Neuroscience

TAU researchers find unresponsive patients’ brains may recognize photographs of their family and friends

Patients in a vegetative state are awake, breathe on their own, and seem to go in and out of sleep. But they do not respond to what is happening around them and exhibit no signs of conscious awareness. With communication impossible, friends and family are left wondering if the patients even know they are there.

Now, using functional magnetic resonance imaging (fMRI), Dr. Haggai Sharon and Dr. Yotam Pasternak of Tel Aviv University’s Functional Brain Center and Sackler Faculty of Medicine and the Tel Aviv Sourasky Medical Center have shown that the brains of patients in a vegetative state emotionally react to photographs of people they know personally as though they recognize them.

"We showed that patients in a vegetative state can react differently to different stimuli in the environment depending on their emotional value," said Dr. Sharon. "It’s not a generic thing; it’s personal and autobiographical. We engaged the person, the individual, inside the patient."

The findings, published in PLOS ONE, deepen our understanding of the vegetative state and may offer hope for better care and the development of novel treatments. Researchers from TAU’s School of Psychological Sciences, Department of Neurology, and Sagol School of Neuroscience and the Loewenstein Hospital in Ranaana contributed to the research.

Talking to the brain

For many years, patients in a vegetative state were believed to have no awareness of self or environment. But in recent years, doctors have made use of fMRI to examine brain activity in such patients. They have found that some patients in a vegetative state can perform complex cognitive tasks on command, like imagining a physical activity such as playing tennis, or, in one case, even answering yes-or-no questions. But these cases are rare and don’t provide any indication as to whether patients are having personal emotional experiences in such a state.

To gain insight into “what it feels like to be in a vegetative state,” the researchers worked with four patients in a persistent (defined as “month-long”) or permanent (persisting for more than three months) vegetative state. They showed them photographs of people they did and did not personally know, then gauged the patients’ reactions using fMRI, which measures blood flow in the brain to detect areas of neurological activity in real time. In response to all the photographs, a region specific to facial recognition was activated in the patients’ brains, indicating that their brains had correctly identified that they were looking at faces.

But in response to the photographs of close family members and friends, brain regions involved in emotional significance and autobiographical information were also activated in the patients’ brains. In other words, the patients reacted with activations of brain centers involved in processing emotion, as though they knew the people in the photographs. The results suggest patients in a vegetative state can register and categorize complex visual information and connect it to memories – a groundbreaking finding.

The ghost in the machine

However, the researchers could not be sure if the patients were conscious of their emotions or just reacting spontaneously. So they then verbally asked the patients to imagine their parents’ faces. Surprisingly, one patient, a 60-year-old kindergarten teacher who was hit by a car while crossing the street, exhibited complex brain activity in the face- and emotion-specific brain regions, identical to brain activity seen in healthy people. The researchers say her response is the strongest evidence yet that vegetative-state patients can be “emotionally aware.” A second patient, a 23-year-old woman, exhibited activity just in the emotion-specific brain regions. (Significantly, both patients woke up within two months of the tests. They did not remember being in a vegetative state.)

"This experiment, a first of its kind, demonstrates that some vegetative patients may not only possess emotional awareness of the environment but also experience emotional awareness driven by internal processes, such as images," said Dr. Sharon.

Research focused on the “emotional awareness” of patients in a vegetative state is only a few years old. The researchers hope their work will eventually contribute to improved care and treatment. They have also begun working with patients in a minimally conscious state to better understand how regions of the brain interact in response to familiar cues. Emotions, they say, could help unlock the secrets of consciousness.

A faultily formed memory sounds like hitting random notes on a keyboard while a proper one sounds more like a song, scientists say.

When they turned off a major switch for learning and memory, brain cells communicated, but the relationship was superficial, said Dr. Joe Tsien, neuroscientist at the Medical College of Georgia at Georgia Regents University and Co-Director of the GRU Brain & Behavior Discovery Institute.

“We have begun to crack the neural code, which allows us to look in real time at how thoughts happen and how memories are made,” Tsien said. “That has enabled us to understand  for the first time how and whether the right keys are struck at the right time and in the right place and manner to make the beautiful sound of coherent memories and to compare what happens when a key element is missing.”

With the NMDA receptor intact, chatter reverberates, associations are made and helpful memories – like how touching a hot stove results in a burn – are easily retrieved.

“You see a face and think of a name, you see your office, and you think you need to work; everything is associative,” said Tsien, corresponding author of the study in the journal PLOS ONE. “But in mice lacking an NMDA receptor, you can tell the memory patterns are dull and dissociated.”

Using the century-old Pavlovian conditioning model that first showed how repetition creates association, they found that mice lacking a functioning NMDA receptor in the hippocampus, the brain’s center of learning and memory, could not recollect even something fearful.

When they played a tone, followed 20 seconds later by a mild foot shock, normal mice quickly made the association, down to the timing. The connection essentially never registered with mice lacking the NMDA receptor. Healthy brain recalling memories and Amnesic brain recalling contextual memories 

“They form the initial patterns, but don’t rehearse them,” said Tsien. “Their tones are flat, the association is poor, while everything we register in the healthy brain is associative.” To illustrate just how flat, Postdoctoral Fellow Hui Kuang assigned musical notes to the memory activity of each, which resulted in random noise by the NMDA knockout mice compared to a dynamic rhythm from normal mice.

“By knowing what these patterns look like and what they mean, you can use this signature to measure, for example, during aging, why we begin to lose memory and to identify and test drugs that are truly effective at aiding memory,” Tsien said.

“You can tell whether there is an issue with reverberation, whether your brain is repeating what you need to remember, or repeats it but somehow stores it badly, so it’s not associated with the right things. This study has revealed a lot of fascinating details about what neuroscientists call the brain’s neural code” Tsien said.”

He wants to look at how aging affects these processes as a next step. The research team also is looking at Doogie, a mouse genetically bred by Tsien and his team in 1999 to be exceptionally smart, to see if they can also learn more about how super memories are made and what they look like.

This ability to decode how and what the brain is remembering, should one day help physicians better assess and treat conditions such as Alzheimer’s and schizophrenia, Tsien said. They may find that some answers are already out there, such as drugs that boost reverberation, or a stimulant like caffeine to help retrieve a memory, Tsien said.

His team first reported decoding brain cell conversations as memories were formed and recalled in PLOS ONE in 2009. As with the new study, they used a computational algorithm to translate the neuronal conversations into some of the first pictures of what memories look like.

The act of laughing at a joke is the result of a two-stage process in the brain, first detecting an incongruity before then resolving it with an expression of mirth. The brain actions involved in understanding humour differ between young boys and girls. These are the conclusions reached by a US-based scientist supported by the Swiss National Science Foundation. 

