Gene Involved in Neurodegeneration Keeps Clock Running

Northwestern University scientists have shown a gene involved in neurodegenerative disease also plays a critical role in the proper function of the circadian clock.

In a study of the common fruit fly, the researchers found the gene, called Ataxin-2, keeps the clock responsible for sleeping and waking on a 24-hour rhythm. Without the gene, the rhythm of the fruit fly’s sleep-wake cycle is disturbed, making waking up on a regular schedule difficult for the fly.

The discovery is particularly interesting because mutations in the human Ataxin-2 gene are known to cause a rare disorder called spinocerebellar ataxia (SCA) and also contribute to amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. People with SCA suffer from sleep abnormalities before other symptoms of the disease appear.

This study linking the Ataxin-2 gene with abnormalities in the sleep-wake cycle could help pinpoint what is causing these neurodegenerative diseases as well as provide a deeper understanding of the human sleep-wake cycle.

The findings will be published May 17 in the journal Science. Ravi Allada, M.D., professor of neurobiology in the Weinberg College of Arts and Sciences, and Chunghun Lim, a postdoctoral fellow in his lab, are authors of the paper.

Period (per) is a well-studied gene in fruit flies that encodes a protein, called PER, which regulates circadian rhythm. Allada and Lim discovered that Ataxin-2 helps activate translation of PER RNA into PER protein, a key step in making the circadian clock run properly.

“It’s possible that Ataxin-2’s function as an activator of protein translation may be central to understanding how, when you mutate the gene and disrupt its function, it may be causing or contributing to diseases such as ALS or spinocerebellar ataxia,” Allada said.

The fruit fly Drosophila melanogaster is a model organism for scientists studying the sleep-wake cycle because the fly’s genes are highly conserved with the genes of humans.

“I like to say that flies sleep similarly to humans, except flies don’t use pillows,” said Allada, who also is associate director for Northwestern’s Center for Sleep and Circadian Biology. The biological timing mechanism for all animals comes from a common ancestor hundreds of millions of years ago.

Ataxin-2 is the second gene in a little more than two years that Northwestern researchers have identified as a core gear of the circadian clock, and the two genes play similar roles.

Allada, Lim and colleagues in 2011 reported their discovery of a gene, which they dubbed “twenty-four,” that plays a role in translating the PER protein, keeping the sleep-wake cycle on a 24-hour rhythm.

Allada and Lim wanted to better understand how twenty-four works, so they looked at proteins that associate with twenty-four. They found the twenty-four protein sticking to ATAXIN-2 and decided to investigate further. In their experiments, reported in Science, Allada and Lim discovered the Ataxin-2 and twenty-four genes appear to be partners in PER protein translation.

“We’ve really started to define a pathway that regulates the circadian clock and seems to be especially important in a specific group of neurons that governs the fly’s morning wake-up,” Allada said. “We saw that the molecular and behavioral consequences of losing Ataxin-2 are nearly the same as losing twenty-four.”

As is the case in a mutation of the twenty-four gene, when the Ataxin-2 gene is not present, very little PER protein is found in the circadian pacemaker neurons of the brain, and the fly’s sleep-wake rhythm is disturbed.

Repeat Brain Injury Raises Soldiers’ Suicide Risk

People in the military who suffer more than one mild traumatic brain injury face a significantly higher risk of suicide, according to research by the National Center for Veterans Studies at the University of Utah.

A survey of 161 military personnel who were stationed in Iraq and evaluated for a possible traumatic brain injury – also known as TBI – showed that the risk for suicidal thoughts or behaviors increased not only in the short term, as measured during the past 12 months, but during the individual’s lifetime.

The risk of suicidal thoughts increased significantly with the number of TBIs, even when controlling for other psychological factors, the researchers say in a paper published online Wednesday, May 15 in JAMA Psychiatry, a specialty journal of the American Medical Association.

“Up to now, no one has been able to say if multiple TBIs, which are common among combat veterans, are associated with higher suicide risk or not,” says the study’s lead author, Craig J. Bryan, assistant professor of psychology at the University of Utah and associate director of the National Center for Veterans Studies. “This study suggests they are, and it provides valuable information for professionals treating wounded combat servicemen and women to help manage the risk of suicide.”

Results showed that one in five patients (21.7 percent) who had ever sustained more than one TBI reported suicidal ideation – thoughts about or preoccupation with suicide – at any time in the past. For patients who had received one TBI, 6.9 percent reported having suicidal thoughts, and zero percent for those with no TBIs. In evaluating the lifetime risk, patients were asked if they had ever experienced suicidal thoughts and behaviors up to the point they were assessed.

