Neuroscience

Researchers from Massachusetts Eye and Ear, Harvard Medical School, Massachusetts Institute of Technology and Massachusetts General Hospital have demonstrated, for the first time, that aspirin intake correlates with halted growth of vestibular schwannomas (also known as acoustic neuromas), a sometimes lethal intracranial tumor that typically causes hearing loss and tinnitus.

Image credit: Stanford School of Medicine/Oghalai Lab

Motivated by experiments in the Molecular Neurotology Laboratory at Mass. Eye and Ear involving human tumor specimens, the researchers performed a retrospective analysis of over 600 people diagnosed with vestibular schwannoma at Mass. Eye and Ear. Their research suggests the potential therapeutic role of aspirin in inhibiting tumor growth and motivates a clinical prospective study to assess efficacy of this well-tolerated anti-inflammatory medication in preventing growth of these intracranial tumors.

“Currently, there are no FDA-approved drug therapies to treat these tumors, which are the most common tumors of the cerebellopontine angle and the fourth most common intracranial tumors,” explains Konstantina Stankovic, M.D., Ph.D., who led the study. “Current options for management of growing vestibular schwannomas include surgery (via craniotomy) or radiation therapy, both of which are associated with potentially serious complications.”

The findings, which are described in the February issue of the journal Otology & Neurotology, were based on a retrospective series of 689 people, 347 of whom were followed with multiple magnetic resonance imaging MRI scans (50.3%). The main outcome measures were patient use of aspirin and rate of vestibular schwannoma growth measured by changes in the largest tumor dimension as noted on serial MRIs. A significant inverse association was found among aspirin users and vestibular schwannoma growth (odds ratio: 0.50, 95 percent confidence interval: 0.29-0.85), which was not confounded by age or gender.

“Our results suggest a potential therapeutic role of aspirin in inhibiting vestibular schwannoma growth,” said Dr. Stankovic, who is an otologic surgeon and researcher at Mass. Eye and Ear, Assistant Professor of Otology and Laryngology, Harvard Medical School (HMS), and member of the faculty of Harvard’s Program in Speech and Hearing Bioscience and Technology.

Neuroscientists from the University of Leicester, in collaboration with the Department of Neurosurgery at the University California Los Angeles (UCLA), are to reveal details of how the brain determines the timing at which neurons in specific areas fire to create new memories.

This research exploits the unique opportunity of recording multiple single-neurons in patients suffering from epilepsy refractory to medication that are implanted with intracranial electrodes for clinical reasons.

The study, which is to be published in the academic journal Current Biology, is the result of collaboration between Professor Rodrigo Quian Quiroga and Dr Hernan Rey at the Centre for Systems Neuroscience at the University of Leicester and Professor Itzhak Fried at UCLA.

The work follows up on the group’s research into what was dubbed the ‘Jennifer Aniston neurons’ – neurons in the hippocampus and its surrounding areas within the brain that specifically fire in an ‘abstract’ manner when we see or hear a certain concept  - such as a person, an animal or a landscape - that we recognise.

Professor Quian Quiroga said: “The firing of these neurons is relatively very late after the moment of seeing the picture, or hearing the person’s name, but is still very precise. These neurons also fire only when the pictures are consciously recognised and remain silent when they are not.

“Our research shows that there is a specific brain response that marks the timing of the firing of these neurons. This response shortly precedes the neuron’s firing and is only present for the consciously recognised pictures - being absent if the pictures were not recognised.

“This brain response thus reflects an activation that provides a temporal window for processing consciously perceived stimuli in the hippocampus and surrounding cortex. Given the proposed role of these neurons in memory formation, we argue that the brain response we found is a gateway for processing consciously perceived stimuli to form or recall memories.”

Dr Hernan Rey, first author of the study, added: “This time-keeping may indeed be critical for synchronizing and combining multisensory information involving different processing times. This, in turn, helps in creating a unified conceptual representation that can be used for memory functions.”

Professor Quian Quiroga’s work is specifically concerned with examining how information about the external world - what we see, hear and touch - is represented by neurons in the brain and how this leads to the creation of our own internal representations and memories.

For example, we can easily recognize a person in a fraction of a second, even when seen from different angles, with different sizes, colours, contrasts and under strikingly different conditions. But how neurons in the brain are capable of creating such an ‘abstract’ representation, disregarding basic visual details, is only starting to be known.

Setting the stage for possible advances in pain treatment, researchers at The Johns Hopkins University and the University of Maryland report they have pinpointed two molecules involved in perpetuating chronic pain in mice. The molecules, they say, also appear to have a role in the phenomenon that causes uninjured areas of the body to be more sensitive to pain when an area nearby has been hurt. A summary of the research will be published on Jan. 23 in the journal Neuron.

Image caption: Nerves in mouse skin that are actively responding to the painful stimulus capsaicin have been genetically engineered to glow green. Hairs appear in yellow. Credit: David Rini

"With the identification of these molecules, we have some additional targets that we can try to block to decrease chronic pain," says Xinzhong Dong, Ph.D., associate professor of neuroscience at the Johns Hopkins University School of Medicine and an early career scientist at Howard Hughes Medical Institute. "We found that persistent pain doesn’t always originate in the brain, as some had believed, which is important information for designing less addictive drugs to fight it."

Chronic pain that persists for weeks, months or years after an underlying injury or condition is resolved afflicts an estimated 20 to 25 percent of the population worldwide and about 116 million people in the U.S., costing Americans a total of $600 billion in medical interventions and lost productivity. It can be caused by everything from nerve injuries and osteoarthritis to cancer and stress.

