Neuroscience

An international team of researchers have identified a previously unknown neurodegenerative disorder and discovered it is caused by a single mutation in one individual born during the height of the Ottoman Empire in Turkey about 16 generations ago.

(Image caption: An fMRI scan of the brain of a patient with CLP1 mutation reveals severe atrophy of the brainstem (red line) and cerebellum (blue) as well as lack of formation of the corpus callosum (green), which connects both sides of the cerebrum (yellow), which is also atrophied. The lines outline approximately the expected sizes of the brain areas. A study traced the mutation to a single individual born in Turkey during the Ottoman Empire, some 16 generations ago.)

The genetic cause of the rare disorder was discovered during a massive analysis of the individual genomes of thousands of Turkish children suffering from neurological disorders.

“The more we learn about basic mechanisms behind rare forms of neuro-degeneration, the more novel insights we can gain into more common diseases such as Alzheimer’s or Lou Gehrig’s Disease,” said Murat Gunel, the Nixdorff-German Professor of Neurosurgery, and professor of genetics and neurobiology at Yale.

Gunel is a senior co-author of one of two papers published in the April 24 issue of the journal Cell that document the devastating effects of a mutation in the CLP1 gene. Gunel and colleagues at Yale Center for Mendelian Genomics along with Joseph Gleeson’s group at University of California-San Diego compared DNA sequencing results of more than 2,000 children from different families with neurodevelopmental disorders. In four apparently unrelated families, they identified the exact same mutation in the CLP1 gene. Working with the Frank Bass group from the Netherlands, the researchers also studied how CLP1 mutations interfered with the transfer of information encoded within genes to cells’ protein-making machinery.

The discovery of the identical mutation in seemingly unrelated families originally from eastern Turkey suggested an ancestral mutation, dating back several generations, noted the researchers.

Affected children suffer from intellectual disability, seizures, and delayed or absent mental and motor development, and their imaging studies show atrophy affecting the cerebral cortex, cerebellum, and the brain stem.

The second Cell paper by researchers from Baylor School of Medicine and Austria also found the identical founder mutation in CLP1 in another 11 children from an additional five families originally from eastern Turkey.

Gunel said that the high prevalence of consanguineous marriages [between closely related people] in Turkey and the Middle East leads to these rare recessive genetic neurodegenerative disorders. Affected children inherit mutations in the same gene from both of their parents, who are closely related to each other, such as first cousins. Without consanguinity between parents, children are very unlikely to inherit two mutations in the same gene.

“By dissecting the genetic basis of these neurodevelopmental disorders, we are gaining fundamental insight into basic physiological mechanisms important for human brain development and function” Gunel said. “We learn a lot about normal biology by studying what happens when things go wrong.”

Better-educated people appear to be significantly more likely to recover from a moderate to severe traumatic brain injury (TBI), suggesting that a brain’s “cognitive reserve” may play a role in helping people get back to their previous lives, new Johns Hopkins research shows.

The researchers, reporting in the journal Neurology, found that those with the equivalent of at least a college education are seven times more likely than those who didn’t finish high school to be disability-free one year after a TBI serious enough to warrant inpatient time in a hospital and rehabilitation facility.

The findings, while new among TBI investigators, mirror those in Alzheimer’s disease research, in which higher educational attainment — believed to be an indicator of a more active, or more effective, use of the brain’s “muscles” and therefore its cognitive reserve — has been linked to slower progression of dementia.

“After this type of brain injury, some patients experience lifelong disability, while others with very similar damage achieve a full recovery,” says study leader Eric B. Schneider, Ph.D., an epidemiologist at the Johns Hopkins University School of Medicine’s Center for Surgical Trials and Outcomes Research. “Our work suggests that cognitive reserve ¬— the brain’s ability to be resilient in the face of insult or injury — could account for the difference.”

Schneider conducted the research in conjunction with Robert D. Stevens. M.D., a neuro-intensive care physician with Johns Hopkins’ Department of Anesthesiology and Critical Care Medicine.

For the study, the researchers studied 769 patients enrolled in the TBI Model Systems database, an ongoing multi-center cohort of patients funded by the National Institute on Disability and Rehabilitation Research. The patients had been hospitalized with a moderate to severe TBI and subsequently admitted to a rehabilitation facility.

