Neuroscience

Scientists have identified a channel present in many pain detecting sensory neurons that acts as a ‘brake’, limiting spontaneous pain. It is hoped that the new research, published today [22 January] in the Journal of Neuroscience, will ultimately contribute to new pain relief treatments.

Spontaneous pain is ongoing pathological pain that occurs constantly (slow burning pain) or intermittently (sharp shooting pain) without any obvious immediate cause or trigger. The slow burning pain is the cause of much suffering and debilitation. Because the mechanisms underlying this type of slow burning pain are poorly understood, it remains very difficult to treat effectively.

Spontaneous pain of peripheral origin is pathological, and is associated with many types of disease, inflammation or damage of tissues, organs or nerves (neuropathic pain). Examples of neuropathic pain are nerve injury/crush, post-operative pain, and painful diabetic neuropathy.

Previous research has shown that this spontaneous burning pain is caused by continuous activity in small sensory nerve fibers, known as C-fiber nociceptors (pain neurons). Greater activity translates into greater pain, but what causes or limits this activity remained poorly understood.

Now, new research from the University of Bristol, has identified a particular ion channel present exclusively in these C-fiber nociceptors This ion channel, known as TREK2, is present in the membranes of these neurons, and the researchers showed that it provides a natural innate protection against this pain.

Ion channels are specialised proteins that are selectively permeable to particular ions. They form pores through the neuronal membrane. Leak potassium channels are unusual, in that they are open most of the time allowing positive potassium ions (K+) to leak out of the cell. This K+ leakage is the main cause of the negative membrane potentials in all neurons. TREK2 is one of these leak potassium channels. Importantly, the C-nociceptors that express TREK2 have much more negative membrane potentials than those that do not.

Researchers showed that when TREK2 was removed from the proximity of the cell membrane, the potential in those neurons became less negative. In addition, when the neuron was prevented from synthesizing the TREK2, the membrane potential also became less negative.

They also found that spontaneous pain associated with skin inflammation, was increased by reducing the levels of synthesis of TREK2 in these C-fiber neurons.

They concluded that in these C-fiber nociceptors the TREK2 keeps membrane potentials more negative, stabilizing their membrane potential, reducing firing and thus limiting the amount of spontaneous burning pain.

Professor Sally Lawson, from the School of Physiology and Pharmacology at Bristol University, explained: “It became evident that TREK2 kept the C-fiber nociceptor membrane at a more negative potential. Despite the difficulties inherent in the study of spontaneous pain, and the lack of any drugs that can selectively block or activate TREK2, we demonstrated that TREK2 in C-fiber nociceptors is important for stabilizing their membrane potential and decreasing the likelihood of firing. It became apparent that TREK2 was thus likely to act as a natural innate protection against pain. Our data supported this, indicating that in chronic pain states, TREK2 is acting as a brake on the level of spontaneous pain.”

Dr Cristian Acosta, the first author on the paper and now working at the Institute of Histology and Embriology of Mendoza in Argentina, said “Given the role of TREK2 in protecting against spontaneous pain, it is important to advance our understanding of the regulatory mechanisms controlling its expression and trafficking in these C-fiber nociceptors. We hope that this research will enable development of methods of enhancing the actions of TREK2 that could potentially some years hence provide relief for sufferers of ongoing spontaneous burning pain.”

Using a simple study of eye movements, Johns Hopkins scientists report evidence that people who are less patient tend to move their eyes with greater speed. The findings, the researchers say, suggest that the weight people give to the passage of time may be a trait consistently used throughout their brains, affecting the speed with which they make movements, as well as the way they make certain decisions.

Caption: Despite claims to the contrary, the eyes of the Mona Lisa do not make saccades. Credit: Leonardo da Vinci

In a summary of the research to be published Jan. 21 in The Journal of Neuroscience, the investigators note that a better understanding of how the human brain evaluates time when making decisions might also shed light on why malfunctions in certain areas of the brain make decision-making harder for those with neurological disorders like schizophrenia, or for those who have experienced brain injuries.

Principal investigator Reza Shadmehr, Ph.D., professor of biomedical engineering and neuroscience at The Johns Hopkins University, and his team set out to understand why some people are willing to wait and others aren’t. “When I go to the pharmacy and see a long line, how do I decide how long I’m willing to stand there?” he asks. “Are those who walk away and never enter the line also the ones who tend to talk fast and walk fast, perhaps because of the way they value time in relation to rewards?”

To address the question, the Shadmehr team used very simple eye movements, known as saccades, to stand in for other bodily movements. Saccades are the motions that our eyes make as we focus on one thing and then another. “They are probably the fastest movements of the body,” says Shadmehr. “They occur in just milliseconds.” Human saccades are fastest when we are teenagers and slow down as we age, he adds.

