disorder called leg motor restlessness, but not true restless legs syndrome as previous studies have suggested, according to a study published in the Nov. 9, 2011, online issue of Neurology®, the medical journal of the American Academy of Neurology. 

Restless legs syndrome is a sleep and movement disorder. People with the disorder have the urge to move their legs to stop uncomfortable sensations. The urge occurs when the person is at rest, in the evening, and is temporarily relieved by movement. In leg motor restlessness, people also have the urge to move their legs, but it is either not worse when they are at rest or during the evening or it does not go away when they move their legs. 

Because restless legs syndrome and Parkinson's disease both respond to the drug dopamine, researchers have looked for connections between the two disorders. Some studies have shown that people with Parkinson's disease are more likely also to have restless legs syndrome than people who don't have Parkinson's disease. But those studies have looked at people with advanced cases of Parkinson's who have taken dopamine drugs for many years. 

The current study is the first to look at the issue in people who were recently diagnosed with Parkinson's disease and have not yet taken any dopamine drugs. The Norwegian study compared 200 people with early Parkinson's disease to 173 people of similar ages who did not have Parkinson's disease. 

The study found that restless legs syndrome was not significantly more common in people with Parkinson's disease than it was in those without the disease. But people with Parkinson's were nearly three times more likely to have leg motor restlessness than those without Parkinson's. A total of 26 people with Parkinson's disease and 10 people without the disease had leg motor restlessness. 

"This finding could possibly be because people who have not yet taken dopamine for their Parkinson's disease have a dopamine deficiency in their brains, which is similar to when people develop motor restlessness after taking antipsychotic drugs that block dopamine in the brain," said study author Michaela D. Gjerstad, PhD, of Stavanger University Hospital in Norway and a Fellow of the American Academy of Neurology. 

John Morgan, MD, PhD, of Georgia Health Sciences University in Augusta, who wrote an editorial regarding the study, said, "Time will tell whether the majority of these people with leg motor restlessness will go on to develop restless legs syndrome, or whether the restlessness improves after they start taking dopamine drugs. Further study of this group of people will be quite interesting." 

Source: American Academy of Neurology [November 09, 2011]

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Researchers identify diabetes link to cognitive impairment in older adults

Many complications of diabetes, including kidney disease, foot problems and vision problems are generally well recognized. But the disease's impact on the brain is often overlooked. 

For the past five years, a team led by Beth Israel Deaconess Medical Center (BIDMC) neurophysiologist Vera Novak, MD, PhD, has been studying the effects of diabetes on cognitive health in older individuals and has determined that memory loss, depression and other types of cognitive impairment are a serious consequence of this widespread disease. 

Now, Novak's team has identified a key mechanism behind this course of events. In a study published in the November 2011 issue of the journal Diabetes Care, they report that in older patients with diabetes, two adhesion molecules – sVCAM and sICAM – cause inflammation in the brain, triggering a series of events that affect blood vessels and, eventually, cause brain tissue to atrophy. Importantly, they found that the gray matter in the brain's frontal and temporal regions -- responsible for such critical functions as decision-making, language, verbal memory and complex tasks – is the area most affected by these events. 

"In our previous work, we had found that patients with diabetes had significantly more brain atrophy than did a control group," explains Novak, Director of the Syncope and Falls in the Elderly (SAFE) Program in the Division of Gerontology at BIDMC and Associate Professor of Medicine at Harvard Medical School. "In fact, at the age of 65, the average person's brain shrinks about one percent a year, but in a diabetic patient, brain volume can be lowered by as much as 15 percent." 

Diabetes develops when glucose builds up in the blood instead of entering the body's cells to be used as energy. Known as hyperglycemia, this condition often goes hand-in-hand with inflammation. Novak wanted to determine if chronic inflammation of the blood vessels was causing altered blood flow to the brain in patients with diabetes. 

To test this hypothesis, Novak's team recruited 147 study subjects, averaging 65 years of age. Seventy one of the subjects had type 2 diabetes and had been taking medication to manage their conditions for at least five years. The other 76 were age and sex-matched non-diabetic controls. 

Study subjects underwent a series of cognitive tests, balance tests and standard blood-pressure and blood-glucose tests. Serum samples were also collected to measure adhesion molecules and several other markers of systemic inflammation. To determine perfusion (blood flow) measures in the brain, patients also underwent functional MRI testing, in which a specialized imaging technique known as arterial spin labeling (developed by BIDMC MR physicist David Alsop, PhD) was used in conjunction with a standard MRI to measure vascular reactivity in several brain regions and to show changes in blood flow. 