Since science has demonstrated that animals are also capable of planning into the future, the once deep cleft between the brain capacities of humans and animals is rapidly disappearing. Fortunately, we can still claim humour as our unique selling point. This makes it even more astonishing that researchers have considered this attribute but fleetingly (and have spent much more time on negative emotions such as fear), write the Swiss neuroscientist Pascal Vrticka and his US colleagues at Stanford University, in the journal “Nature Reviews Neuroscience”.

Strangely cheerful feelings

In their recently published article (*), the researchers demonstrate that, while laughter at a joke requires activity in many different areas of the brain, just two separate elements can be identified among the complex patterns of activity. In the first part, the brain detects a logical incongruity, which, in the second part, it proceeds to resolve. The ensuing feeling of cheerfulness arises from a brain activity that can be clearly differentiated from that of other positive emotions.

Moreover, in the study of 22 children aged between six and thirteen, the research team led by Vrticka showed that sex-specific differences in the processing of humour are formed early on in life. The researchers recorded the children’s brain activity while they were enjoying film clips that were either funny – slapstick home video – or entertaining – such as clips of children break-dancing. On average, the girls’ brains responded more to the funny scenes, while the boys showed greater reaction to the entertaining clips.

Benefits of improved understanding

Vrticka speculates that these sex-based differences could play a role in helping women to select a suitable (and humorous) mate. Aside from this, humour also plays a key role in psychological health. This is demonstrated, among other things, in the fact that adults with psychological disorders such as autism or depression often have a modified humour processing activity and respond less markedly to humour than people who do not have these disorders. Vrticka believes that an improved understanding of the processes that take place in our brain when we enjoy the effects of an amusing joke could be of great benefit in the development of treatments.

A study in mice shows a breakdown of the brain’s blood vessels may amplify or cause problems associated with Alzheimer’s disease. The results published in Nature Communications suggest that blood vessel cells called pericytes may provide novel targets for treatments and diagnoses.

“This study helps show how the brain’s vascular system may contribute to the development of Alzheimer’s disease,” said study leader Berislav V. Zlokovic, M.D. Ph.D., director of the Zilkha Neurogenetic Institute at the Keck School of Medicine of the University of Southern California, Los Angeles. The study was co-funded by the National Institute of Neurological Diseases and Stroke (NINDS) and the National Institute on Aging (NIA), parts of the National Institutes of Health

Alzheimer’s disease is the leading cause of dementia.  It is an age-related disease that gradually erodes a person’s memory, thinking, and ability to perform everyday tasks.  Brains from Alzheimer’s patients typically have abnormally high levels of plaques made up of accumulations of beta-amyloid protein next to brain cells, tau protein that clumps together to form neurofibrillary tangles inside neurons, and extensive neuron loss. 

Vascular dementias, the second leading cause of dementia, are a diverse group of brain disorders caused by a range of blood vessel problems.  Brains from Alzheimer’s patients often show evidence of vascular disease, including ischemic stroke, small hemorrhages, and diffuse white matter disease, plus a buildup of beta-amyloid protein in vessel walls.  Furthermore, previous studies suggest that APOE4, a genetic risk factor for Alzheimer’s disease, is linked to brain blood vessel health and integrity.

“This study may provide a better understanding of the overlap between Alzheimer’s disease and vascular dementia,” said Roderick Corriveau, Ph.D., a program director at NINDS.

One hypothesis about Alzheimer’s disease states that increases in beta-amyloid lead to nerve cell damage.  This is supported by genetic studies that link familial forms of the disease to mutations in amyloid precursor protein (APP), the larger protein from which plaque-forming beta-amyloid molecules are derived.  Nonetheless, previous studies on mice showed that increased beta-amyloid levels reproduce some of the problems associated with Alzheimer’s.  The animals have memory problems, beta-amyloid plaques in the brain and vascular damage but none of the neurofibrillary tangles and neuron loss that are hallmarks of the disease.

In this study, the researchers show that pericytes may be a key to whether increased beta-amyloid leads to tangles and neuron loss.

Pericytes are cells that surround the outside of blood vessels.  Many are found in a brain plumbing system, called the blood-brain barrier.  It is a network that exquisitely controls the movement of cells and molecules between the blood and the interstitial fluid that surrounds the brain’s nerve cells.  Pericytes work with other blood-brain barrier cells to transport nutrients and waste molecules between the blood and the interstitial brain fluid.

To study how pericytes influence Alzheimer’s disease, Dr. Zlokovic and his colleagues crossbred mice genetically engineered to have a form of APP linked to familial Alzheimer’s with ones that have reduced levels of platelet-derived growth factor beta receptor (PDGFR-beta), a protein known to control pericyte growth and survival.  Previous studies showed that PDGFR-beta mutant mice have fewer pericytes than normal, decreased brain blood flow, and damage to the blood-brain barrier.

“Pericytes act like the gatekeepers of the blood-brain barrier,” said Dr. Zlokovic.

Both the APP and PDGFR-beta mutant mice had problems with learning and memory.  Crossbreeding the mice slightly enhanced these problems.  The mice also had increased beta-amyloid plaque deposition near brain cells and along brain blood vessels.  Surprisingly, the brains of the crossbred mice had enhanced neuronal cell death and extensive neurofibrillary tangles in the hippocampus and cerebral cortex, regions that are typically affected during Alzheimer’s.

“Our results suggest that damage to the vascular system may be a critical step in the development of full-blown Alzheimer’s disease pathology,” said Dr. Zlokovic.

Further experiments suggested that pericytes may transport beta-amyloid across the blood-brain barrier into the blood and showed that crossbreeding the mice slowed the rate at which beta-amyloid was cleared away from nerve cells in the brain.

Next, the researchers addressed how beta-amyloid may affect the vascular system.  The crossbred mutants had more pericyte death and more damage to the blood-brain barrier than the PDGFR-beta mutant mice, suggesting beta-amyloid may enhance vascular damage.  The investigators also confirmed previous findings showing that beta-amyloid accumulation leads to pericyte death.

Dr. Zlokovic and his colleagues concluded that their results support a two-hit vascular hypothesis of Alzheimer’s.  The hypothesis states that the toxic effects of increased beta-amyloid deposition on pericytes in aged blood vessels leads to a breakdown of the blood-brain barrier and a reduced ability to clear amyloid from the brain.  In turn, the progressive accumulation of beta-amyloid in the brain and death of pericytes may become a damaging feedback loop that causes dementia.  If true, then pericytes and other blood-brain barrier cells may be new therapeutic targets for treating Alzheimer’s disease.

If you have ever said or done the wrong thing at the wrong time, you should read this. Neuroscientists at The University of Texas Health Science Center at Houston (UTHealth) and the University of California, San Diego, have successfully demonstrated a technique to enhance a form of self-control through a novel form of brain stimulation.

Study participants were asked to perform a simple behavioral task that required the braking/slowing of action – inhibition – in the brain. In each participant, the researchers first identified the specific location for this brake in the prefrontal region of the brain. Next, they increased activity in this brain region using stimulation with brief and imperceptible electrical charges. This led to increased braking – a form of enhanced self-control.