In earlier work, using a mathematical theory, Shadmehr and colleagues had shown that, in principle, the speed at which people move could be a reflection of the way the brain calculates the passage of time to reduce the value of a reward. In the current study, the team wanted to test the idea that differences in how subjects moved were a reflection of differences in how they evaluated time and reward.

For the study, the team first asked healthy volunteers to look at a screen upon which dots would appear one at a time –– first on one side of the screen, then on the other, then back again. A camera recorded their saccades as they looked from one dot to the other. The researchers found a lot of variability in saccade speed among individuals but very little variation within individuals, even when tested at different times and on different days. Shadmehr and his team concluded that saccade speed appears to be an attribute that varies from person to person. “Some people simply make fast saccades,” he says.

To determine whether saccade speed correlated with decision-making and impulsivity, the volunteers were told to watch the screen again. This time, they were given visual commands to look to the right or to the left. When they responded incorrectly, a buzzer sounded.

After becoming accustomed to that part of the test, they were forewarned that during the following round of testing, if they followed the command right away, they would be wrong 25 percent of the time. In those instances, after an undetermined amount of time, the first command would be replaced by a second command to look in the opposite direction.

To pinpoint exactly how long each volunteer was willing to wait to improve his or her accuracy on that phase of the test, the researchers modified the length of time between the two commands based on a volunteer’s previous decision. For example, if a volunteer chose to wait until the second command, the researchers increased the time they had to wait each consecutive time until they determined the maximum time the volunteer was willing to wait — only 1.5 seconds for the most patient volunteer. If a volunteer chose to act immediately, the researchers decreased the wait time to find the minimum time the volunteer was willing to wait to improve his or her accuracy.

When the speed of the volunteers’ saccades was compared to their impulsivity during the patience test, there was a strong correlation. “It seems that people who make quick movements, at least eye movements, tend to be less willing to wait,” says Shadmehr. “Our hypothesis is that there may be a fundamental link between the way the nervous system evaluates time and reward in controlling movements and in making decisions. After all, the decision to move is motivated by a desire to improve one’s situation, which is a strong motivating factor in more complex decision-making, too.”

A new brain-imaging technique enables people to ‘watch’ their own brain activity in real time and to control or adjust function in pre-determined brain regions. The study from the Montreal Neurological Institute and Hospital – The Neuro, McGill University and the McGill University Health Centre, published in NeuroImage, is the first to demonstrate that magnetoencephalography (MEG) can be used as a potential therapeutic tool to control and train specific targeted brain regions. This advanced brain-imaging technology has important clinical applications for numerous neurological and neuropsychiatric conditions.

MEG is a non-invasive imaging technology that measures magnetic fields generated by nerve cell circuits in the brain. MEG captures these tiny magnetic fields with remarkable accuracy and has unrivaled time resolution - a millisecond time scale across the entire brain. “This means you can observe your own brain activity as it happens,” says Dr. Sylvain Baillet, acting Director of the Brain Imaging Centre at The Neuro and lead investigator on the study. “We can use MEG for neurofeedback – a process by which people can see on-going physiological information that they aren’t usually aware of, in this case, their own brain activity, and use that information to train themselves to self-regulate. Our ultimate hope and aim is to enable patients to train specific regions of their own brain, in a way that relates to their particular condition. For example neurofeedback can be used by people with epilepsy so that they could train to modify brain activity in order to avoid a seizure.”

In this proof of concept study, participants had nine sessions in the MEG and used neurofeedback to reach a specific target. The target was to look at a coloured disc on a display screen and find  their own strategy to change the disc’s colour from dark red to bright yellow white, and to maintain that bright colour for as long as possible. The disc colour was indexed on a very specific aspect of their ongoing brain activity: the researchers had set it up so that the experiment was accessing predefined regions of the motor cortex in the participants’ brain. The colour presented was changing according to a predefined combination of slow and faster brain activity within these regions. This was possible because the researchers combined MEG with MRI, which provides information on the brain’s structures, known as magnetic source imaging (MSI).

“The remarkable thing is that with each training session, the participants were able to reach the target aim faster, even though we were raising the bar for the target objective in each session, the way you raise the bar each time in a high jump competition. These results showed that participants were successfully using neurofeedback to alter their pattern of brain activity according to a predefined objective in specific regions of their brain’s motor cortex, without moving any body part. This demonstrates that MEG source imaging can provide brain region-specific real time neurofeedback and that longitudinal neurofeedback training is possible with this technique.”

These findings pave the way for MEG as an innovative therapeutic approach for treating patients. To date, work with epilepsy patients has shown the most promise but there is great potential to use MEG to investigate other neurological syndromes and neuropsychiatric disorders (e.g., stroke, dementia, movement disorders, chronic depression, etc). MEG has potential to reveal dynamics of brain activity involved in perception, cognition and behaviour: it has provided unique insight on brain functions (language, motor control, visual and auditory perception, etc.) and dysfunctions (movement disorders, tinnitus, chronic pain, dementia, etc.).