In their new research, the scientists focused on a system of pain-sensing nerves within the faces of mice, known collectively as the trigeminal nerve. The trigeminal nerve is a large bundle of tens of thousands of nerve cells. Each cell is a long “wire” with a hub at its center; the hubs are grouped together into a larger hub. On one side of this hub, three smaller bundles of wires — V1, V2 and V3 — branch off. Each bundle contains individual pain-sensing wires that split off to cover a specific territory of the face. Signals are sent through the wires to the hubs of the cells and then travel to the spinal cord through a separate set of bundles. From the spinal cord, the signals are relayed to the brain, which interprets them as pain. 

When the researchers pinched the V2 branch of the trigeminal nerve for a prolonged period of time, they found that the V2 and V3 territories were extra sensitive to additional pain. This spreading of pain to uninjured areas is typical of those experiencing chronic pain, but it can also be experienced during acute injuries, as when a thumb is hit with a hammer and the whole hand throbs with pain.

To figure out why, the researchers studied pain-sensing nerves in the skin of mouse ears. The smaller branches of the trigeminal V3 reach up into the skin of the lower ear. But an entirely different set of nerves is responsible for the skin of the upper ear. This distinction allowed the researchers to compare the responses of two unrelated groups of nerves that are in close proximity to each other.

To overcome the difficulty of monitoring nerve responses, Dong’s team inserted a gene into the DNA of mice so that the primary sensory nerve cells would glow green when activated. The pain-sensing nerves of the face are a subset of these.

When skin patches were then bathed in a dose of capsaicin — the active ingredient in hot peppers — the pain-sensing nerves lit up in both regions of the ear. But the V3 nerves in the lower ear were much brighter than those of the upper ear. The researchers concluded that pinching the connected-but-separate V2 branch of the trigeminal nerve had somehow sensitized the V3 nerves to “overreact” to the same amount of stimulus. (Watch nerves light up in this video.)

Applying capsaicin again to different areas, the researchers found that more nerve branches coming from a pinched V2 nerve lit up than those coming from an uninjured one. This suggests that nerves that don’t normally respond to pain can modify themselves during prolonged injury, adding to the pain signals being sent to the brain.

Knowing from previous studies that the protein TRPV1 is needed to activate pain-sensing nerve cells, the researchers next looked at its activity in the trigeminal nerve. They showed it was hyperactive in injured V2 nerve branches and in uninjured V3 branches, as well as in the branches that extended beyond the hub of the trigeminal nerve cell and into the spinal cord.

Next, University of Maryland experts in the neurological signaling molecule serotonin, aware that serotonin is involved in chronic pain, investigated its role in the TRPV1 activation study. The team, led by Feng Wei, M.D., Ph.D., blocked the production of serotonin, which is released from the brain stem into the spinal cord, and found that TRPV1 hyperactivity nearly disappeared.

Says Dong: “Chronic pain seems to cause serotonin to be released by the brain into the spinal cord. There, it acts on the trigeminal nerve at large, making TRPV1 hyperactive throughout its branches, even causing some non-pain-sensing nerve cells to start responding to pain. Hyperactive TRPV1 causes the nerves to fire more frequently, sending additional pain signals to the brain.”

TAU researcher finds that adults still think about numbers like kids

Children understand numbers differently than adults. For kids, one and two seem much further apart then 101 and 102, because two is twice as big as one, and 102 is just a little bigger than 101. It’s only after years of schooling that we’re persuaded to see the numbers in both sets as only one integer apart on a number line.

Now Dror Dotan, a doctoral student at Tel Aviv University’s School of Education and Sagol School of Neuroscience and Prof. Stanislas Dehaene of the Collège de France, a leader in the field of numerical cognition, have found new evidence that educated adults retain traces of their childhood, or innate, number sense — and that it’s more powerful than many scientists think.

"We were surprised when we saw that people never completely stop thinking about numbers as they did when they were children," said Dotan. "The innate human number sense has an impact, even on thinking about double-digit numbers." The findings, a significant step forward in understanding how people process numbers, could contribute to the development of methods to more effectively educate or treat children with learning disabilities and people with brain injuries.

Digital proof of a primal sense

Educated adults understand numbers “linearly,” based on the familiar number line from 0 to infinity. But children and uneducated adults, like tribespeople in the Amazon, understand numbers “logarithmically” — in terms of what percentage one number is of another. To analyze how educated adults process numbers in real time, Dotan and Dehaene asked the participants in their study to place numbers on a number line displayed on an iPad using a finger.

Previous studies showed that people who understand numbers linearly perform the task differently than people who understand numbers logarithmically. For example, linear thinkers place the number 20 in the middle of a number line marked from 0 to 40. But logarithmic thinkers like children may place the number 6 in the middle of the number line, because 1 is about the same percentage of 6 as 6 is of 40.

On the iPad used in the study, the participants were shown a number line marked only with “0” on one end and “40” on the other. Numbers popped up one at a time at the top of the iPad screen, and the participants dragged a finger from the middle of the screen down to the place on the number line where they thought each number belonged. Software tracked the path the finger took.

Changing course

Statistical analysis of the results showed that the participants placed the numbers on the number line in a linear way, as expected. But surprisingly — for only a few hundred milliseconds — they appeared to be influenced by their innate number sense. In the case of 20, for example, the participants drifted slightly rightward with their finger — toward where 20 would belong in a ratio-based number line — and then quickly corrected course. The results provide some of the most direct evidence to date that the innate number sense remains active, even if largely dormant, in educated adults.

"It really looks like the two systems in the brain compete with each other," said Dotan.

Significantly, the drift effect was found with two-digit as well as one-digit numbers. Many researchers believe that people can only convert two-digit numbers into quantities using the learned linear numerical system, which processes the quantity of each digit separately — for example, 34 is processed as 3 tens plus 4 ones. But Dotan and Dehaene’s research showed that the innate number sense is, in fact, capable of handling the complexity of two-digit numbers as well.

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.