Of the 769 patients, 219 — or 27.8 percent — were free of any detectable disability one year after their injury. Twenty-three patients who didn’t complete high school — 9.7 percent of those at that education level — recovered, while 136 patients with between 12 and 15 years of schooling — 30.8 percent of those at that educational level — did. Nearly 40 percent of patients — 76 of the 194 — who had 16 or more years of education fully recovered.

Schneider says researchers don’t currently understand the biological mechanisms that might account for the link between years of schooling and improved recovery.

“People with increased cognitive reserve capabilities may actually heal in a different way that allows them to return to their pre–injury function and/or they may be able to better adapt and form new pathways in their brains to compensate for the injury,” Schneider says. “Further studies are needed to not only find out, but also to use that knowledge to help people with less cognitive reserve.”

Meanwhile, he says, “What we learned may point to the potential value of continuing to educate yourself and engage in cognitively intensive activities. Just as we try to keep our bodies strong in order to help us recover when we are ill, we need to keep the brain in the best shape it can be.”

Adds Stevens: “Understanding the underpinnings of cognitive reserve in terms of brain biology could generate ideas on how to enhance recovery from brain injury.”

Neuroscientists have discovered a brain pathway that underlies the emotional behaviours critical for survival.

New research by the University of Bristol, published in the Journal of Physiology, has identified a chain of neural connections which links central survival circuits to the spinal cord, causing the body to freeze when experiencing fear.

Understanding how these central neural pathways work is a fundamental step towards developing effective treatments for emotional disorders such as anxiety, panic attacks and phobias.

An important brain region responsible for how humans and animals respond to danger is known as the PAG (periaqueductal grey), and it can trigger responses such as freezing, a high heart rate, increase in blood pressure and the desire for flight or fight.

This latest research has discovered a brain pathway leading from the PAG to a highly localised part of the cerebellum, called the pyramis. The research went on to show that the pyramis is involved in generating freezing behaviour when central survival networks are activated during innate and learnt threatening situations.

The pyramis may therefore serve as an important point of convergence for different survival networks in order to react to an emotionally challenging situation.

Dr Stella Koutsikou, first author of the study and Research Associate in the School of Physiology and Pharmacology at the University of Bristol, said: “There is a growing consensus that understanding the neural circuits underlying fear behaviour is a fundamental step towards developing effective treatments for behavioural changes associated with emotional disorders.”

Professor Bridget Lumb, Professor of Systems Neuroscience, added: “Our work introduces the novel concept that the cerebellum is a promising target for therapeutic strategies to manage dysregulation of emotional states such as panic disorders and phobias.”

The researchers involved in this work are all members of Bristol Neuroscience which fosters interactions across one of the largest communities of neuroscientists in the UK.

Professor Richard Apps said: “This is a great example of how Bristol Neuroscience brings together expertise in different fields of neuroscience leading to exciting new insights into brain function.”

A study of older adults at increased risk for Alzheimer’s disease shows that moderate physical activity may protect brain health and stave off shrinkage of the hippocampus – the brain region responsible for memory and spatial orientation that is attacked first in Alzheimer’s disease. Dr. J. Carson Smith, a kinesiology researcher in the University of Maryland School of Public Health who conducted the study, says that while all of us will lose some brain volume as we age, those with an increased genetic risk for Alzheimer’s disease typically show greater hippocampal atrophy over time. The findings are published in the open-access journal Frontiers in Aging Neuroscience.

"The good news is that being physically active may offer protection from the neurodegeneration associated with genetic risk for Alzheimer’s disease," Dr. Smith suggests. "We found that physical activity has the potential to preserve the volume of the hippocampus in those with increased risk for Alzheimer’s disease, which means we can possibly delay cognitive decline and the onset of dementia symptoms in these individuals. Physical activity interventions may be especially potent and important for this group."

Dr. Smith and colleagues, including Dr. Stephen Rao from the Cleveland Clinic, tracked four groups of healthy older adults ages 65-89, who had normal cognitive abilities, over an 18-month period and measured the volume of their hippocampus (using structural magnetic resonance imaging, or MRI) at the beginning and end of that time period. The groups were classified both for low or high Alzheimer’s risk (based on the absence or presence of the apolipoprotein E epsilon 4 allele) and for low or high physical activity levels.

Of all four groups studied, only those at high genetic risk for Alzheimer’s who did not exercise experienced a decrease in hippocampal volume (3 percent) over the 18-month period. All other groups, including those at high risk for Alzheimer’s but who were physically active, maintained the volume of their hippocampus.