This proof-of-principle study appears in the Dec. 11 issue of The Journal of Neuroscience and its methods may one day be useful for treating attention deficit hyperactivity disorder (ADHD), Tourette’s syndrome and other severe disorders of self-control.

“There is a circuit in the brain for inhibiting or braking responses,” said Nitin Tandon, M.D., the study’s senior author and associate professor in The Vivian L. Smith Department of Neurosurgery at the UTHealth Medical School. “We believe we are the first to show that we can enhance this braking system with brain stimulation.”

A computer stimulated the prefrontal cortex exactly when braking was needed. This was done using electrodes implanted directly on the brain surface.

When the test was repeated with stimulation of a brain region outside the prefrontal cortex, there was no effect on behavior, showing the effect to be specific to the prefrontal braking system.

This was a double-blind study, meaning that participants and scientists did not know when or where the charges were being administered.

The method of electrical stimulation was novel in that it apparently enhanced prefrontal function, whereas other human brain stimulation studies mostly disrupt normal brain activity. This is the first published human study to enhance prefrontal lobe function using direct electrical stimulation, the researchers report.

The study involved four volunteers with epilepsy who agreed to participate while being monitored for seizures at the Mischer Neuroscience Institute at Memorial Hermann-Texas Medical Center (TMC). Stimulation enhanced braking in all four participants.

Tandon has been working on self-control research with researchers at the University of California, San Diego, for five years. “Our daily life is full of occasions when one must inhibit responses. For example, one must stop speaking when it’s inappropriate to the social context and stop oneself from reaching for extra candy,” said Tandon, who is a neurosurgeon with the Mischer Neuroscience Institute at Memorial Hermann-TMC. 

The researchers are quick to point out that while their results are promising, they do not yet point to the ability to improve self-control in general. In particular, this study does not show that direct electrical stimulation is a realistic option for treating human self-control disorders such as obsessive-compulsive disorder, Tourette’s syndrome and borderline personality disorder. Notably, direct electrical stimulation requires an invasive surgical procedure, which is now used only for the localization and treatment of severe epilepsy.

A research team from The University of Nottingham has helped uncover a second rare genetic mutation which strongly increases the risk of Alzheimer’s disease in later life.

In an international collaboration, the University’s Translational Cell Sciences Human Genetics research group has pinpointed a rare coding variation in the Phospholipase D3 (PLD3) gene which is more common in people with late-onset Alzheimer’s than non-sufferers.

The discovery is an important milestone on the road to early diagnosis of the disease and eventual improved treatment. Having surveyed the human genome for common variants associated with Alzheimer’s, geneticists are now turning the spotlight on rare mutations which may be even stronger risk factors.

More than 820,000 people in the UK have dementia and the number is rising as the population ages. The condition, of which Alzheimer’s disease is the predominant cause, costs the UK economy £23 billion per year, much more than other diseases like cancer and heart disease.

Nottingham’s genetic experts have been working with long-term partners from Washington University, St Louis, USA and University College, London, to carry out next-generation whole exome sequencing on families where Alzheimer’s affects several members.

Earlier this year the collaboration uncovered the first ever rare genetic mutation implicated in disease risk, linking the TREM2 gene to a higher risk of Alzheimer’s (published in the New England Journal of Medicine). Now, in a new study published today in the international journal, Nature, the team reveal that after analysis of the genes of around 2,000 people with Alzheimer’s, a second genetic variation has been found, in the PLD3 gene.

PLD3 influences processing of amyloid precursor protein which results in the generation of the characteristic amyloid plaques seen in AD brain tissue, suggesting that it may be a potential therapeutic target.

The international research team used Nottingham’s Alzheimer’s Research UK DNA bank, one of the largest collections of DNA from Alzheimer’s patients, to completely sequence the entire coding region (exome) of the PLD3 gene. The results showed several mutations in the gene occurred more frequently in people who had the disease than in non-sufferers. Carriers of PLD3 coding variants showed a two-fold increased risk for the disease.

Leading the team at Nottingham, Professor of Human Genomics and Molecular Genetics, Kevin Morgan, said:

“This second crucial discovery has confirmed that this latest scientific approach does deliver, it is able to find these clues. However, it is also inferring that there are lots more AD-significant variations out there and before we can use it for diagnosis we need to find all of the other genetic variations involved in Alzheimer’s too.

“Our research is forming the basis of potential diagnostics later on and more importantly it shows pathways that can be diagnostic targets which could lead to therapeutic interventions in the future.

“The next step will be to examine how this particular rare gene variant functions in the cell and see if it can be targeted, to see if there are any benefits to finding out how this gene operates in both normal and diseased cells. If we can do this, we may be able eventually to correct the defect with drug therapy. Here in Nottingham we will keep looking for more rare gene variations.

“Even if we could eventually slow or halt the progress of the disease with new drugs rather than curing it completely, the benefits would be huge in terms of the real impact on patients’ lives and also in vast savings to the health economy. The group The University of Nottingham has played a significant role in all of the recent AD genetics discoveries that have highlighted 20 new regions of interest in the genome in the last five years and we will continue to do so into the future.”

Rebecca Wood, Chief Executive of Alzheimer’s Research UK, the UK’s leading dementia research charity, said: “Advances in genetic technology are allowing researchers to understand more than ever about the genetic risk factors for the most common form of Alzheimer’s. This announcement, made just off the back of the G8 dementia research summit, is a timely reminder of the progress that can be made by worldwide collaboration. We know that late-onset Alzheimer’s is caused by a complex mix of risk factors, including both genetic and lifestyle. Understanding all of these risk factors and how they work together to affect someone’s likelihood of developing Alzheimer’s is incredibly important for developing interventions to slow the onset of the disease. Alzheimer’s Research UK is proud to have contributed to this discovery, both by funding researchers and through the establishment of a DNA collection that has been used in many of the recent genetic discoveries in Alzheimer’s.”

Most people – including scientists – assumed we can’t just sniff out danger.

It was thought that we become afraid of an odor – such as leaking gas – only after information about a scary scent is processed by our brain.

But neuroscientists at Rutgers University studying the olfactory – sense of smell – system in mice have discovered that this fear reaction can occur at the sensory level, even before the brain has the opportunity to interpret that the odor could mean trouble.

In a new study published today in Science, John McGann, associate professor of behavioral and systems neuroscience in the Department of Psychology, and his colleagues, report that neurons in the noses of laboratory animals reacted more strongly to threatening odors before the odor message was sent to the brain.

“What is surprising is that we tend to think of learning as something that only happens deep in the brain after conscious awareness,” says McGann whose laboratory studies the sense of smell. “But now we see how the nervous system can become especially sensitive to threatening stimuli and that fear-learning can affect the signals passing from sensory organs to the brain.”