Dr. Baillet and his team are collaborating presently with Prof. Isabelle Peretz at Université de Montréal to use this technique with people that have amusia, a disorder that makes them unable to process musical pitch. It is hypothesized that amusia results from poor connectivity between the auditory cortex and prefrontal regions in the brain. In an ongoing study, the team is measuring the intensity of functional connectivity between these brain regions in amusic patients and aged-matched healthy controls. Using MEG-neurofeedback, they hope to take advantage of the brain’s plasticity to reinforce the functional connectivity between the target brain regions. If the approach demonstrates an improvement in pitch discrimination in participants, that will demonstrate the clinical and rehabilitative applications of this approach. The baseline measurements have been taken already, and the training sessions will take place over this year.

Scientists from the Montreal Neurological Institute and Hospital in Canada have discovered that two genes linked to hereditary Parkinson’s disease are involved in the early-stage quality control of mitochondria. The protective mechanism, which is reported in The EMBO Journal, removes damaged proteins that arise from oxidative stress from mitochondria.

“PINK1 and parkin, are implicated in selectively targeting dysfunctional components of mitochondria to the lysosome under conditions of excessive oxidative damage within the organelle,” said Edward Fon, Professor at the McGill Parkinson Program at the Montreal Neurological Institute and Hospital.  “Our study reveals a quality control mechanism where vesicles bud off from mitochondria and proceed to the lysosome for degradation. This method is distinct from the degradation pathway for damaged whole mitochondria which has been known for some time. It is also an early response, proceeding on a timescale of hours instead of days.”

The deterioration of mechanisms designed to maintain the integrity and function of mitochondria throughout the lifetime of a cell has been suggested to underlie the progression of several neurodegenerative diseases, including Parkinson’s disease. When mitochondria, the “power plants” of the cell that provide energy, malfunction they can contribute to Parkinson’s disease. If they are to survive and function mitochondria need to degrade oxidized and damaged proteins.

In the study, immunofluorescence and confocal microscopy were used to observe how the vesicles “pinch off” from mitochondria with their damaged cargo. “Our conclusion is that the loss of this PINK1 and parkin-dependent trafficking system impairs the ability of mitochondria to selectively degrade oxidized and damaged proteins and leads, over time, to the mitochondrial dysfunction noted in hereditary Parkinson’s disease,” said Heidi McBride, Professor in the Neuromuscular Group in the Department of Neurology and Neurosurgery at the Montreal Neurological Institute and Hospital.

Both salvage pathways are operational in the cell. If the vesicular pathway, the first line of defense, is overwhelmed and the damage is irreversible then the entire organelle is targeted for degradation.

Cleveland Clinic researchers have identified a protein in the brain that plays a critical role in the memory loss seen in Alzheimer’s patients, according to a study to be published in the journal Nature Neuroscience and posted online today.

The protein – Neuroligin-1 (NLGN1) – is known to be involved in memory formation; this is the first time it’s been linked to amyloid-associated memory loss.

In Alzheimer’s disease, amyloid beta proteins accumulate in the brains of Alzheimer’s patients and induce inflammation. This inflammation leads to certain gene modifications that interrupt the functioning of synapses in the brain, leading to memory loss.

Using animal models, Cleveland Clinic researchers have discovered that during this neuroinflammatory process, the epigenetic modification of NLGN1 disrupts the synaptic network in the brain, which is responsible for developing and maintaining memories. Destroying this network can lead to the type of memory loss seen in Alzheimer’s patients.

"Alzheimer’s is a challenging disease that researchers have been approaching from all angles," said Mohamed Naguib, M.D., the Cleveland Clinic physician who lead the study. "This discovery could provide us with a new approach for preventing and treating Alzheimer’s disease."

Previous studies from this group of researchers have also identified a novel compound called MDA7, which can potentially stop the neuroinflammatory process that leads to the modification of NLGN1. Treatment with the compound restored cognition, memory and synaptic plasticity – a key neurological foundation of learning and memory – in an animal model. Significant preliminary work for the first-in-man study has been completed for MDA7 including in-vitro studies and preliminary clinical toxicology and pharmacokinetic work. The Cleveland Clinic plans to initiate Phase I human studies on the safety of this class of compounds in the near future.

Alzheimer’s disease is an irreversible, fatal brain disease that slowly destroys memory and thinking skills. About 5 million people in the United States have Alzheimer’s disease. With the aging of the population, and without successful treatment, there will be 16 million Americans and 106 million people worldwide with Alzheimer’s by 2050, according to the 2011 Alzheimer’s Disease Facts and Figures report from the Alzheimer’s Association.