"This is the first study to look at how physical activity may impact the loss of hippocampal volume in people at genetic risk for Alzheimer’s disease," says Dr. Kirk Erickson, an associate professor of psychology at the University of Pittsburgh. "There are no other treatments shown to preserve hippocampal volume in those that may develop Alzheimer’s disease. This study has tremendous implications for how we may intervene, prior to the development of any dementia symptoms, in older adults who are at increased genetic risk for Alzheimer’s disease."

Individuals were classified as high risk for Alzheimer’s if a DNA test identified the presence of a genetic marker – having one or both of the apolipoprotein E-epsilon 4 allele (APOE-e4 allele) on chromosome 19 – which increases the risk of developing the disease. Physical activity levels were measured using a standardized survey, with low activity being two or fewer days/week of low intensity activity, and high activity being three or more days/week of moderate to vigorous activity.

"We know that the majority of people who carry the E4 allele will show substantial cognitive decline with age and may develop Alzheimer’s disease, but many will not. So, there is reason to believe that there are other genetic and lifestyle factors at work," Dr. Smith says. "Our study provides additional evidence that exercise plays a protective role against cognitive decline and suggests the need for future research to investigate how physical activity may interact with genetics and decrease Alzheimer’s risk."

Dr. Smith has previously shown that a walking exercise intervention for patients with mild cognitive decline improved cognitive function by improving the efficiency of brain activity associated with memory. He is planning to conduct a prescribed exercise intervention in a population of healthy older adults with genetic and other risk factors for Alzheimer’s disease and to measure the impact on hippocampal volume and brain function.

TAU discovers that protein clusters implicated in neurodegenerative diseases actually serve to protect brain cells

People diagnosed with Huntington’s disease, most in their mid-thirties and forties, face a devastating prognosis: complete mental, physical, and behavioral decline within two decades. “Mutant” protein clusters, long blamed for the progression of the genetic disease, have been the primary focus of therapies in development by pharmaceutical companies. But according to new research from Prof. Gerardo Lederkremer and Dr. Julia Leitman of Tel Aviv University’s Department of Cell Research and Immunology, in collaboration with Prof. Ulrich Hartl of the Max Planck Institute for Biochemistry, these drugs may not only be ineffective — they may pose a serious threat to patients.

In two ground-breaking studies, published in the journals PLOS ONE and Nature Communications, Prof. Lederkremer and his team demonstrated that protein clusters are not the cause of toxicity in Huntington’s disease. On the contrary, these aggregates actually serve as a defense mechanism for “stressed” brain cells. Conducted on tissue cultures using cutting-edge microscopic technology, their studies identified a different causative agent — the “stress response” of affected brain cells.

"The upsetting implication for therapy of this disease is that drugs being developed to interfere with the formation of protein aggregates may in fact be detrimental," said Prof. Lederkremer. "The identification of the new cause will hopefully lead to the development of new therapeutic approaches. This may hold true for other neurodegenerative diseases as well."

Starting from genetic scratch

Prof. Lederkremer and his team chose to examine the effect of protein aggregates in the pathology of Huntington’s disease because its genetic cause is well-known, unlike those of other neurodegenerative diseases, such as Parkinson’s, whose origins remain less clear.

"What we found in this study — a surprise, although we suspected it — was that damage to the cells, the cell ‘stress’ that leads to death of cells, appeared well before the protein aggregates did," said Prof. Lederkremer. "And even more surprising, when the aggregates finally appeared, the stress was reduced, in some cases even stopping. The actual process of forming an aggregate was protective, isolating and segregating the problematic proteins. This explains why in autopsies of people who died of Huntington’s and other diseases like Alzheimer’s or old age, the protein aggregates in the brains were all quite similar, reflecting no specific disease link."

By interfering with the stress response of brain cells, rather than the formation of protein clusters, scientists may be able to slow, or even halt, the progression of neurodegenerative diseases. According to Prof. Lederkremer, this research paves the way for a revolutionary new direction for pharmaceutical research to treat Huntington’s, Alzheimer’s, Parkinson’s, and other neurodegenerative diseases.

Response to stress

"The practical consequences are that several companies are already in advanced stages of development of drugs inhibiting this form of protein aggregate, interfering with the body’s natural process to protect the brain," said Prof. Lederkremer. "But the drugs should be focused on another area altogether, and the protein aggregates, a protective resource for the brain, should be left intact."