McGann and students Marley Kass and Michelle Rosenthal made this discovery by using light to observe activity in the brains of genetically engineered mice through a window in the mouse’s skull. They found that those mice that received an electric shock simultaneously with a specific odor showed an enhanced response to the smell in the cells in the nose, before the message was delivered to the neurons in the brain.

This new research – which indicates that fearful memories can influence the senses – could help to better understand conditions like Post Traumatic Stress Disorder, in which feelings of anxiety and fear exist even though an individual is no longer in danger.

“We know that anxiety disorders like PTSD can sometimes be triggered by smell, like the smell of diesel exhaust for a soldier,” says McGann who received funding from the National Institute of Mental Health and the National Institute on Deafness and Other Communication Disorders for this research. “What this study does is gives us a new way of thinking about how this might happen.”

In their study, the scientists also discovered a heightened sensitivity to odors in the mice traumatized by shock. When these mice smelled the odor associated with the electrical shocks, the amount of neurotransmitter – chemicals that carry communications between nerve cells – released from the olfactory nerve into the brain was as big as if the odor were four times stronger than it actually was.

This created mice whose brains were hypersensitive to the fear-associated odors. Before now, scientists did not think that reward or punishment could influence how the sensory organs process information.

The next step in the continuing research, McGann says, is to determine whether the hypersensitivity to threatening odors can be reversed by using exposure therapy to teach the mice that the electrical shock is no longer associated with a specific odor. This could help develop a better understanding of fear learning that might someday lead to new therapeutic treatments for anxiety disorders in humans, he says.

To evaluate school quality, states require students to take standardized tests; in many cases, passing those tests is necessary to receive a high-school diploma. These high-stakes tests have also been shown to predict students’ future educational attainment and adult employment and income.

Such tests are designed to measure the knowledge and skills that students have acquired in school — what psychologists call “crystallized intelligence.” However, schools whose students have the highest gains on test scores do not produce similar gains in “fluid intelligence” — the ability to analyze abstract problems and think logically — according to a new study from MIT neuroscientists working with education researchers at Harvard University and Brown University.

In a study of nearly 1,400 eighth-graders in the Boston public school system, the researchers found that some schools have successfully raised their students’ scores on the Massachusetts Comprehensive Assessment System (MCAS). However, those schools had almost no effect on students’ performance on tests of fluid intelligence skills, such as working memory capacity, speed of information processing, and ability to solve abstract problems.

“Our original question was this: If you have a school that’s effectively helping kids from lower socioeconomic environments by moving up their scores and improving their chances to go to college, then are those changes accompanied by gains in additional cognitive skills?” says John Gabrieli, the Grover M. Hermann Professor of Health Sciences and Technology, professor of brain and cognitive sciences, and senior author of a forthcoming Psychological Science paper describing the findings.

Instead, the researchers found that educational practices designed to raise knowledge and boost test scores do not improve fluid intelligence. “It doesn’t seem like you get these skills for free in the way that you might hope, just by doing a lot of studying and being a good student,” says Gabrieli, who is also a member of MIT’s McGovern Institute for Brain Research.

Measuring cognition

This study grew out of a larger effort to find measures beyond standardized tests that can predict long-term success for students. “As we started that study, it struck us that there’s been surprisingly little evaluation of different kinds of cognitive abilities and how they relate to educational outcomes,” Gabrieli says.

The data for the Psychological Science study came from students attending traditional, charter, and exam schools in Boston. Some of those schools have had great success improving their students’ MCAS scores — a boost that studies have found also translates to better performance on the SAT and Advanced Placement tests.

The researchers calculated how much of the variation in MCAS scores was due to the school that students attended. For MCAS scores in English, schools accounted for 24 percent of the variation, and they accounted for 34 percent of the math MCAS variation. However, the schools accounted for very little of the variation in fluid cognitive skills — less than 3 percent for all three skills combined.

In one example of a test of fluid reasoning, students were asked to choose which of six pictures completed the missing pieces of a puzzle — a task requiring integration of information such as shape, pattern, and orientation.

“It’s not always clear what dimensions you have to pay attention to get the problem correct. That’s why we call it fluid, because it’s the application of reasoning skills in novel contexts,” says Amy Finn, an MIT postdoc and lead author of the paper.

Even stronger evidence came from a comparison of about 200 students who had entered a lottery for admittance to a handful of Boston’s oversubscribed charter schools, many of which achieve strong improvement in MCAS scores. The researchers found that students who were randomly selected to attend high-performing charter schools did significantly better on the math MCAS than those who were not chosen, but there was no corresponding increase in fluid intelligence scores.

However, the researchers say their study is not about comparing charter schools and district schools. Rather, the study showed that while schools of both types varied in their impact on test scores, they did not vary in their impact on fluid cognitive skills. 

The researchers plan to continue tracking these students, who are now in 10th grade, to see how their academic performance and other life outcomes evolve. They have also begun to participate in a new study of high school seniors to track how their standardized test scores and cognitive abilities influence their rates of college attendance and graduation.

Implications for education

Gabrieli notes that the study should not be interpreted as critical of schools that are improving their students’ MCAS scores. “It’s valuable to push up the crystallized abilities, because if you can do more math, if you can read a paragraph and answer comprehension questions, all those things are positive,” he says.

He hopes that the findings will encourage educational policymakers to consider adding practices that enhance cognitive skills. Although many studies have shown that students’ fluid cognitive skills predict their academic performance, such skills are seldom explicitly taught.

“Schools can improve crystallized abilities, and now it might be a priority to see if there are some methods for enhancing the fluid ones as well,” Gabrieli says.

Some studies have found that educational programs that focus on improving memory, attention, executive function, and inductive reasoning can boost fluid intelligence, but there is still much disagreement over what programs are consistently effective.

Scientists who fed a cocktail of key amino acids to mice improved sleep disturbances caused by brain injuries in the animals. These new findings suggest a potential dietary treatment for millions of people affected by traumatic brain injury (TBI)—a condition that is currently untreatable.

“If this type of dietary treatment is proved to help patients recover function after traumatic brain injury, it could become an important public health benefit,” said study co-leader Akiva S. Cohen, Ph.D., a neuroscientist at The Children’s Hospital of Philadelphia (CHOP).

Cohen is the co-senior author of the animal TBI study appearing today in Science Translational Medicine. He collaborated with two experts in sleep medicine: co-senior author Allan I. Pack, M.D., Ph.D., director of the Center for Sleep and Circadian Neurobiology in the Perelman School of Medicine at the University of Pennsylvania; and first author Miranda M. Lim, M.D., Ph.D., formerly at the Penn Sleep Center, and now on faculty at the Portland VA Medical Center and Oregon Health and Science University.

Every year in the U.S., an estimated 2 million people suffer a TBI, accounting for a major cause of disability across all age groups. Although 75 percent of reported TBI cases are milder forms such as concussion, even concussion may cause chronic neurological impairments, including cognitive, motor and sleep problems.