As predicted, the scans showed that the diabetic patients not only had greater blood vessel constriction than the control subjects, but they also had more atrophied brain tissue, particularly gray matter. The results also showed that, in the patients with diabetes, the frontal, temporal and parietal regions of the brain were most affected. Similarly, the team's measurements of serum markers confirmed that high glucose levels were strongly correlated with higher levels of inflammatory cytokines. 

"It appears that chronic hyperglycemia and insulin resistance – the hallmarks of diabetes – trigger the release of adhesion molecules [sVCAM and sICAM] and set off a cascade of events leading to the development of chronic inflammation," says Novak. "Once chronic inflammation sets in, blood vessels constrict, blood flow is reduced, and brain tissue is damaged. " 

This discovery now provides two biomarkers of altered vascular reactivity in the brain. "If these markers can be identified before the brain is damaged, we can take steps to try and intervene," says Novak, explaining that some data indicates that medications may improve vascoreactivity. 

But more important, she says, the new findings provide still more reason for doctors and patients to focus greater attention on the management – and prevention – of diabetes. 

"Cognitive decline affects a person's ability to successfully complete even the simplest of everyday tasks, such as walking, talking or writing," says Novak. "There are currently 25.8 million cases of type 2 diabetes in the United States alone, which is more than eight percent of our total population. The effects of diabetes on the brain have been grossly neglected, and, as our findings confirm, are issues that need to be addressed." 

Source: Beth Israel Deaconess Medical Center [November 08, 2011]

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Brain stimulator shown to reduce 'untreatable' epileptic seizures

Brain stimulation, already approved by the U.S. Food and Drug Administration for the treatment of Parkinson's disease and essential tremor, has now been shown to offer significant relief to patients with intractable seizures for whom drugs and other treatments have not worked. 

This is the major finding of a first-of-its-kind study of responsive electric brain stimulation in adults with "medically refractory," or hard to treat, epilepsy. 

The NeuroPace Responsive Neurostimulation (RNS) System consists of a miniaturized, implanted computer which can detect seizures from electrodes implanted into or on the surface of the brain and deliver an electrical pulse to stop them. 

Henry Ford Hospital was the only site in Michigan to participate in this multicenter investigation, which was based in California. The study is published in the current issue of Neurology. 

"For the third of people who have tried two or three medications for their epilepsy, but are still having seizures, the standard of care is removing the abnormal part of the brain that is causing seizures. Over 50 percent of patients undergoing surgical removal of brain tissue causing seizures will be cured of their epilepsy," says Jason M. Schwalb, M.D., Director, Movement Disorder and Behavioral Neurosurgery at Henry Ford Health System. 

"However, there are people who are not candidates for this type of surgery because of potential side effects. Until now, we have not had great treatment options. The RNS system is an attractive option for these patients, especially since it is reversible." 

A total of 191 adults, ages 18 to 70, whose disabling epileptic seizures had not been controlled by at least two medications, were chosen. They were studied at 32 medical sites throughout the U.S. for three years, beginning in late 2005. 

All patients were implanted with electric leads attached to one or two seizure focal points in their brains. Their abnormal brain activity was recorded for a month, and then they were chosen at random either to receive electric stimulation or to be given "sham," or no treatment. 

The researchers found: 

• The 97 patients who were treated with the RNS system had 37.9 percent fewer seizures than before surgery. Those 94 patients in the sham, or untreated group, had only 17.3 fewer seizures than before surgery. 

• When those in the sham group had the RNS system turned on, seizures were significantly reduced. 

• There was no difference between the two groups in the number of adverse events associated with the treatment. 

• The effects of the treatment led to significant improvements in patients' quality of life. (Medically refractory epilepsy patients with frequent seizures are at risk of depression, suicidal thoughts and actions, memory loss, and SUDEP, or sudden unexplained death in epilepsy.)  

Source: Henry Ford Health System [November 08, 2011]

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Study suggests increased risk of schizophrenia in heavy methamphetamine users

In the first worldwide study of its kind, scientists from Toronto's Centre for Addiction and Mental Health (CAMH) found evidence that heavy methamphetamine users might have a higher risk of developing schizophrenia. This finding was based on a large study comparing the risk among methamphetamine users not only to a group that did not use drugs, but also to heavy users of other drugs. 

The report will be published online on Nov. 8, 2011, at AJP in Advance, the advance edition of the American Journal of Psychiatry, the official journal of the American Psychiatric Association. 