Samples of brain cells from mouse models afflicted with Huntington’s disease were examined using “live cell imaging,” the study of live cells through time-lapse microscopy. Prof. Lederkremer and his team were thus able to identify a compound that modified brain cells’ response to stress, promoting their survival.

"Our approach was to interfere with the stress response instead of the formation of the protein aggregates, and the lab succeeded in identifying a compound that altered the response, rescuing affected cells from death," said Prof. Lederkremer. "Our findings are most encouraging for the development of a therapy for this devastating disease, which is presently incurable."

Chimpanzees may throw tantrums like toddlers, but their total brain size suggests they have more self-control than, say, a gerbil or fox squirrel, according to a new study of 36 species of mammals and birds ranging from orangutans to zebra finches.

Scientists at Duke University, UC Berkeley, Stanford, Yale and more than two-dozen other research institutions collaborated on this first large-scale investigation into the evolution of self-control, defined in the study as the ability to inhibit powerful but ultimately counter-productive behavior. They found that the species with the largest brain volume – not volume relative to body size – showed superior cognitive powers in a series of food-foraging experiments.

Moreover, animals with the most varied diets showed the most self-restraint, according to the study published in the journal of the Proceedings of the National Academy of Sciences.

“The study levels the playing field on the question of animal intelligence,” said UC Berkeley psychologist Lucia Jacobs, a co-author of this study and of its precursor, a 2012 paper in the journal, Animal Cognition.

This latest study was led by evolutionary anthropologists Evan MacLean, Brian Hare and Charles Nunn of Duke University. The findings challenge prevailing assumptions that “relative” brain size is a more accurate predictor of intelligence than “absolute” brain size. One possibility, they posited, is that “as brains get larger, the total number of neurons increases and brains tend to become more modularized, perhaps facilitating the evolution of new cognitive networks.”

While participating researchers all performed the same series of experiments, they did so on their own turf and on their own animal subjects. Data was provided on bonobos, chimpanzees, gorillas, olive baboons, stump-tailed macaques, golden snub-nosed monkeys, brown, red-bellied and aye-aye lemurs, coyotes, dogs, gray wolves, Asian elephants, domestic pigeons, orange-winged amazons, Eurasian jays, western scrub jay, zebra finches and swamp sparrows. 

Food inside a tube used as bait

In one experiment, creatures large and small were tested to see if they would advance toward a clear cylinder visibly containing food – showing a lack of self-restraint – after they had been trained to access the food through a side opening in an opaque cylinder. Large-brained primates such as gorillas quickly navigated their way to the treat or “bait.” Smaller-brained animals did so with mixed results.

Jacobs and UC Berkeley doctoral student Mikel Delgado contributed the only rodent data in the study, putting some of the campus’s fox squirrels and some Mongolian gerbils in their lab through food-foraging tasks.

Mixed results on campus squirrels’ self-restraint

In the case of the fox squirrels, the red-hued, bushy-tailed critters watched as the food was placed in a side opening of an opaque cylinder. Once they demonstrated a familiarity with the location of the opening, the food was moved to a transparent cylinder and the real test began.  If the squirrels lunged directly at the food inside the bottle, they had failed to inhibit their response. But if they used the side entrance, the move was deemed a success.

“About half of the squirrels and gerbils did well and inhibited the direct approach in more than seven out of 10 trials,” Delgado said. “The rest didn’t do so well.”

In a second test, three cups (A, B and C) were placed in a row on their sides so the animals could see which one contained food. It was usually cup A. The cups were then turned upside down so the “baited” cup could no longer be seen. If the squirrels touched the cup with the food three times in a row, they graduated to the next round. This time, the food was moved from cup A to cup C at the other end of the row.

“The question was, would they approach cup A, where they had originally learned the food was placed, or could they update this learned response to get the food from a new location?” Delgado said. “The squirrels and gerbils tended to go to the original place they had been trained to get food, showing a failure to inhibit what they originally learned.” Click here for video showing other animals doing the cup test.

“It might be that a squirrel’s success in life is affected the same way as in people,” Jacobs said. “By its ability to slow down and think a bit before it snatches at a reward.”