Memories of traumatic events often last a lifetime because they are so difficult to treat through behavioral approaches. A preclinical study in mice published by Cell Press January 16th in the journal Cell reveals that drugs known as histone deacetylase inhibitors (HDACis) can enhance the brain’s ability to permanently replace old traumatic memories with new memories, opening promising avenues for the treatment of posttraumatic stress disorder (PTSD) and other anxiety disorders.

Caption: Metabolic activity (green and red colors) in the hippocampus (white dotted line) of animals that underwent extinction training in combination with HDACis (right) is significantly higher than in animals that underwent extinction training alone (left). Metabolic activity serves to estimate the learning capacity of an animal. Credit: Cell, Gräff et al.

"Psychotherapy is often used for treating PTSD, but it doesn’t always work, especially when the traumatic events occurred many years earlier," says senior study author Li-Huei Tsai of the Massachusetts Institute of Technology. "This study provides a mechanism explaining why old memories are difficult to extinguish and shows that HDACis can facilitate psychotherapy to treat anxiety disorders such as PTSD."

One common treatment for anxiety disorders is exposure-based therapy, which involves exposing patients to fear-evoking thoughts or events in a safe environment. This process reactivates the traumatic memory, opening a short time window during which the original memory can be disrupted and replaced with new memories. Exposure-based therapy is effective when the traumatic events occurred recently, but until now, it was not clear whether it would also be effective for older traumatic memories.

To address this question, Tsai and her team used a protocol for studying fear responses associated with traumatic memories. In the first phase, the researchers exposed mice to a tone followed by an electrical footshock. Once the mice learned to associate these two events, they began to freeze in fear upon hearing the tone by itself, even when they did not receive a shock. Using an extinction protocol, which is similar to exposure-based therapy, the researchers repeatedly presented the tone without the shock to test whether the mice could unlearn the association between these two events and would stop freezing in response to the tone. The extinction protocol was successful for mice that were exposed to the tone-shock pairing just one day earlier, but it was not effective for mice that originally formed the traumatic memory one month earlier. The researchers hypothesized that epigenetic modification of genes involved in learning and memory might be responsible for the diminished response of treatment for older memories.

The researchers tested whether HDACis, which promote long-lasting activation of genes involved in learning and memory, could help replace old traumatic memories with new memories. Mice previously exposed to the tone-shock pairing received HDACis and then underwent the extinction protocol. These mice learned to stop freezing in response to the tone, even when they originally formed the traumatic memory one month earlier. “Collectively, our findings suggest that exposure-based therapy alone does not effectively weaken traumatic memories that were formed a long time ago, but that HDACis can be combined with exposure-based therapy to substantially improve treatment for the most enduring traumatic memories,” Tsai says.

An Auburn University researcher teamed up with the National Institutes of Health to study how brain networks shape an individual’s religious belief, finding that brain interactions were different between religious and non-religious subjects.

Gopikrishna Deshpande, an assistant professor in the Department of Electrical and Computer Engineering in Auburn’s Samuel Ginn College of Engineering, and the NIH researchers recently published their results in the journal, “Brain Connectivity.”

The group found differences in brain interactions that involved the theory of mind, or ToM, brain network, which underlies the ability to relate between one’s personal beliefs, intents and desires with those of others. Individuals with stronger ToM activity were found to be more religious. Deshpande says this supports the hypothesis that development of ToM abilities in humans during evolution may have given rise to religion in human societies.

“Religious belief is a unique human attribute observed across different cultures in the world, even in those cultures which evolved independently, such as Mayans in Central America and aboriginals in Australia,” said Deshpande, who is also a researcher at Auburn’s Magnetic Resonance Imaging Research Center. “This has led scientists to speculate that there must be a biological basis for the evolution of religion in human societies.”

Deshpande and the NIH scientists were following up a study reported in the Proceedings of the National Academy of Sciences, which used functional magnetic resonance imaging, or fMRI, to scan the brains of both self-declared religious and non-religious individuals as they contemplated three psychological dimensions of religious beliefs.

The fMRI – which allows researchers to infer specific brain regions and networks that become active when a person performs a certain mental or physical task – showed that different brain networks were activated by the three psychological dimensions; however, the amount of activation was not different in religious as compared to non-religious subjects.

A world-first study led by the National Cannabis Prevention and Information Centre (NCPIC) at UNSW has revealed a breakthrough for dependent cannabis users, employing a cannabis-based medication, Sativex (nabiximols), that has been shown to provide significant relief from withdrawal symptoms.

“One in ten people who try cannabis go on to become dependent. As cannabis use increases around the world and more people seek treatment to help them quit, it is surprising there is no approved medication to alleviate symptoms of withdrawal. The success of this study offers considerable hope for those struggling to get through a cannabis withdrawal and remain abstinent into the future,” said Professor Jan Copeland, Director of NCPIC and Chief Investigator of the study.

“One of the greatest barriers to quitting cannabis is withdrawal and while symptoms aren’t life-threatening, they are of a severity level that causes marked distress. For many people, symptoms including irritability, depression, cannabis cravings and sleep problems, can overcome their strong desire to quit and they find themselves using again.”