Methamphetamine and other amphetamine-type stimulants are the second most common type of illicit drug used worldwide. 

"We found that people hospitalized for methamphetamine dependence who did not have a diagnosis of schizophrenia or psychotic symptoms at the start of our study period had an approximately 1.5 to 3.0-fold risk of subsequently being diagnosed with schizophrenia, compared with groups of patients who used cocaine, alcohol or opioid drugs," says Dr. Russ Callaghan, the CAMH scientist who led the study. Dr. Callaghan also found that the increased risk of schizophrenia in methamphetamine users was similar to that of heavy users of cannabis. 

To establish this association, the researchers examined California hospital records of patients admitted between 1990 and 2000 with diagnosis of dependence or abuse for several major abused drugs: methamphetamine, cannabis, alcohol, cocaine or opioids. They also included a control group of patients with appendicitis and no drug use. The methamphetamine group had 42,412 cases, while cannabis had 23,335. 

Records were excluded if patients were dependent on more than one drug or had a diagnosis of schizophrenia or drug-induced psychosis during their initial hospitalization. Readmission records within California hospitals were analyzed for up to 10 years after the initial admission. The researchers then identified patients who were readmitted with a schizophrenia diagnosis in each drug group. 

There has been a longstanding debate as to whether there is a connection between methamphetamine use and schizophrenia. Many Japanese clinicians have long believed that methamphetamine might cause a schizophrenia-like illness, based on their observations of high rates of psychosis among methamphetamine users admitted to psychiatric hospitals. However, they lacked long-term follow-up studies of methamphetamine users initially free of psychosis. In North America, this link has mostly been discounted, as psychiatrists believed that the psychosis was already present and undiagnosed in these methamphetamine users. 

"We really do not understand how these drugs might increase schizophrenia risk," says Dr. Stephen Kish, senior scientist and head of CAMH's Human Brain Laboratory. "Perhaps repeated use of methamphetamine and cannabis in some susceptible individuals can trigger latent schizophrenia by sensitizing the brain to dopamine, a brain chemical thought to be associated with psychosis." Dr. Kish also cautions that the findings do not apply to patients who take much lower and controlled doses of amphetamines or cannabis for medical purposes. 

Since this is the first such study showing this potential link, the researchers emphasize that the results need to be confirmed in additional research involving long-term follow-up studies of methamphetamine users. 

"We hope that understanding the nature of the drug addiction-schizophrenia relationship will help in developing better therapies for both conditions," says Dr. Callaghan. 

In an earlier study using California hospital records, the researchers found evidence for a possible association between heavy methamphetamine use and Parkinson's disease. 

Source: Centre for Addiction and Mental Health [November 08, 2011]

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Brain parasite directly alters brain chemistry

A research group from the University of Leeds has shown that infection by the brain parasite Toxoplasma gondii, found in 10-20 per cent of the UK's population, directly affects the production of dopamine, a key chemical messenger in the brain. Their findings are the first to demonstrate that a parasite found in the brain of mammals can affect dopamine levels. 

Toxoplasma gondii [Credit: Ke Hu and John Murray]

Whilst the work has been carried out with rodents, lead investigator Dr Glenn McConkey of the University's Faculty of Biological Sciences, believes that the findings could ultimately shed new light on treating human neurological disorders that are dopamine-related such as schizophrenia, attention deficit hyperactivity disorder, and Parkinson's disease. 

This research may explain how these parasites, remarkably, manipulate rodents' behaviour for their own advantage. Infected mice and rats lose their innate fear of cats, increasing the chances of being caught and eaten, which enables the parasite to return to its main host to complete its life cycle. 

In this study, funded by the Stanley Medical Research Institute and Dunhill Medical Trust, the research team found that the parasite causes production and release of many times the normal amount of dopamine in infected brain cells. 

Dopamine is a natural chemical which relays messages in the brain controlling aspects of movement, cognition and behaviour. It helps control the brain's reward and pleasure centres and regulates emotional responses such as fear. The presence of a certain kind of dopamine receptor is also associated with sensation-seeking, whereas dopamine deficiency in humans results in Parkinson's disease. 

These findings build on earlier studies in which Dr McConkey's group found that the parasite actually encodes the enzyme for producing dopamine in its genome. 

"Based on these analyses, it was clear that T. gondii can orchestrate a significant increase in dopamine production in neural cells," says Dr McConkey. 

"Humans are accidental hosts to T. gondii and the parasite could end up anywhere in the brain, so human symptoms of toxoplasmosis infection may depend on where parasite ends up. This may explain the observed statistical link between incidences of schizophrenia and toxoplasmosis infection." 