A recently FDA-approved device has been shown to reduce seizures in patients with medication-resistant epilepsy by as much as 50 percent. When coupled with an innovative electrode placement planning system developed by physicians at Rush, the device facilitated the complete elimination of seizures in nearly half of the implanted Rush patients enrolled in the decade-long clinical trials.

That’s good news for a large portion of the nearly 400,000 people in the U.S. living with epilepsy whose seizures can’t be controlled with medications and who are not candidates for brain surgery.

Epilepsy is a chronic neurological condition characterized by recurrent seizures that disrupt the senses, or can involve short periods of unconsciousness or convulsions. “Many people with epilepsy have scores of unpredictable seizures every day that make it impossible for them to drive, work or even get a good night’s sleep,” said Dr. Marvin Rossi, co-principal investigator of the NeuroPace Pivotal Clinical Trial and assistant professor of neurology at the Rush Epilepsy Center.

The NeuroPace RNS System uses responsive, or ‘on-demand’ direct stimulation to detect abnormal electrical activity in the brain and deliver small amounts of electrical stimulation to suppress seizures before they begin.

The device is surgically placed underneath the scalp within the skull and connected to electrodes that are strategically placed within the brain where the seizures originate (called the seizure focus). A programmed computer chip in the skull communicates with the system to record data and to help regulate responsive stimulation.

The unique electrode placement planning modeling system developed at Rush uses a computer-intensive mapping system that facilitates surgical placement of electrodes at the precise location in the brain’s temporal lobe circuitry. When stimulated, these extensive epileptic circuits are calmed. The modeling system predicts where in the brain the activity begins and spreads, so that the device can better influence the maximal extent of the epileptic pathway.

The device also acts as an implanted EEG for recording brain activity. This function was first shown at Rush to help determine whether the patient will further benefit from a surgical resection, in which surgeons remove a portion of the temporal lobe network. Dr. Richard Byrne, chairman of Neurosurgery at Rush, implants the electrodes in the temporal lobes.

As a result, physicians at Rush can offer patients the new implantable neurostimulator device, a surgical resection or both with the possibility of completely eliminating seizures. “This device is also being used at Rush as a foundation and inspiration for building cutting-edge hybrid stimulation therapy-drug molecule delivery systems,” said Rossi.

“Devices that treat epilepsy may offer new hope to patients when medication is ineffective and resection is not an option,” said Rossi. “Not long ago, it was highly unlikely that these patients would ever be free of their seizures. Now, several of our Rush patients with this device are actually able to drive, lower or even eliminate their medications and aren’t as limited as they once were. There is no doubt that quality of life of the majority of our implanted patients is significantly improved.”

According to the Centers for Disease Control and Prevention, in 2010, epilepsy affected approximately 2.3 million adults in the U.S. and 467,711 children under the age of 17.

Researchers at the University of Toronto say a sleep disorder that causes people to act out their dreams is the best current predictor of brain diseases like Parkinson’s and many other forms of dementia.

"Rapid-eye-movement sleep behaviour disorder (RBD) is not just a precursor but also a critical warning sign of neurodegeneration that can lead to brain disease," says associate professor and lead author Dr. John Peever. In fact, as many as 80 to 90 per cent of people with RBD will develop a brain disease."

As the name suggests, the disturbance occurs during the rapid-eye-movement (REM) stage of sleep and causes people to act out their dreams, often resulting in injury to themselves and/or bed partner. In healthy brains, muscles are temporarily paralyzed during sleep to prevent this from happening.

"It’s important for clinicians to recognize RBD as a potential indication of brain disease in order to diagnose patients at an earlier stage," says Peever. "This is important because drugs that reduce neurodegeneration could be used in RBD patients to prevent (or protect) them from developing more severe degenerative disorders."

His research examines the idea that neurodegeneration might first affect areas of the brain that control sleep before attacking brain areas that cause more common brain diseases like Alzheimer’s.

Peever says he hopes the results of his study lead to earlier and more effective treatment of neurodegenerative diseases.

A research team led by the National Neuroscience Institute (NNI) has uncovered a novel function of the Amyloid Precursor Protein (APP), one of the main pathogenic culprits of Alzheimer’s disease. This discovery may help researchers understand how the protein goes awry in the brains of Alzheimer’s disease patients, and potentially paves the way for the development of innovative therapeutics to improve the brain function of dementia patients.