The increases were similar for suicidal thoughts during the previous year rather than at any time: 12 percent of those with multiple TBIs had entertained suicidal ideas during the past year, compared with 3.4 percent with one TBI and zero percent for no TBIs.

In this study, suicidal ideation was used as the indicator of suicide risk because too few patients reported a history of suicide plan or had made a suicide attempt for statistically valid conclusions to be made.

Researchers found that multiple TBIs also were associated with a significant increase in other psychological symptoms already tied to single traumatic head injuries, including depression, post-traumatic stress disorder or PTSD, and the severity of the concussive symptoms. However, only the increase in depression severity predicted an increased suicide risk.

“That head injury and resulting psychological effects increase the risk of suicide is not new,” says Bryan. “But knowing that repetitive TBIs may make patients even more vulnerable provides new insight for attending to military personnel over the long-term, particularly when they are experiencing added emotional distress in their lives.”

How the Study was Conducted

During a six-month period in 2009, 161 patients who received a suspected brain injury while on duty in Iraq were referred to an outpatient TBI clinic at a combat support hospital there. Patients were predominantly male, average age of 27, with 6.5 years of military service.

Diagnosis of traumatic brain injury was made by a clinical psychologist specifically trained in the assessment, diagnosis and management of the condition. Only patients with mild or no TBI completed all assessments; patients with moderate to severe TBI were immediately evacuated from Iraq.

TBI was confirmed if at least one clinical event was newly presented or worsened following the injury: loss of consciousness or memory, alteration of mental state, some neurological decline or brain damage.

Patients were divided into three groups based the total number of TBIs during their entire lives – zero, single TBI and two or more – the most recent of which was typically within the days immediately preceding their evaluation and inclusion in the study.

Each individual was also given surveys as part of his or her evaluation and treatment. Using standard evaluation tools, patients were surveyed about their symptoms of depression, PTSD and concussions, and their suicidal thoughts and behaviors.

“An important feature of the study is that by being on the ground in Iraq, we were able to compile a unique data set on active military personnel and head injury,” Bryan says. “We collected data on a large number of service members within two days of impact.”

At the same time, because the results of this study are based on a single clinical sample –active military in a war zone within days of the injury – the researchers note that caution is advised before assuming that the results from this particular group will apply to every other group. Studies with larger sample sizes and conducted over longer periods of time will be needed.

Why TBI is of Concern for Military Personnel

As defined by the Centers for Disease Control and Prevention, a traumatic brain injury is caused by a bump, blow or jolt to the head, or a penetrating head injury that disrupts the normal function of the brain. Effects can be mild to severe. The majority of TBIs that occur each year are concussions or other mild forms.

TBI is considered a “signature injury” of the Iraq and Afghanistan conflicts and is of particular concern because of the frequency of concussive injuries from explosions and other combat-related incidents. Estimated prevalence of TBI for those deployed in these two countries ranges from 8 percent to 20 percent, according to a 2008 study.

In addition, according to studies by the RAND Corp., suicide is the second-leading cause of death among U.S. military personnel, and the rate has risen steadily since the conflicts began in Iraq and Afghanistan. Prevalence of PTSD, depression and substance abuse have risen as well, especially among those in combat, and each has been shown to increase risk for suicidal behaviors.

“Being aware of the number of a patient’s head injuries and the interrelation with depression and other psychological symptoms may help us better understand, and thus moderate, the risk of suicide over time,” Bryan says. “Ultimately, we would like to know why people do not kill themselves. Despite facing similar issues and circumstances, some people recover. Understanding that is the real goal.”

Researchers develop novel Brain Training Device to reconnect the brain and paralyzed limb after stroke

The world’s first Brain Training Device has given a ray of new hope to the recovery of survivors after stroke. Developed by researchers of The Hong Kong Polytechnic University (PolyU)’s Interdisciplinary Division of Biomedical Engineering (BME), this novel device which can detect brainwave, and thereby control the movement of paralyzed limbs, or go even further to control a robotic hand based on its sophisticated algorithm.