“Sleep disturbances, such as excessive daytime sleepiness and nighttime insomnia, disrupt quality of life and can delay cognitive recovery in patients with TBI,” said Lim, a neurologist and sleep medicine specialist. Although physicians can relieve the dangerous swelling that occurs after a severe TBI, there are no existing treatments to address the underlying brain damage associated with neurobehavioral problems such as impaired memory, learning and sleep patterns.

Cohen and team investigate the use of selected branched chain amino acids (BCAA)—precursors of the neurotransmitters glutamate and GABA, which are involved in communication among neurons and help to maintain a normal balance in brain activity. His research team previously showed that a BCAA diet restored cognitive ability in brain-injured mice. The current study was the first to analyze sleep-wake patterns in an animal model.

Comparing mice with experimentally induced mild TBI to uninjured mice, the scientists found the injured mice were unable to stay awake for long periods of time. The injured mice had lower activity among orexin neurons, which help to maintain the animals’ wakefulness. This is similar to results in human studies showing decreased orexin levels in the spinal fluid after TBI.

In the current study, the dietary therapy restored the orexin neurons to a normal activity level and improved wakefulness in the brain-injured mice. EEG recordings also showed improved brain wave patterns among the mice that consumed the BCAA diet.

“These results in an animal model provide a proof-of-principle for investigating this dietary intervention as a treatment for TBI patients,” said Cohen. “If a dietary supplement can improve sleeping and waking patterns as well as cognitive problems, it could help brain-injured patients regain crucial functions.” Cohen cautioned that current evidence does not support TBI patients medicating themselves with commercially available amino acids.

Huntington’s disease is a devastating, incurable disorder that results from the death of certain neurons in the brain. Its symptoms show as progressive changes in behavior and movements.

The neurodegenerative disease is caused by a defect in the huntingtin gene (Htt) that causes an abnormal expansion in a part of DNA, called a CAG codon or triplet that codes for the amino acid glutamine. A healthy version of the Htt gene has between 20 and 23 CAG triplets. The mutational expansion in Htt can lead to long repeats of the CAG triplet, resulting in the mutant protein having a long sequence of several glutamine residues called a polyglutamine tract. This CAG triplet expansion in unrelated genes is the root of at least nine neurodegenerative disorders, including Huntington’s disease.

Rohit Pappu, PhD, professor of biomedical engineering at Washington University in St. Louis, and his colleagues in the School of Engineering & Applied Science and in the School of Medicine, are working to understand how expanded polyglutamine tracts form the types of supramolecular structures that are presumed to be toxic to neurons – a feature that polyglutamine expansions share with proteins associated with Alzheimer’s disease and Parkinson’s disease.

In recent work, Pappu and his research team showed that the amino acid sequences on either side of the polyglutamine tract within Htt can act as natural gatekeepers because they control the fundamental ability of polyglutamine tracts to form structures that are implicated in cellular toxicity. The results were published in PNAS Early Edition Nov.25.

“These are progressive onset disorders,” Pappu says. “The longer the polyglutamine tract gets, the more severe the disease, and the symptoms worsen with age. Our results are exciting because it means that any success we have in mimicking the effects of naturally occurring gatekeepers would be a significant step forward. And mechanistic studies are important in this regard because they enable us to learn from nature’s own strategies.

“Previous studies from other labs showed that the toxic effects of polyglutamine expansions are tempered by the sequence contexts of polyglutamine tracts in Htt, not just the lengths of the polyglutamine tracts”, Pappu says.

He and his research team focused on understanding the effects of sequence stretches that lie on either side of the polyglutamine tract in Htt.  The results show that the N-terminal stretch accelerates the formation of ordered structures that are presumed to be benign to cells, whereas the C-terminal stretch slows the overall transition into structures that are expected to create trouble for cells, suggesting that these naturally occurring sequences behave as gatekeepers. 

“It appears that where polyglutamine stretches are of functional importance, nature has ensured that they are flanked by gatekeeping sequences,” Pappu says.

Pappu and his team are now working to find way s to mimic the effects of the N- and C-terminal flanking sequences from Htt. His team is working closely with Marc Diamond, MD, the David Clayson Professor of Neurology at the School of Medicine, to understand how naturally occurring proteins interact with flanking sequences and see if they can coopt them to ameliorate the toxic functions in the polyglutamine expansions.

Scientists from Case Western Reserve University and University of Kansas Medical Center have restored behavior—in this case, the ability to reach through a narrow opening and grasp food—using a neural prosthesis in a rat model of brain injury.

Ultimately, the team hopes to develop a device that rapidly and substantially improves function after brain injury in humans. There is no such commercial treatment for the 1.5 million Americans, including soldiers in Afghanistan and Iraq, who suffer traumatic brain injuries (TBI), or the nearly 800,000 stroke victims who suffer weakness or paralysis in the United States, annually.

The prosthesis, called a brain-machine-brain interface, is a closed-loop microelectronic system. It records signals from one part of the brain, processes them in real time, and then bridges the injury by stimulating a second part of the brain that had lost connectivity.
Their work is published online this week in the science journal Proceedings of the National Academy of Sciences.

“If you use the device to couple activity from one part of the brain to another, is it possible to induce recovery from TBI? That’s the core of this investigation,” said Pedram Mohseni, professor of electrical engineering and computer science at Case Western Reserve, who built the brain prosthesis.

“We found that, yes, it is possible to use a closed-loop neural prosthesis to facilitate repair of a brain injury,” he said.

The researchers tested the prosthesis in a rat model of brain injury in the laboratory of Randolph J. Nudo, professor of molecular and integrative physiology at the University of Kansas. Nudo mapped the rat’s brain and developed the model in which anterior and posterior parts of the brain that control the rat’s forelimbs are disconnected.

Atop each animal’s head, the brain-machine-brain interface is a microchip on a circuit board smaller than a quarter connected to microelectrodes implanted in the two brain regions.

The device amplifies signals, which are called neural action potentials and produced by the neurons in the anterior of the brain. An algorithm separates these signals, recorded as brain spike activity, from noise and other artifacts. With each spike detected, the microchip sends a pulse of electric current to stimulate neurons in the posterior part of the brain, artificially connecting the two brain regions.

Two weeks after the prosthesis had been implanted and run continuously, the rat models using the full closed-loop system had recovered nearly all function lost due to injury, successfully retrieving a food pellet close to 70 percent of the time, or as well as normal, uninjured rats. Rat models that received random stimuli from the device retrieved less than half the pellets and those that received no stimuli retrieved about a quarter of them.

“A question still to be answered is must the implant be left in place for life?” Mohseni said. “Or can it be removed after two months or six months, if and when new connections have been formed in the brain?”

Brain studies have shown that, during periods of growth, neurons that regularly communicate with each other develop and solidify connections.

Mohseni and Nudo said they need more systematic studies to determine what happens in the brain that leads to restoration of function. They also want to determine if there is an optimal time window after injury in which they must implant the device in order to restore function.