The findings were published in the prestigious scientific research journal Nature Communications last month. The study, which is led by Dr Zeng Li and her team from NNI, involved investigators from Duke-NUS Graduate Medical School and the Agency for Science and Technology (A*STAR).

Alzheimer’s disease is the most common form of dementia, which is set to rise significantly from the current 28,000 cases to 80,000 cases in 2030 among Singaporeans aged 60 and above. With a rapidly aging population, the burden of the disease will be profound affecting not just the person afflicted, but also the caregiver and family. While the exact cause of Alzheimer’s disease remains unknown, one of its pathological hallmarks is clear – the clumping of APP product in the brain when the protein is abnormally processed.

Finding out more about APP can help researchers gain a better understanding of the disease, and potentially identify biomarkers and therapeutic targets for it. However up till this point, little was known about the APP’s primary function in the brain.

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Researchers may have identified key genes linked to why some people have a higher tolerance for pain than others, according to a study released today that will be presented at the American Academy of Neurology’s 66th Annual Meeting in Philadelphia, April 26 to May 3, 2014.

“Our study is quite significant because it provides an objective way to understand pain and why different individuals have different pain tolerance levels,” said study author Tobore Onojjighofia, MD, MPH, with Proove Biosciences and a member of the American Academy of Neurology. “Identifying whether a person has these four genes could help doctors better understand a patient’s perception of pain.”

Researchers evaluated 2,721 people diagnosed with chronic pain for certain genes. Participants were taking prescription opioid pain medications. The genes involved were COMT, DRD2, DRD1 and OPRK1. The participants also rated their perception of pain on a scale from zero to 10. People who rated their pain as zero were not included in the study. Low pain perception was defined as a score of one, two or three; moderate pain perception was a score of four, five or six; and high pain perception was a score of seven, eight, nine or 10.

Nine percent of the participants had low pain perception, 46 percent had moderate pain perception and 45 percent had high pain perception.

The researchers found that the DRD1 gene variant was 33 percent more prevalent in the low pain group than in the high pain group. Among people with a moderate pain perception, the COMT and OPRK variants were 25 percent and 19 percent more often found than in those with a high pain perception. The DRD2 variant was 25 percent more common among those with a high pain perception compared to people with moderate pain.

“Chronic pain can affect every other part of life,” said Onojjighofia. “Finding genes that may be play a role in pain perception could provide a target for developing new therapies and help physicians better understand their patients’ perceptions of pain.”

Older people who have apathy but not depression may have smaller brain volumes than those without apathy, according to a new study published in the April 16, 2014, online issue of Neurology®, the medical journal of the American Academy of Neurology. Apathy is a lack of interest or emotion.

“Just as signs of memory loss may signal brain changes related to brain disease, apathy may indicate underlying changes,” said Lenore J. Launer, PhD, with the National Institute on Aging at the National Institutes of Health (NIH) in Bethesda, MD, and a member of the American Academy of Neurology. “Apathy symptoms are common in older people without dementia. And the fact that participants in our study had apathy without depression should turn our attention to how apathy alone could indicate brain disease.”

Launer’s team used brain volume as a measure of accelerated brain aging. Brain volume losses occur during normal aging, but in this study, larger amounts of brain volume loss could indicate brain diseases.

For the study, 4,354 people without dementia and with an average age of 76 underwent an MRI scan. They were also asked questions that measure apathy symptoms, which include lack of interest, lack of emotion, dropping activities and interests, preferring to stay at home and having a lack of energy.

The study found that people with two or more apathy symptoms had 1.4 percent smaller gray matter volume and 1.6 percent less white matter volume compared to those who had less than two symptoms of apathy. Excluding people with depression symptoms did not change the results.

Gray matter is where learning takes place and memories are stored in the brain. White matter acts as the communication cables that connect different parts of the brain.

“If these findings are confirmed, identifying people with apathy earlier may be one way to target an at-risk group,” Launer said.

A new study points to a conceptually novel therapeutic strategy for treating depression. Instead of dampening neuron firing found with stress-induced depression, researchers demonstrated for the first time that further activating these neurons opens a new avenue to mimic and promote natural resilience. The findings were so surprising that the research team thinks it may lead to novel targets for naturally acting antidepressants. Results from the study are published online April 18 in the journal Science.