The study was conducted at inpatient services of South Eastern Sydney and Hunter New England Local Health Districts.

Associate Professor Nicolas Lintzeris, Director of Drug and Alcohol Services at South Eastern Sydney Local Health District and a trial investigator said: “The study found patients treated with Sativex stayed in treatment longer, and experienced a shorter and milder withdrawal than patients receiving placebo.”

Administered as an oral spray, Sativex is only licensed in Australia for the treatment of spasticity and pain in Multiple Sclerosis (MS) patients when other medications have failed. The spray contains the cannabis extracts, cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), which is the substance primarily responsible for the psychoactive effects of cannabis.

The lead author of the paper and study investigator Dr David Allsop noted, “While most people who use cannabis do not become dependent, those who use regularly or for an extended period run that risk. Sativex is not licensed or available for treating cannabis users at this time. Our hope is that this study will lead to further research, and possibly approval of the drug for use as a treatment for people experiencing problematic cannabis use.”

The full findings of this study have been published in international psychiatry journal, JAMA Psychiatry.

A new study by scientists at McGill University and the University of Zurich shows a direct link between metabolism in brain cells and their ability to signal information. The research may explain why the seizures of many epilepsy patients can be controlled by a specially formulated diet. 

(Image caption: Neurons in the cerebellum. Credit: Bowie Lab/McGill University)

The findings, published Jan. 16 in Nature Communications, reveal that metabolism controls the processes that inhibit brain activity, such as that involved in convulsions. The study uncovers a link between how brain cells make energy and how the same cells signal information – processes that neuroscientists have often assumed to be distinct and separate. 

“Inhibition in the brain is commonly targeted in clinical practice,” notes Derek Bowie, Canada Research Chair in Receptor Pharmacology at McGill and corresponding author of the study. “For example, drugs that alleviate anxiety, induce anesthesia, or even control epilepsy work by strengthening brain inhibition. These pharmacological approaches can have their drawbacks, since patients often complain of unpleasant side effects.” 

The experiments showed an unexpected link between how the mitochondria of brain cells make energy and how the same cells signal information. Brain cells couple these two independent functions by using small chemical messengers, called reactive oxygen species (or ROS), that are normally associated with signaling cell death. While ROS are known to have roles in diseases of aging, such as Alzheimer’s and Parkinson’s, the new study shows they also play important roles in the healthy brain.  

The findings emerged from an ongoing collaboration between Prof. Bowie’s laboratory in McGill’s Department of Pharmacology and Therapeutics and a research team headed by Dr. Jean-Marc Fritschy, Professor of Pharmacology at the University of Zurich and current director of the Neuroscience Center Zurich (ZNZ). The researchers have the longer term aim of trying to understand why the seizures of many epilepsy patients — especially young children – can be treated with a high-fat, low-carbohydrate diet known as the ketogenic diet. 

The idea that diet can control seizures was noticed as far back as ancient Greece, during periods of fasting. From the 1920s until the 1950s, the ketogenic diet was widely used to treat epilepsy patients. With the introduction of anticonvulsant drugs in the 1950s, the dietary approach fell out of favour with doctors. But because anticonvulsant drugs don’t work for 20% to 30% of patients, there has been a resurgence in use of the ketogenic diet. 

“Since our study shows that brain cells have their own means to strengthen inhibition,” explains Prof Bowie, “our work points to potentially new ways in which to control a number of important neurological conditions including epilepsy.”

Middle-aged men who drink more than 36 grams of alcohol, or two and a half US drinks per day, may speed their memory loss by up to six years later on, according to a study published in the January 15, 2014, online issue of Neurology®, the medical journal of the American Academy of Neurology. On the other hand, the study found no differences in memory and executive function in men who do not drink, former drinkers and light or moderate drinkers. Executive function deals with attention and reasoning skills in achieving a goal.

“Much of the research evidence about drinking and a relationship to memory and executive function is based on older populations,” said study author Séverine Sabia, PhD, of the University College London in the United Kingdom. “Our study focused on middle-aged participants and suggests that heavy drinking is associated with faster decline in all areas of cognitive function in men.”

The study involved 5,054 men and 2,099 women whose drinking habits were assessed three times over 10 years. A drink was considered wine, beer or liquor. Then, when the participants were an average age of 56, they took their first memory and executive function test. The tests were repeated twice over the next 10 years.

The study found that there were no differences in memory and executive function decline between men who did not drink and those who were light or moderate drinkers—those who drank less than 20 grams, or less than two US drinks per day. Heavy drinkers showed memory and executive function declines between one-and-a-half to six years faster than those who had fewer drinks per day.

Survivors of traumatic brain injuries (TBI) are three times more likely to die prematurely than the general population, often from suicide or fatal injuries, finds an Oxford University-led study.