For patients recovering from a traumatic brain injury (TBI), the rehabilitation process – compensating for changes in functioning, adaptation and even community reintegration – can be challenging. Unfortunately, not all rehab programs are created equal, and with the differences comes a difference in outcomes, according to a first-of-its-kind study published in The Journal of Head Trauma Rehabilitation.

Collectively authored by Baylor researchers, the outcomes study (titled “Comparative Effectiveness of Traumatic Brain Injury Rehabilitation: Differential Outcomes Across TBI Model Systems Centers”), set out to identify if outcomes at the post-discharge and one-year points varied across 21 Traumatic Brain Injury Model System (TBIMS) centers. The Baylor Institute of Rehabilitation (BIR) was one of the centers studied.

At the study’s onset, researchers had an idea of what they might find, but their findings revealed the opposite.

“We expected that, after accounting for differences in patient characteristics and severity of injury, patient outcomes would be similar across centers,” said Marie Dahdah, PhD, investigator at the Baylor Institute for Rehabilitation. “They were not. There were significant variations, with a 25 percent to 45 percent difference between the best performing site and the site with the lowest outcomes at discharge.”

While differences in outcomes have long been reported in designated trauma centers (and for other specialties, including general and cardiac surgery, transplant and oncology), the study was the first piece of research to demonstrate that those differences exist in the rehabilitation context.

The team acknowledged that those variances could be attributed to institutional structures, resources and clinical practices, but that more research is needed to determine which of these factors is associated with optimum outcomes.

“In order to identify factors that contribute to variation in patient outcomes across centers, we are undertaking research that identifies different patient, injury and process-level factors associated with functional outcomes of patients,” Dr. Dahdah said. “Those factors can then be targeted to improve patient outcomes.”

In other phases of this study, these Baylor investigators (along with teams from three other TBIMS sites) are reviewing the quantity and frequency of various types of rehabilitation therapies used in inpatient TBI settings. The team will also study evidenced-based best practices for speech, occupational, physical and recreational therapy interventions, as well as neurocognitive and psychosocial interventions.

The results from those subsequent studies could help identify gaps between current practices and evidence-based best practices, with the aim of helping inform rehabilitation programs across the country and ensuring that all centers have the same opportunities for quality outcomes.

“I think I speak for my entire research team when I say that our involvement in this type of research comes out of our collective desire to improve quality of rehabilitation care, thereby enhancing outcomes following TBI,” Dr. Dahdah said. “My hope is that by synthesizing and disseminating what is known about effective evidence-based rehabilitation interventions, BIR as part of the North Texas TBIMS will be able to encourage changes necessary to help institutions, clinicians and therapists to provide the best quality TBI rehabilitation care to their patients.”

Of course, with the Baylor Institute of Rehabilitation being among the 21-center pool, one very obvious question remains. How did BIR’s outcomes compare with the other 20 centers?

“I cannot count for you the number of times I have been asked that question,” Dr. Dahdah said. “To ensure the integrity of our study, even our research team is blind to the identity of the centers.”

But despite how well even the strongest inpatient rehab centers perform in a comparative context, there is always room for improvement, especially with best-practice regimens.

“Our research has already started discussions within the TBI Model Systems research community,” Dr. Dahdah said. “We believe more research needs to be done to identify the key determinants of patient outcomes so that benchmarks for quality rehabilitation care can be derived for patients and their families.”

TAU researchers discover gene that may predict human responses to specific antidepressants

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants, but they don’t work for everyone. What’s more, patients must often try several different SSRI medications, each with a different set of side effects, before finding one that is effective. It takes three to four weeks to see if a particular antidepressant drug works. Meanwhile, patients and their families continue to suffer.

Now researchers at Tel Aviv University have discovered a gene that may reveal whether people are likely to respond well to SSRI antidepressants, both generally and in specific formulations. The new biomarker, once it is validated in clinical trials, could be used to create a genetic test, allowing doctors to provide personalized treatment for depression.

Doctoral students Keren Oved and Ayelet Morag led the research under the guidance of Dr. David Gurwitz of the Department of Molecular Genetics and Biochemistry at TAU’s Sackler Faculty of Medicine and Dr. Noam Shomron of the Department of Cell and Developmental Biology at TAU’s Sackler Faculty of Medicine and Sagol School of Neuroscience. Sackler faculty members Prof. Moshe Rehavi of the Department of Physiology and Pharmacology and Dr. Metsada Pasmnik-Chor of the Bioinformatics Unit were coauthors of the study, published in Translational Psychiatry.

"SSRIs only work for about 60 percent of people with depression," said Dr. Gurwitz. "A drug from other families of antidepressants could be effective for some of the others. We are working to move the treatment of depression from a trial-and-error approach to a best-fit, personalized regimen."

Good news for the depressed

More than 20 million Americans each year suffer from disabling depression that requires clinical intervention. SSRIs such as Prozac, Zoloft, and Celexa are the newest and the most popular medications for treatment. They are thought to work by blocking the reabsorption of the neurotransmitter serotonin in the brain, leaving more of it available to help brain cells send and receive chemical signals, thereby boosting mood. It is not currently known why some people respond to SSRIs better than others.

To find genes that may be behind the brain’s responsiveness to SSRIs, the TAU researchers first applied the SSRI Paroxetine — brand name Paxil — to 80 sets of cells, or “cell lines,” from the National Laboratory for the Genetics of Israeli Populations, a biobank of genetic information about Israeli citizens located at TAU’s Sackler Faculty of Medicine and directed by Dr. Gurwitz. The TAU researchers then analyzed and compared the RNA profiles of the most and least responsive cell lines. A gene called CHL1 was produced at lower levels in the most responsive cell lines and at higher levels in the least responsive cell lines. Using a simple genetic test, doctors could one day use CHL1 as a biomarker to determine whether or not to prescribe SSRIs.

"We want to end up with a blood test that will allow us to tell a patient which drug is best for him," said Oved. "We are at the early stages, working on the cellular level. Next comes testing on animals and people."

Rethinking how antidepressants work

The TAU researchers also wanted to understand why CHL1 levels might predict responsiveness to SSRIs. To this end, they applied Paroxetine to human cell lines for three weeks — the time it takes for a clinical response to SSRIs. They found that Paroxetine caused increased production of the gene ITGB3 — whose protein product is thought to interact with CHL1 to promote the development of new neurons and synapses. The result is the repair of dysfunctional signaling in brain regions controlling mood, which may explain the action of SSRI antidepressants.

This explanation differs from the conventional theory that SSRIs directly relieve depression by inhibiting the reabsorption of the neurotransmitter serotonin in the brain. Dr. Shomron adds that the new explanation resolves the longstanding mystery as to why it takes at least three weeks for SSRIs to ease the symptoms of depression when they begin inhibiting reabsorption after a couple days — the development of neurons and synapses takes weeks, not days.