Researchers from the Icahn School of Medicine at Mount Sinai point out that in mice resilient to social defeat stress (a source of constant stress brought about by losing a dispute or from a hostile interaction), their cation channel currents, which pass positive ions in dopamine neurons, are paradoxically elevated to a much greater extent than those of depressed mice and control mice. This led researchers to experimentally increase the current of cation channels with drugs in susceptible mice, those prone to depression, to see whether it would enhance coping and resilience. They found that such boosting of cation channels in dopamine neurons caused the mice to tolerate the increased stress without succumbing to depression-related symptoms, and unexpectedly the hyperactivity of the dopamine neurons was normalized.

Allyson K. Friedman, PhD, Postdoctoral Fellow in Pharmacology and Systems Therapeutics at the Icahn School of Medicine at Mount Sinai, and the study’s lead author said: “To achieve resiliency when under social stress, the brain must perform a complex balancing act in which negative stress-related changes in the brain actively trigger positive changes. But that can only happen once the negative changes reach a tipping point.”

The research team used optogenetics, a combination of laser optics and gene virus transfer, to control firing activity of the dopamine neurons. When light activation or the drug lamotrigine is given to these neurons, it drives the current and neuron firing higher. But at a certain point, it triggers compensatory mechanisms, normalizes neuron firing, and achieves a kind of homeostatic (or balanced) resilience.

"To our surprise, we found that resilient mice, instead of avoiding deleterious changes in the brain, experience further deleterious changes in response to stress, and use them beneficially," said Ming-Hu Han, PhD, at Icahn School of Medicine at Mount Sinai, who leads the study team as senior author.

Drs. Friedman and Han see this counterintuitive finding as stimulating research in a conceptually novel antidepressant strategy. If a drug could enhance coping and resilience by pushing depressed (or susceptible) individuals past the tipping point, it potentially might have fewer side effects, and work as a more naturally acting antidepressant.

Eric Nestler, MD, PhD, at the Icahn School of Medicine at Mount Sinai praised the study. “In this elegant study, Drs. Friedman and Han and their colleagues reveal a highly novel mechanism that controls an individual’s susceptibility or resilience to chronic social stress. The discoveries have important implications for the development of new treatments for depression and other stress-related disorders.”

What’s one of your worst memories? How did it make you feel? According to psychologists, remembering the emotions felt during a negative personal experience, such as how sad you were or how embarrassed you felt, can lead to emotional distress, especially when you can’t stop thinking about it. 

(Image: iStockphoto)

When these negative memories creep up, thinking about the context of the memories, rather than how you felt, is a relatively easy and effective way to alleviate the negative effects of these memories, a new study suggests.

Researchers at the Beckman Institute at the University of Illinois, led by psychology professor Florin Dolcos of the Cognitive Neuroscience Group, studied the behavioral and neural mechanisms of focusing away from emotion during recollection of personal emotional memories, and found that thinking about the contextual elements of the memories significantly reduced their emotional impact.

“Sometimes we dwell on how sad, embarrassed, or hurt we felt during an event, and that makes us feel worse and worse. This is what happens in clinical depression—ruminating on the negative aspects of a memory,” Dolcos said. “But we found that instead of thinking about your emotions during a negative memory, looking away from the worst emotions and thinking about the context, like a friend who was there, what the weather was like, or anything else non-emotional that was part of the memory, will rather effortlessly take your mind away from the unwanted emotions associated with that memory. Once you immerse yourself in other details, your mind will wander to something else entirely, and you won’t be focused on the negative emotions as much.”

This simple strategy, the study suggests, is a promising alternative to other emotion-regulation strategies, like suppression or reappraisal. 

“Suppression is bottling up your emotions, trying to put them away in a box. This is a strategy that can be effective in the short term, but in the long run, it increases anxiety and depression,” explains Sanda Dolcos, co-author on the study and postdoctoral research associate at the Beckman Institute and in the Department of Psychology. 

“Another otherwise effective emotion regulation strategy, reappraisal, or looking at the situation differently to see the glass half full, can be cognitively demanding. The strategy of focusing on non-emotional contextual details of a memory, on the other hand, is as simple as shifting the focus in the mental movie of your memories and then letting your mind wander.”

Not only does this strategy allow for effective short-term emotion regulation, but it has the possibility of lessening the severity of a negative memory with prolonged use.