A TBI is a blow to the head that leads to a skull fracture, internal bleeding, loss of consciousness for longer than an hour or a combination of these symptoms. Michael Schumacher’s recent skiing injury is an example of a TBI. Concussions, sometimes called mild TBIs, do not present with these symptoms and were analysed separately in this study.

Researchers examined Swedish medical records going back 41 years covering 218,300 TBI survivors, 150,513 siblings of TBI survivors and over two million control cases matched by sex and age from the general population. The work was carried out by researchers at Oxford University and the Karolinska Institute in Stockholm.

'We found that people who survive six months after TBI remain three times more likely to die prematurely than the control population and 2.6 times more likely to die than unaffected siblings,' said study leader Dr Seena Fazel, a Wellcome Trust Senior Research Fellow in Oxford University's Department of Psychiatry. 'Looking at siblings who did not suffer TBIs allows us to control for genetic factors and early upbringing, so it is striking to see that the effect remains strong even after controlling for these.'

The results, published in the journal JAMA Psychiatry, show that TBI survivors who also have a history of substance abuse or psychiatric disorders are at highest risk of premature death. Premature deaths were defined as before age 56. The main causes of premature death in TBI survivors are suicide and fatal injuries such as car accidents and falls.

'TBI survivors are more than twice as likely to kill themselves as unaffected siblings, many of whom were diagnosed with psychiatric disorders after their TBI,' said Dr Fazel. 'Current guidelines do not recommend assessments of mental health or suicide risk in TBI patients, instead focusing on short-term survival. Looking at these findings, it may make more sense to treat some TBI patients as suffering from a chronic problem requiring longer term management just like epilepsy or diabetes. TBI survivors should be monitored carefully for signs of depression, substance abuse and other psychiatric disorders, which are all treatable conditions.'

The exact reasons for the increased risk of premature death are unknown but may involve damage to the parts of the brain responsible for judgement, decision making and risk taking. TBI survivors are three times more likely to die from fatal injuries which may be a result of impaired judgement or reactions.

'This study highlights the important and as yet unanswered question of why TBI survivors are more likely to die young, but it may be that serious brain trauma has lasting effects on people's judgement,' suggests Dr Fazel. 'People who have survived the acute effects of TBI should be more informed about these risks and how to reduce their impact.'

'When treating traumatic brain injuries focus is placed on immediate treatment and recovery of patients,' says Dr John Williams, Head of Neuroscience and Mental Health at the Wellcome Trust. 'This new finding offers important insight into the longer-term impact of TBIs on the brain and their effect on survival later in life. We hope that further research into understanding which parts of the brain are responsible will help improve future management programmes and reduce the potential for premature death.'

Even relatively minor brain injuries, concussions, had a significant impact on early mortality. People with concussion were found to be twice as likely to die prematurely as the control population, with suicide and fatal injuries as the main causes of death. This raises issues surrounding concussions in a wide range of sports, from American football, rugby and soccer to baseball and cricket.

We use both sides of our brain for speech, a finding by researchers at New York University and NYU Langone Medical Center that alters previous conceptions about neurological activity. The results, which appear in the journal Nature, also offer insights into addressing speech-related inhibitions caused by stroke or injury and lay the groundwork for better rehabilitation methods.

“Our findings upend what has been universally accepted in the scientific community—that we use only one side of our brains for speech,” says Bijan Pesaran, an associate professor in NYU’s Center for Neural Science and the study’s senior author. “In addition, now that we have a firmer understanding of how speech is generated, our work toward finding remedies for speech afflictions is much better informed.”

Many in the scientific community have posited that both speech and language are lateralized—that is, we use only one side of our brains for speech, which involves listening and speaking, and language, which involves constructing and understanding sentences. However, the conclusions pertaining to speech generally stem from studies that rely on indirect measurements of brain activity, raising questions about characterizing speech as lateralized.

To address this matter, the researchers directly examined the connection between speech and the neurological process.

Specifically, the study relied on data collected at NYU ECoG, a center where brain activity is recorded directly from patients implanted with specialized electrodes placed directly inside and on the surface of the brain while the patients are performing sensory and cognitive tasks. Here, the researchers examined brain functions of patients suffering from epilepsy by using methods that coincided with their medical treatment.

“Recordings directly from the human brain are a rare opportunity,” says Thomas Thesen, director of the NYU ECoG Center and co-author of the study.

“As such, they offer unparalleled spatial and temporal resolution over other imaging technologies to help us achieve a better understanding of complex and uniquely human brain functions, such as language,” adds Thesen, an assistant professor at NYU Langone.

In their examination, the researchers tested the parts of the brain that were used during speech. Here, the study’s subjects were asked to repeat two “non-words”—“kig” and “pob.” Using non-words as a prompt to gauge neurological activity, the researchers were able to isolate speech from language.