Dr McConkey says his next experiments will investigate how the parasite enzyme triggers dopamine production and how this may change behaviour. 

Source: University of Leeds [November 04, 2011]

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Obesity and depression independently increase health costs

Obesity and depression both dramatically increase health care costs, but they mainly act separately, according to a study published in the November 2011 Journal of General Internal Medicine by Group Health Research Institute scientists. Gregory Simon, MD, MPH, a Group Health psychiatrist and Group Health Research Institute senior investigator, led the research. 

“Previous research shows that both depression and obesity are associated with higher health care costs,” he said. “But depression and obesity often occur together, so it was important to know if the relationship between obesity and cost is really due to depression—or vice versa.” 

Simon and his colleagues tested whether depression confounds the increase in health care use that is associated with obesity. Confounding means an apparent connection—such as the link between increased health care costs and obesity—is influenced or even caused by a third factor. In this study, the authors tested if depression confounds the increase in health care seen in obese patients. 

The study used telephone interviews to determine obesity and depression, and Group Health’s extensive medical records to calculate health care costs for 4,462 women aged 40–65. All were enrolled in Group Health Cooperative, a nonprofit health care system in Washington and northern Idaho. Obesity was measured as body mass index (BMI), a standard obesity measure that is calculated from height and weight. A BMI below 25 is considered normal weight, 25-30 considered overweight, and over 30 is considered obese. Depression was measured with a 9-item American Psychiatric Association questionnaire. 

The researchers found: 

• In middle-aged women, health care costs increased with obesity. Specifically, costs increased 65 percent in women with a BMI of 30-35, and 157 percent in women with a BMI higher than 35, compared to women of normal weight. 

• The trend was similar for all types of health care that the researchers examined: primary care, outpatient prescriptions, specialist visits, inpatient care, and mental health care. 

• Health care costs increased with higher depression scores, but depression was a not a major confounder of the obesity results. 

• Even accounting for depression, health costs increased with every rise in BMI category. 

The study concluded that in this population of women, obesity is associated with higher health care costs, but not because of co-occurring depression. Similarly, depression is associated with higher costs, but not because of co-occurring obesity. These higher costs have an economic impact. Increased costs associated with depression were spread across all types of health care, not just mental health care. 

“Obesity and depression are both very common,” Dr. Simon said, “so the increased costs we find add up to a very large amount in the general population.” The relationships among obesity, depression, and chronic illness related to obesity are complex, as are the effects of depression on behavior and health. But one thing is clear, the study’s authors said: Effective obesity prevention is a crucial factor in tackling our rising health care costs. 

Source: Group Health Research Institute [October 31, 2011]

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People with dementia less likely to return home after stroke

New research shows people with dementia who have a stroke are more likely to become disabled and not return home compared to people who didn't have dementia at the time they had a stroke. The study is published in the November 1, 2011, issue of Neurology®, the medical journal of the American Academy of Neurology. 

"Our findings represent a growing challenge for the health care system as baby boomers age and their risk of stroke and dementia increases," said lead study author Gustavo Saposnik, MD, MSc, of the University of Toronto in Canada and member of the American Academy of Neurology. 

The study involved 9,304 people who had a stroke between 2003 and 2008. Of the group, 702 people had dementia at the time they had a stroke. 

Researchers found the people with dementia who had a stroke were three times more likely to have greater disability at discharge from the hospital compared to people without dementia who had a stroke, with 81 percent of those with dementia having moderate to severe disability compared to 57 percent of those without dementia. In addition, only 24 percent of the people in the dementia group returned to the place they lived prior to the stroke compared to 45 percent of people without dementia. 

People with dementia were also more likely to have severe stroke and an abnormal heart rhythm and less likely to receive tPA, a clot-busting drug used to treat stroke. 

"How to best manage stroke patients with pre-existing dementia is under debate and raises several diagnostic, management and ethical issues as some facilities may limit access to specialized stroke care for dementia patients unless the care is likely to improve outcomes," said Saposnik. "The lack of established guidelines for the management and treatment of stroke patients with dementia contributes to this uncertainty." Another study is underway to determine whether dementia or other comorbid conditions (e.g. hypertension, diabetes, atrial fibrillation, smoking) are responsible for the observed outcomes. 

Source: American Academy of Neurology [October 31, 2011]

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Putting the body back into the mind of schizophrenia

A study using a procedure called the rubber hand illusion has found striking new evidence that people experiencing schizophrenia have a weakened sense of body ownership and has produced the first case of a spontaneous, out-of-body experience in the laboratory. 