The research was led by Prof. Raymond Tong Kai-yu, Professor of PolyU’s Interdisciplinary Division of Biomedical Engineering, who is also the Principal Investigator of the award-winning Exoskeleton Hand Robotic Training Device or the “Hand of Hope”. His team members include the BME research team (Newmen Ho, Xiaoling Hu, Ching-hang Fong, Xinxin Lou, Lawrence Chong and Nathan Lam) and the Industrial Centre team of PolyU (Robert Tam, Bun Yu, Shu-to Ng and Peter Pang).

The latest breakthrough “Brain Training Device” can be coupled with the use of the “Hand of Hope” to achieve higher degree of recovery for stroke patients. While effective motor recovery after stroke depends on early rehabilitation program and intensive voluntary practice of the paretic limbs, current rehabilitation products have not use brainwave to guide the stroke survivors to identify voluntary intention and to relearn how to reconnect to their paralyzed limb again.

Prof. Raymond Tong and his team therefore developed the Brain Training Device with a new coherence algorithm for hand function training. The new algorithm is based on frequency coherence on surface electroencephalography (EEG, brainwave) and electromyography (EMG, muscle activities) to identify voluntary intention and their connection.

"The Brain Training Device is able to guide the stroke patients to relearn the reconnection between the brain and the limb, with a new design on the EEG headset and the EMG forearm brace to transmit data for controlling a hand robotic system interfaced by a telecare software platform using iPad app." Prof. Raymond Tong explained.

The patented Brain Training System, which looks like a helmet for cyclist and can read brainwaves, also has new features to find the specific EEG electrode locations for each individual stroke patient and reduce the number of EEG electrodes, which can reduce the system cost and the preparation time for brain training, added by Prof. Tong. 

To find a minimal set of electrodes to control the device with accuracy higher than 90%, five chronic stroke patients were recruited to be trained for 20 sessions in the study. The researchers found that, in general, 32 electrodes are needed to maintain accuracy higher than 90%.

The high accuracy and low number of channels needed means that the Brain Training Device is a viable tool for assistive aid and rehabilitation training. The futuristic system will be made portable and easy-to-use at hospital and home settings.

PolyU researchers have already filed patents for this Brain Training Device in both the United States and China. This project is funded by the HKSAR Government’s Innovation and Technology Fund (ITF). The findings of this brain control algorithm have been published as the cover story in top international journal IEEE Transactions on Neural Systems and Rehabilitation Engineering (2011.12).

Brain rewires itself after damage or injury

When the brain’s primary “learning center” is damaged, complex new neural circuits arise to compensate for the lost function, say life scientists from UCLA and Australia who have pinpointed the regions of the brain involved in creating those alternate pathways — often far from the damaged site.

The research, conducted by UCLA’s Michael Fanselow and Moriel Zelikowsky in collaboration with Bryce Vissel, a group leader of the neuroscience research program at Sydney’s Garvan Institute of Medical Research, appears this week in the early online edition of the journal Proceedings of the National Academy of Sciences.

The researchers found that parts of the prefrontal cortex take over when the hippocampus, the brain’s key center of learning and memory formation, is disabled. Their breakthrough discovery, the first demonstration of such neural-circuit plasticity, could potentially help scientists develop new treatments for Alzheimer’s disease, stroke and other conditions involving damage to the brain.

For the study, Fanselow and Zelikowsky conducted laboratory experiments with rats showing that the rodents were able to learn new tasks even after damage to the hippocampus. While the rats needed more training than they would have normally, they nonetheless learned from their experiences — a surprising finding.

"I expect that the brain probably has to be trained through experience," said Fanselow, a professor of psychology and member of the UCLA Brain Research Institute, who was the study’s senior author. "In this case, we gave animals a problem to solve."

After discovering the rats could, in fact, learn to solve problems, Zelikowsky, a graduate student in Fanselow’s laboratory, traveled to Australia, where she worked with Vissel to analyze the anatomy of the changes that had taken place in the rats’ brains. Their analysis identified significant functional changes in two specific regions of the prefrontal cortex.

"Interestingly, previous studies had shown that these prefrontal cortex regions also light up in the brains of Alzheimer’s patients, suggesting that similar compensatory circuits develop in people," Vissel said. "While it’s probable that the brains of Alzheimer’s sufferers are already compensating for damage, this discovery has significant potential for extending that compensation and improving the lives of many."

The hippocampus, a seahorse-shaped structure where memories are formed in the brain, plays critical roles in processing, storing and recalling information. The hippocampus is highly susceptible to damage through stroke or lack of oxygen and is critically inolved in Alzheimer’s disease, Fanselow said.