In the study, participants were asked to share their most emotional negative and positive memories, such as the birth of a child, winning an award, or failing an exam, explained Sanda Dolcos. Several weeks later participants were given cues that would trigger their memories while their brains were being scanned using magnetic resonance imaging (MRI). Before each memory cue, the participants were asked to remember each event by focusing on either the emotion surrounding the event or the context. For example, if the cue triggered a memory of a close friend’s funeral, thinking about the emotional context could consist of remembering your grief during the event. If you were asked to remember contextual elements, you might instead remember what outfit you wore or what you ate that day.

“Neurologically, we wanted to know what happened in the brain when people were using this simple emotion-regulation strategy to deal with negative memories or enhance the impact of positive memories,” explained Ekaterina Denkova, first author of the report. “One thing we found is that when participants were focused on the context of the event, brain regions involved in basic emotion processing were working together with emotion control regions in order to, in the end, reduce the emotional impact of these memories.” 

Using this strategy promotes healthy functioning not only by reducing the negative impact of remembering unwanted memories, but also by increasing the positive impact of cherished memories, Florin Dolcos said. 

In the future, the researchers hope to determine if this strategy is effective in lessening the severity of negative memories over the long term. They also hope to work with clinically depressed or anxious participants to see if this strategy is effective in alleviating these psychiatric conditions. 

These results were published in Social Cognitive and Affective Neuroscience.

The cause of neuronal death in Parkinson’s disease is still unknown, but a new study proposes that neurons may be mistaken for foreign invaders and killed by the person’s own immune system, similar to the way autoimmune diseases like type I diabetes, celiac disease, and multiple sclerosis attack the body’s cells. The study was published April 16, 2014, in Nature Communications.

(Image caption: Four images of a neuron from a human brain show that neurons produce a protein (in red) that can direct an immune attack against the neuron (green). Credit: Carolina Cebrian.)

“This is a new, and likely controversial, idea in Parkinson’s disease; but if true, it could lead to new ways to prevent neuronal death in Parkinson’s that resemble treatments for autoimmune diseases,” said the study’s senior author, David Sulzer, PhD, professor of neurobiology in the departments of psychiatry, neurology, and pharmacology at Columbia University College of Physicians & Surgeons.

The new hypothesis about Parkinson’s emerges from other findings in the study that overturn a deep-seated assumption about neurons and the immune system.

For decades, neurobiologists have thought that neurons are protected from attacks from the immune system, in part, because they do not display antigens on their cell surfaces. Most cells, if infected by virus or bacteria, will display bits of the microbe (antigens) on their outer surface. When the immune system recognizes the foreign antigens, T cells attack and kill the cells. Because scientists thought that neurons did not display antigens, they also thought that the neurons were exempt from T-cell attacks.

“That idea made sense because, except in rare circumstances, our brains cannot make new neurons to replenish ones killed by the immune system,” Dr. Sulzer says. “But, unexpectedly, we found that some types of neurons can display antigens.”

Cells display antigens with special proteins called MHCs. Using postmortem brain tissue donated to the Columbia Brain Bank by healthy donors, Dr. Sulzer and his postdoc Carolina Cebrián, PhD, first noticed—to their surprise—that MHC-1 proteins were present in two types of neurons. These two types of neurons—one of which is dopamine neurons in a brain region called the substantia nigra—degenerate during Parkinson’s disease.

To see if living neurons use MHC-1 to display antigens (and not for some other purpose), Drs. Sulzer and Cebrián conducted in vitro experiments with mouse neurons and human neurons created from embryonic stem cells. The studies showed that under certain circumstances—including conditions known to occur in Parkinson’s—the neurons use MHC-1 to display antigens. Among the different types of neurons tested, the two types affected in Parkinson’s were far more responsive than other neurons to signals that triggered antigen display.

The researchers then confirmed that T cells recognized and attacked neurons displaying specific antigens.

The results raise the possibility that Parkinson’s is partly an autoimmune disease, Dr. Sulzer says, but more research is needed to confirm the idea.

“Right now, we’ve showed that certain neurons display antigens and that T cells can recognize these antigens and kill neurons,” Dr. Sulzer says, “but we still need to determine whether this is actually happening in people. We need to show that there are certain T cells in Parkinson’s patients that can attack their neurons.”

If the immune system does kill neurons in Parkinson’s disease, Dr. Sulzer cautions that it is not the only thing going awry in the disease. “This idea may explain the final step,” he says. “We don’t know if preventing the death of neurons at this point will leave people with sick cells and no change in their symptoms, or not.”