The TAU researchers are working to confirm their findings on the molecular level and with animal models. Adva Hadar, a master’s student in Dr. Gurwitz’s lab, is using the same approach to find biomarkers for the personalized treatment of Alzheimer’s disease.

According to Gertrude Stein, “A rose is a rose is a rose,” but new research indicates that might not be the case when it comes to the rose’s scent. Researchers from the Monell Center and collaborating institutions have found that as much as 30 percent of the large array of human olfactory receptor differs between any two individuals. This substantial variation is in turn reflected by variability in how each person perceives odors.

Humans have about 400 different types of specialized sensors, known as olfactory receptor proteins, that somehow work together to detect a large variety of odors.

"Understanding how this huge array of receptors encodes odors is a challenging task," says study lead author Joel Mainland, PhD, a molecular biologist at Monell. "The activation pattern of these 400 receptors encodes both the intensity of an odor and the quality – for example, whether it smells like vanilla or smoke – for the tens of thousands of different odors that represent everything we smell.

Right now, nobody knows how the activity patterns are translated into a signal that our brain registers as the odor.”

Adding to the complexity of the problem, the underlying amino acid sequence can vary slightly for each of the 400 receptor proteins, resulting in one or more variants for each of the receptors. Each receptor variant responds to odors in a slightly different way and the variants are distributed across individuals such that nearly everyone has a unique combination of olfactory receptors.

To gain a better understanding of the extent of olfactory receptor variation and how this impacts human odor perception, Mainland and his collaborators used a combination of high-throughput assays to measure how single receptors and individual humans respond to odors. The results, published in Nature Neuroscience, provide a critical step towards understanding how olfactory receptors encode the intensity, pleasantness and quality of odor molecules.

The researchers first cloned 511 known variants of human olfactory receptors and embedded them in host cells that are easy to grow in the laboratory. The next step was to measure whether each receptor variant responded to a panel of 73 different odor molecules. This process identified 28 receptor variants that responded to at least one of the odor molecules.

Drilling down, the researchers next examined the DNA of 16 olfactory receptor genes, discovering considerable variation within the genes for discrete receptors.

Using sophisticated mathematical modeling to extrapolate from these results, Mainland predicts that the olfactory receptors of any two individuals differ by about 30 percent. This means that for any two randomly chosen individuals, approximately 140 of their 400 olfactory receptors will differ in how they respond to odor molecules.

To understand how variation in a single olfactory receptor affects odor perception, the researchers studied responses to odors in individuals having different variants of a receptor known as OR10G4. They found that variations in the OR10G4 receptor were related to how people perceive the intensity and pleasantness of guaiacol, a molecule that often is described as having a ‘smoky’ characteristic.

Moving forward, a current study is relating the olfactory receptor repertoire of hundreds of people with how those people respond to odors. The data will enable the researchers to identify additional examples of how changes in individual receptors affect olfactory perception.

"The long-term goal is to figure out how the receptors encode odor molecules well enough that we can actually create any odor we want by manipulating the receptors directly," said Mainland. "In essence, this would allow us to ‘digitize’ olfaction."

Researchers at University of Colorado School of Medicine may have figured out what causes Meniere’s disease and how to attack it. According to Carol Foster, MD, from the department of otolaryngology and Robert Breeze, MD, a neurosurgeon, there is a strong association between Meniere’s disease and conditions involving temporary low blood flow in the brain such as migraine headaches.

Meniere’s affects approximately 3 to 5 million people in the United States. It is a disabling disorder resulting in repeated violent attacks of dizziness, ringing in the ear and hearing loss that can last for hours and can ultimately cause permanent deafness in the affected ear. Up until now, the cause of the attacks has been unknown, with no theory fully explaining the many symptoms and signs of the disorder.

"If our hypothesis is confirmed, treatment of vascular risk factors may allow control of symptoms and result in a decreased need for surgeries that destroy the balance function in order to control the spell" said Foster. "If attacks are controlled, the previously inevitable progression to severe hearing loss may be preventable in some cases."

Foster explains that these attacks can be caused by a combination of two factors: 1) a malformation of the inner ear, endolymphatic hydrops (the inner ear dilated with fluid) and 2) risk factors for vascular disease in the brain, such as migraine, sleep apnea, smoking and atherosclerosis.

The researchers propose that a fluid buildup in part of the inner ear, which is strongly associated with Meniere attacks, indicates the presence of a pressure-regulation problem that acts to cause mild, intermittent decreases of blood flow within the ear. When this is combined with vascular diseases that also lower blood flow to the brain and ear, sudden loss of blood flow similar to transient ischemic attacks (or mini strokes) in the brain can be generated in the inner ear sensory tissues. In young people who have hydrops without vascular disorders, no attacks occur because blood flow continues in spite of these fluctuations. However, in people with vascular diseases, these fluctuations are sufficient to rob the ear of blood flow and the nutrients the blood provides. When the tissues that sense hearing and motion are starved of blood, they stop sending signals to the brain, which sets off the vertigo, tinnitus and hearing loss in the disorder.

Restoration of blood flow does not resolve the problem. Scientists believe it triggers a damaging after-effect called the ischemia-reperfusion pathway in the excitable tissues of the ear that silences the ear for several hours, resulting in the prolonged severe vertigo and hearing loss that is characteristic of the disorder. Although most of the tissues recover, each spell results in small areas of damage that over time results in permanent loss of both hearing and balance function in the ear.

Since the first linkage of endolymphatic hydrops and Meniere’s disease in 1938, a variety of mechanisms have been proposed to explain the attacks and the progressive deafness, but no answer has explained all aspects of the disorder, and no treatment based on these theories has proven capable of controlling the progression of the disease. This new theory, if proven, would provide many new avenues of treatment for this previously poorly-controlled disorder.

Life presents us with choices all the time: salad or pizza for lunch? Tea or coffee afterward? How we make these everyday decisions has been a topic of great interest to economists, who have devised theories about how we assign values to our options and use those values to make decisions.

An emerging field of study known as neuroeconomics is combining the economists’ insights with scientific study of the brain to learn more about decision-making processes and how they can go awry. In the Dec. 8 issue of Neuron, one of the field’s founders reports new links between brain cell activity and choices where two options have equal appeal.

“Neuroeconomics is not only helpful for the development of better economic theory, it is also relevant from a clinical point of view,” said author Camillo Padoa-Schioppa, PhD, assistant professor of neurobiology, economics and of biomedical engineering at Washington University School of Medicine in St. Louis. “There are a number of conditions that involve impaired economic decision-making, including drug addiction, brain injury, some forms of dementia, schizophrenia and obsessive-compulsive disorder.”

Scientists know that the orbitofrontal cortex, a region of the brain behind and above the eyes, plays a key role in making decisions. Patients with injuries to this part of the brain are often spectacularly bad at making decisions. They may do things like abandon longstanding relationships, gamble away money or lose it to swindlers, or become addicted to drugs.