Research analyst Lindsey McIntosh demonstrates the procedure that elicits the rubber hand illusion on senior Michael Geoghegan [Credit: John Russell/Vanderbilt University]

These findings suggest that movement therapy, which trains people to be focused and centered on their own bodies, including some forms of yoga and dance, could be helpful for many of the 2.2 million people in the United States who suffer from this mental disorder. 

The study, which appears in the Oct. 31 issue of the scientific journal Public Library of Science One, measured the strength of body ownership of 24 schizophrenia patients and 21 matched control subjects by testing their susceptibility to the "rubber hand illusion" or RHI. This tactile illusion, which was discovered in 1998, is induced by simultaneously stroking a visible rubber hand and the subject's hidden hand. 

"After a while, patients with schizophrenia begin to 'feel' the rubber hand and disown their own hand. They also experience their real hand as closer to the rubber hand." said Sohee Park, the Gertrude Conaway Vanderbilt Chair of Psychology and Psychiatry, who conducted the study with doctoral candidate Katharine Thakkar and research analysts Heathman Nichols and Lindsey McIntosh. 

“Healthy people get this illusion too, but weakly,” Park continued. “Some don’t get it at all, and there is a wide range of individual differences in how people experience this illusion that is related to a personality trait called schizotypy, associated with psychosis?proneness.” 

Body ownership is one of two aspects of a person's sense of self awareness. (The other aspect is self-agency, the sense that a person is initiating his or her own actions.) According to the researchers, the finding that schizophrenia patients are more susceptible to the rubber hand illusion suggests that they have a more flexible body representation and weakened sense of self compared to healthy people. 

"What’s so interesting about Professor Park’s study is that they have found that the sense of bodily ownership does not diminish among patients with schizophrenia, but it can be extended to other objects more easily,” observed David Gray, Mellon assistant professor of philosophy at Vanderbilt, who is an expert on the philosophy of the mind. He did not participate in the study but is familiar with it. “Much of the literature concerning agency and ownership in schizophrenia focuses on the sense of lost agency over one’s own movements: But, in these cases, the sense of ownership is neither diminished nor extended.” 

Before they began the procedure, the researchers gave participants a questionnaire to rate their degree of schizotypy: the extent to which they experience perceptual effects related to the illusion. The researchers found that the individuals who rated higher on the scale were more susceptible to the illusion. 

The researchers gauged the relative strength of the RHI by asking participants to estimate the position of the index finger of their hidden hand on rulers placed on top of the box that conceals it before and after stimulation. The stronger the effect, the more the subjects' estimate of the position of their hidden hand shifted in the direction of the rubber hand. Even the estimates of those who did not experience the effect subjectively shifted slightly. 

The rubber hand illusion also has a physiological signature. Scientists don't know why, but the temperature of the hidden hand drops by a few tenths of a degree when a person experiences the illusion. "It's almost as if the hand is disowned and rejected, no longer part of the self," Park commented. 

The researchers were surprised when one of the patients undergoing the procedure experienced a full out-of-body experience. He reported that he was floating above his own body for about 15 minutes. According to Park, it is extremely rare to observe spontaneous out-of-body experiences in the laboratory. When they invited the patient back for a second session, he once again had an out-of-body experience during the rubber hand procedure, proving that the experience is repeatable. 

"Anomalous experiences of the self were considered to be core features of schizophrenia decades ago but in recent years much of the emphasis has been on cognitive functions such as working memory," said Park. 

According to the psychologist, out-of-body experiences and body ownership are associated with a particular area in the brain called the temporoparietal junction. Lesions in this area and stimulation by strong magnetic fields can elicit out-of-body experiences. The new study suggests that disorders in this part of the brain may also contribute to the symptoms of schizophrenia. 

The relationship between schizophrenia and body ownership may help explain the results of a German study published in 2008 that found a 12-week exercise program reduced the symptoms and improved the behavior of a small group of patients with chronic schizophrenia when compared to a control group that did not exercise. The study also found that the exercise increased size of the patients' hippocampus slightly – a smaller-than-normal hippocampus is a well established symptom of schizophrenia. 

"Exercise is inexpensive and obviously has a broad range of beneficial effects, so if it can also reduce the severity of schizophrenia it is all to the good," said Park. These findings suggest that focused physical exercise which involves precise body control, such as yoga and dancing, could be a beneficial form of treatment for this disorder. 

Source: Vanderbilt University [October 31, 2011]

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