"Until now, we’ve been trying to figure out how to stimulate repair within the hippocampus," he said. "Now we can see other structures stepping in and whole new brain circuits coming into being."

Zelikowsky said she found it interesting that sub-regions in the prefrontal cortex compensated in different ways, with one sub-region — the infralimbic cortex — silencing its activity and another sub-region — the prelimbic cortex — increasing its activity.

"If we’re going to harness this kind of plasticity to help stroke victims or people with Alzheimer’s," she said, "we first have to understand exactly how to differentially enhance and silence function, either behaviorally or pharmacologically. It’s clearly important not to enhance all areas. The brain works by silencing and activating different populations of neurons. To form memories, you have to filter out what’s important and what’s not."

Complex behavior always involves multiple parts of the brain communicating with one another, with one region’s message affecting how another region will respond, Fanselow noted. These molecular changes produce our memories, feelings and actions.

"The brain is heavily interconnected — you can get from any neuron in the brain to any other neuron via about six synaptic connections," he said. "So there are many alternate pathways the brain can use, but it normally doesn’t use them unless it’s forced to. Once we understand how the brain makes these decisions, then we’re in a position to encourage pathways to take over when they need to, especially in the case of brain damage.

"Behavior creates molecular changes in the brain; if we know the molecular changes we want to bring about, then we can try to facilitate those changes to occur through behavior and drug therapy," he added. I think that’s the best alternative we have. Future treatments are not going to be all behavioral or all pharmacological, but a combination of both."

New drug enhances radiation treatment for brain cancer in preclinical studies

A novel drug may help increase the effectiveness of radiation therapy for the most deadly form of brain cancer, report scientists at Virginia Commonwealth University Massey Cancer Center. In mouse models of human glioblastoma multiforme (GBM), the new drug helped significantly extend survival when used in combination with radiation therapy.

Recently published in the journal Clinical Cancer Research, the study provides the first preclinical evidence demonstrating that an ATM kinase inhibitor radiosensitizes gliomas. Gliomas are brain tumors that originate from glial cells, which provide support for nerve cells and help regulate the internal environment of the brain. ATM, or ataxia telangiectasia mutated, is an enzyme that helps repair DNA damage. The scientists used an experimental drug, KU-60019, to block the activation of ATM, which led to the enhanced destruction of the gliomas due to their reduced ability to repair the DNA damage caused by the radiation treatment. The new approach was particularly effective against gliomas that have a mutation in the p53 tumor suppressor gene, which accounts for approximately 30 percent of all glioma cases.

"Sadly, the average life expectancy of patients diagnosed with glioblastoma is just 12 to 15 months," says the study’s lead researcher Kristoffer Valerie, Ph.D., co-leader of the Radiation Biology and Oncology research program and a professor in the Department of Radiation Oncology at VCU Massey Cancer Center. "By limiting the tumor’s ability to combat DNA damage caused by treatments such as radiation, we are hopeful that we can enhance our ability to specifically target the glioma, prolong survival and reduce damage to surrounding brain tissue."

Currently, GBM is treated with surgery, followed by chemotherapy and radiation therapy. Potentially, ATM kinase inhibitors like the one used in this study could enhance the effectiveness of some other cancer treatments that kill tumor cells by damaging DNA. The scientists chose radiation therapy in this study since it is already standard care and can be delivered to brain tumors with extreme accuracy, minimizing damage to surrounding healthy tissue.

"If these findings hold up in early phase clinical trials, we expect patients with p53 mutant gliomas to respond well to this treatment while showing few side effects. Also, we anticipate that this same treatment strategy could be effective for other cancers that are treated with DNA-damaging chemotherapies," says Valerie. "We are encouraged by these early findings and will continue to move forward with our research. However, more studies are needed before we can proceed with testing this new therapy in humans."

This first, ‘proof-of-principle’ study is an important follow-up of a study published several years ago on KU-60019 by Valerie and his research team that demonstrated KU-60019’s superior efficacy, specificity and potency on glioma cells as compared to a predecessor ATM inhibitor.

Valerie and his team are conducting additional studies examining the effects of KU-60019 and other ATM kinase inhibitors on gliomas, including studies that combine ATM kinase inhibitors with a type of drug known as a PARP inhibitor to increase the effectiveness of the treatment. PARP inhibitors block the action of poly ADP ribose polymerase (PARP), an enzyme that also aids in the repair of DNA damage. The researchers believe that combining an ATM kinase inhibitor with a PARP inhibitor may cause a condition referred to as “synthetic lethality,” which arises when the functions of at least two interacting genes are simultaneously inhibited, which, in turn, leads to tumor cell death.