An analysis of brain activity as patients engaged in speech tasks showed that both sides of the brain were used—that is, speech is, in fact, bi-lateral.

“Now that we have greater insights into the connection between the brain and speech, we can begin to develop new ways to aid those trying to regain the ability to speak after a stroke or injuries resulting in brain damage,” observes Pesaran. “With this greater understanding of the speech process, we can retool rehabilitation methods in ways that isolate speech recovery and that don’t involve language.”

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have described a pair of drug candidates that advance the search for new treatments for pain, addiction and other disorders.

The two new drug scaffolds, described in a recent edition of The Journal of Biological Chemistry, offer researchers novel tools that act on a demonstrated therapeutic target, the kappa opioid receptor (KOR), which is located on nerve cells and plays a role in the release of the neurotransmitter dopamine. While compounds that activate KOR are associated with positive therapeutic effects, they often also recruit a molecule known as βarrestin2 (beta arrestin), which is associated with depressed mood and severely limits any therapeutic potential.

“Compounds that act at kappa receptors may provide a means for treating addiction and for treating pain; however, there is the potential for the development of depression or dysphoria associated with this receptor target,” said Laura Bohn, a TSRI associate professor who led the study. “There is evidence that the negative feelings caused by kappa receptor drugs may be, in part, due to receptor actions through proteins called beta arrestins. Developing compounds that activate the receptors without recruiting beta arrestin function may serve as a means to improve the therapeutic potential and limit side effects.”

The new compounds are called “biased agonists,” activating the receptor without engaging the beta arrestins.

Research Associate Lei Zhou, first author of the study with Research Associate Kimberly M. Lovell, added, “The importance of these biased agonists is that we can manipulate the activation of one particular signaling cascade that produces analgesia, but not the other one that could lead to dysphoria or depression.”

The researchers note that the avoidance of depression is particularly important in addiction treatment, where depressed mood can play a role in relapse. 

The two drug candidates also have a high affinity and selectivity for KOR over other opioid receptors and are able to pass through the blood-brain barrier. Given these promising attributes, the scientists plan to continue developing the compounds.

When an MRI scan uncovers an unusual architecture or shape in a child’s brain, it’s cause for concern: The malformation may be a sign of disease. But deciding whether that odd-looking anatomy is worrisome or harmless can be difficult. To help doctors reach the right decision, Johns Hopkins researchers are building a detailed digital library of MRI scans collected from children with normal and abnormal brains. The goal, the researchers say, is to give physicians a Google-like search system that will enhance the way they diagnose and treat young patients with brain disorders.

This cloud-computing project, being developed by a team of engineers and radiologists, should allow physicians to access thousands of pediatric scans to look for some that resemble their own patient’s image. The project is supported by a three-year $600,000 grant from the National Institutes of Health.

"We’re creating a pediatric brain data bank that will let doctors look at MRI brain scans of children who have already been diagnosed with illnesses like epilepsy or psychiatric disorders," said Michael I. Miller, a lead investigator on the project. "It will provide a way to share important new discoveries about how changes in brain structures are linked to brain disorders. For the medical imaging world, this system will do what a search engine like Google does when you ask it to look for specific information on the Web."

Miller, a pioneer in the field of computational anatomy, the technology used for “brain parsing,” is the Herschel and Ruth Seder Professor of Biomedical Engineering at Johns Hopkins and director of the university’s Center for Imaging Science. He also is a core faculty member in the university’s Institute for Computational Medicine.

The new pediatric brain imaging data bank, Miller said, will be useful in at least two ways.

"If doctors aren’t sure which disease is causing a child’s condition, they could search the data bank for images that closely match their patient’s most recent scan," he said. "If a diagnosis is already attached to an image from the data bank that could steer the physician in the right direction. Also, the scans in our library may help a physician identify a change in the shape of a brain structure that occurs very early in the course of a disease, even before clinical symptoms appear. That could allow the physician get an early start on the treatment."

Miller’s co-lead investigator on the project is Susumu Mori, a professor of radiology in the Johns Hopkins School of Medicine. One of Mori’s primary research interests is studying the anatomy of brain structures captured in MRI scans. 

Mori points out that such a “biobank” has the potential to impact doctors’ workflow dramatically.

"We empirically know that a certain type of anatomical abnormality is related to specific brain diseases," he said. "This relationship, however, is not always clear and often is compounded by anatomical changes during the normal course of brain development. Therefore, neuro-radiologists need extensive training to accumulate the knowledge. We hope our brain imaging data bank will not only assist such a learning process but also enhance the physician’s ability to understand the pathology and reach the best medical decision."