Trying to be Happier Works When Listening to Upbeat Music

The song, “Get Happy,” famously performed by Judy Garland, has encouraged people to improve their mood for decades. Recent research at the University of Missouri discovered that an individual can indeed successfully try to be happier, especially when cheery music aids the process. This research points to ways that people can actively improve their moods and corroborates earlier MU research.

“Our work provides support for what many people already do – listen to music to improve their moods,” said lead author Yuna Ferguson, who performed the study while she was an MU doctoral student in psychological science. “Although pursuing personal happiness may be thought of as a self-centered venture, research suggests that happiness relates to a higher probability of socially beneficial behavior, better physical health, higher income and greater relationship satisfaction.”

In two studies by Ferguson, participants successfully improved their moods in the short term and boosted their overall happiness over a two week period. During the first study, participants improved their mood after being instructed to attempt to do so, but only if they listened to the upbeat music of Copland, as opposed to the more somber Stravinsky. Other participants, who simply listened to the music without attempting to change their mood, also didn’t report a change in happiness. In the second study, participants reported higher levels of happiness after two weeks of lab sessions in which they listened to positive music while trying to feel happier, compared to control participants who only listened to music.

However, Ferguson noted that for people to put her research into practice, they must be wary of too much introspection into their mood or constantly asking, “Am I happy yet?”

“Rather than focusing on how much happiness they’ve gained and engaging in that kind of mental calculation, people could focus more on enjoying their experience of the journey towards happiness and not get hung up on the destination,” said Ferguson.

Ferguson’s work corroborated earlier findings by Ferguson’s doctoral advisor and co-author of the current study, Kennon Sheldon, professor of psychological science in MU’s College of Arts and Science.

“The Hedonic Adaptation Prevention model, developed in my earlier research, says that we can stay in the upper half of our ‘set range’ of potential happiness as long as we keep having positive experiences, and avoid wanting too much more than we have,” said Sheldon. “Yuna’s research suggests that we can intentionally seek to make mental changes leading to new positive experiences of life. The fact that we’re aware we’re doing this, has no detrimental effect.”

Ferguson is now assistant professor of psychology at Pennsylvania State University Shenango. The study, “Trying to Be Happier Really Can Work: Two Experimental Studies,” was published in The Journal of Positive Psychology.

Getting a grip on sleep

All mammals sleep, as do birds and some insects. However, how this basic function is regulated by the brain remains unclear. According to a new study by researchers from the RIKEN Brain Science Institute, a brain region called the lateral habenula plays a central role in the regulation of REM sleep. In an article published today in the Journal of Neuroscience, the team shows that the lateral habenula maintains and regulates REM sleep in rats through regulation of the serotonin system. This study is the first to show a role of the lateral habenula in linking serotonin metabolism and sleep.

The lateral habenula is a region of the brain known to regulate the metabolism of the neurotransmitter serotonin in the brain and to play a key role in cognitive functions.

“Serotonin plays a central role in the pathophysiology of depression, however, it is not clear how abnormalities in regulation of serotonin metabolism in the brain lead to symptoms such as insomnia in depression,” explain Dr. Hidenori Aizawa and Dr. Hitoshi Okamoto who led the study.

Since animals with increased serotonergic activity at the synapse experienced less REM sleep, the researchers hypothesized that the lateral habenula, which regulates serotonergic activity in the brain, must modulate the duration of REM sleep.

They show that removing the lateral habenula in rats results in a reduction of theta rhythm, an oscillatory activity that appears during REM sleep, in the hippocampus, and shortens the rats’ REM sleep periods. However, this inhibitory effect of the lateral habenular lesion on REM sleep disappears when the serotonergic neurons in the midbrain are lesioned.

The team recorded neural activity simultaneously in the lateral habenula and hippocampus in a sleeping rat. They find that the lateral habenular neurons, which fire persistently during non-REM sleep, begin to fire rhythmically in accordance with the theta rhythm in the hippocampus when the animal is in REM sleep.

“Our results indicate that the lateral habenula is essential for maintaining theta rhythms in the hippocampus, which characterize REM sleep in the rat, and that this is done via serotonergic modulation,” concludes Dr Aizawa.

“This study reveals a novel role of the lateral habenula, linking serotonin and REM sleep, which suggests that an hyperactive habenula in patients with depression may cause altered REM sleep,” add the authors.