Mori and his collaborator, Thierry Huisman, a professor of radiology and pediatrics and the director of pediatric radiology at the Johns Hopkins Children’s Center, have been working for more than four years to establish a clinical database of more than 5,000 whole-brain MRI scans of children treated at Johns Hopkins. The patients’ names and other identifying information were withheld, but details related to their medical conditions were included. The computer software indexed anatomical information involving up to 1,000 structural measurements in 250 regions of the brain. These images were also sorted into 22 brain disease categories, including chromosomal abnormalities, congenital malformations, vascular diseases, infections, epilepsy and psychiatric disorders.

According to Huisman, the new data bank now under development not only facilitates recognition and correct classification of pediatric brain disorders, but the more objective image analysis also allows identification of injury and disease that may go undetected by the classical, more subjective radiological “eyeballing” of MR images. Furthermore, he said, recognition of distinct patterns of injury and the subsequent grouping of these children based upon their characteristic patterns of MRI findings allow recognition and identification of new diseases as well as reclassification of previously unclassified diseases. Finally, he added, the data acquisition is free of ionizing radiation, allowing doctors to study the most vulnerable, youngest patients and perhaps to help initiate disease-specific treatment before irreversible injury to the developing brain occurs.

Beyond the brain imaging data bank for children, the researchers have begun building a similar MRI brain image library with Marilyn Albert, a Johns Hopkins neurology professor. This library focuses on brain disorders commonly found in elderly patients. That project is associated with the National Institute of Aging’ Alzheimer’s Disease Research Center.

With all of this data in place, physicians will be able to conduct a Google-like search for images associated with normal and abnormal pediatric and aging brain conditions. For example, a physician who is uncertain about a child’s diagnosis could submit that patient’s latest brain scan and request the medical records of children with similar images. Alternatively, for studying neurodegenerative diseases such as Alzheimer’s in aging patients, a physician might ask to see the medical records associated with all images that display neurofibrillary tangles in the temporal lobe, a condition seen in his or her patient’s scan.

Jonathan Lewin, the chairman and radiologist-in-chief of the Johns Hopkins Department of Radiology and Radiological Science, noted that this approach could help patients with both common and uncommon diseases. “This research is one of the first real applications of ‘Big Data’ analytics, taking medical information from large numbers of patients, removing anything that would identify specific individuals, and then bringing the data into the ‘cloud’ to allow very high-powered analysis,” Lewin said. “This has been a goal of the medical community for almost a decade, and professors Miller and Mori have found a way to implement this technology in a manner that can bring its benefit to our patients, and can assist in the classification and identification of rare and subtle brain disorders as well as uncommon manifestations of more common diseases of the brain.”

Currently, the pilot pediatric brain imaging data bank is limited to physicians and patients within the Johns Hopkins medical system, but the researchers say the data bank could be expanded or replicated elsewhere in coming years.

A new form of cell sub-division that is key to the development of the nervous system has been identified by researchers at the University of Dundee.

Image caption: Image shows two newborn neurons shedding their tip ends, or abscising

Neurons are vital to the development of the nervous system and in some regions of our brains they are continually produced throughout our lives. They are ‘born’ in a particular place in the early nervous system and then have to migrate to the correct place to make functional neural structures.

A team led by Professor Kate Storey and Dr Raman Das in the College of Life Sciences at Dundee have now identified a new process, apical abscission, which mediates the detachment of new-born neurons from the neural tube ventricle - freeing these cells to migrate.

'Neuron production is an important process within our bodies. As an example, our memory centre, the hippocampus, continues to produce neurons throughout our lives,' said Professor Storey.

'What we have identified are the molecular events, the 'letting-go' process, which allow newborn neurons to move to their correct place in the nervous system.

'This is a new form of cell sub-division so it is of significant interest as it tells us about mechanisms that control how we develop that we didn't know before. We were very surprised when we first saw cells shedding their tip-ends as they began to differentiate into neurons, it is not what we had expected at all.

'Our discovery comes with the development of novel live-tissue imaging approaches in my lab, which allows us to monitor cell behaviour over long periods. We have also been to make use of state of the art super-resolution microscopy in the Light Microscopy Facility based here within the College of Life Sciences.'

The research has been funded by the Wellcome Trust and the results are published this week in the journal Science.

The work identifies molecular events that control the shedding of the cell’s tip. It takes place as cells lose a key adhesion molecule and involves increased activity of a cell constriction mechanism.

Surprisingly, this event, also involves dismantling of an important structure in the cell, the primary cilium, known to convey signals that promote cell proliferation. Das and Storey propose that Apical Abscission mediates a pivotal cell state transition in the neuronal differentiation process, rapidly altering the polarity and signalling activity of the new-born neuron.

The researchers plan to extend the work to determine if this new mechanism also operates in other contexts including different regions of the brain, but will also address if this takes place in some cancers, where cells are known to lose polarity, shed primary cilia and detach from their neighbours as a prelude to tissue invasion.

'We need to look more widely now to establish whether this regulated mechanism allows other cells to make rapid cell state transitions and to move in other tissues of the body,' said Professor Storey.