To study the roles brain cells play in decision-making, Padoa-Schioppa developed a system for presenting primates a choice between two drinks, such as grape juice or apple juice. The type and amount of the drink varies, and researchers record the activity of individual brain neurons as the primates choose.

Based on the decisions of a single animal over multiple trials, scientists infer the subjective value the animal assigns to each drink and then look for ways this value is encoded in brain cells.

“For example, if we offer a larger amount of apple juice versus a smaller amount of grape juice, and the primate chooses each option equally often, we infer that this primate likes the grape juice better than the apple juice,” he explained. “The primate could be getting more juice by choosing the cup with apple juice, but it doesn’t always do so. That implies that the primate values grape juice more than apple juice.”

In 2006, Padoa-Schioppa and Harvard colleague John Assad, PhD, won international attention for using this system to identify brain cells whose firing rates encoded the subjective value of drink choices.

In a new analysis of data from the original experiment, Padoa-Schioppa showed that different groups of cells in the orbitofrontal cortex reflect different stages of the decision-making process.

“Some neurons encode the value of individual drinks; other neurons encode the choice outcome in a binary way ‒ these cells are either firing or silent depending on the chosen drink,” he explained. “Yet other neurons encode the value of the chosen option.”

Padoa-Schioppa then examined how different groups of cells determine decisions between options of equal value. He showed that toss-up decisions seemed to depend on changes in the initial state of the network of neurons in the orbitofrontal cortex.

“The fluctuations in the network took place before the primates were even offered a choice of juices, but they seem to somehow bias the decision,” Padoa-Schioppa said. “Neuronal signals are always noisy. In essence, close-call decisions are partly determined by random noise.”

He also found that decisions on choices of equal value were linked to the ease or difficulty with which nerve cells in parts of the orbitofrontal cortex communicate with each other. This property, known as synaptic efficacy, can be adjusted by the brain as part of the process of encoding information.

According to Padoa-Schioppa, these results provide new insights into the neuronal circuits that underlie economic decisions. He and his colleagues are using them to create a computational model of decision-making.

“The next step is to test that model,” Padoa-Schioppa said. “For example, we would like to bias decisions by artificially manipulating the activity of specific groups of cells.”

Researchers from the University of Bonn use reprogrammed patient neurons for drug testing

Why do certain Alzheimer medications work in animal models but not in clinical trials in humans? A research team from the University of Bonn and the biomedical enterprise LIFE & BRAIN GmbH has been able to show that results of established test methods with animal models and cell lines used up until now can hardly be translated to the processes in the human brain. Drug testing should therefore be conducted with human nerve cells, conclude the scientists. The results are published by Cell Press in the journal “Stem Cell Reports”.

In the brains of Alzheimer patients, deposits form that consist essentially of beta-amyloid and are harmful to nerve cells. Scientists are therefore searching for pharmaceutical compounds that prevent the formation of these dangerous aggregates. In animal models, certain non-steroidal anti-inflammatory drugs (NSAIDs) were found to a reduced formation of harmful beta-amyloid variants. Yet, in subsequent clinical studies, these NSAIDs failed to elicit any beneficial effects.

"The reasons for these negative results have remained unclear for a long time", says Prof. Dr. Oliver Brüstle, Director of the Institute for Reconstructive Neurobiology of the University of Bonn and CEO of LIFE & BRAIN GmbH. "Remarkably, these compounds were never tested directly on the actual target cells – the human neuron", adds lead author Dr. Jerome Mertens of Prof. Brüstle’s team, who now works at the Laboratory of Genetics in La Jolla (USA). This is because, so far, living human neurons have been extremely difficult to obtain. However, with the recent advances in stem cell research it has become possible to derive limitless numbers of brain cells from a small skin biopsy or other adult cell types.

Scientists transform skin cells into nerve cells

Now a research team from the Institute for Reconstructive Neurobiology and the Department of Neurology of the Bonn University Medical Center together with colleagues from the LIFE & BRAIN GmbH and the University of Leuven (Belgium) has obtained such nerve cells from humans. The researchers used skin cells from two patients with a familial form of Alzheimer’s Disease to produce so-called induced pluripotent stem cells (iPS cells), by reprogramming the body’s cells into a quasi-embryonic stage. They then transformed the resulting so-called “jack-of-all-trades cells” into nerve cells.

Using these human neurons, the scientists tested several compounds in the group of non-steroidal anti-inflammatory drugs. As control, the researchers used nerve cells they had obtained from iPS cells of donors who did not have the disease. Both in the nerve cells obtained from the Alzheimer patients and in the control cells, the NSAIDs that had previously tested positive in the animal models and cell lines typically used for drug screening had practically no effect: The values for the harmful beta-amyloid variants that form the feared aggregates in the brain remained unaffected when the cells were treated with clinically relevant dosages of these compounds.

Metabolic processes in animal models differ from humans

"In order to predict the efficacy of Alzheimer drugs, such tests have to be performed directly on the affected human nerve cells", concludes Prof. Brüstle’s colleague Dr. Philipp Koch, who led the study. Why do NSAIDs decrease the risk of aggregate formation in animal experiments and cell lines but not in human neurons? The scientists explain this with differences in metabolic processes between these different cell types. "The results are simply not transferable", says Dr. Koch.

The scientists now hope that in the future, testing of potential drugs for the treatment of Alzheimer’s disease will be increasingly conducted using neurons obtained from iPS cells of patients. “The development of a single drug takes an average of ten years”, says Prof. Brüstle. “By using patient-specific nerve cells as a test system, investments by pharmaceutical companies and the tedious search for urgently needed Alzheimer medications could be greatly streamlined”.

The body is structured to ensure that any invading organisms have a tough time reaching the brain, an organ obviously critical to survival. Known as the blood-brain barrier, cells that line the brain and spinal cord are tightly packed, making it difficult for anything besides very small molecules to cross from the bloodstream into the central nervous system. While beneficial, this blockade also stands in the way of delivering drugs intended to treat neurological disorders, such as Alzheimer’s.

In a new study published in the journal Molecular Therapy, University of Pennsylvania researchers have found a way of traversing the blood-brain barrier, as well as a similar physiological obstacle in the eye, the retinal-blood barrier. By pairing a receptor that targets neurons with a molecule that degrades the main component of Alzheimer’s plaques, the biologists were able to substantially dissolve these plaques in mice brains and human brain tissue, offering a potential mechanism for treating the debilitating disease, as well as other conditions that involve either the brain or the eyes.

The work was led by Henry Daniell, a professor in Penn’s School of Dental Medicine’s departments of biochemistry and pathology and director of translational research. The research team included Penn Dental Medicine’s Neha Kohli, Donevan R. Westerveld, Alexandra C. Ayache and Sich L. Chan. Co-authors at the University of Florida College of Medicine, including Amrisha Verma, Pollob Shil, Tuhina Prasad, Ping Zhu and Quihong Li, analyzed retinal tissues. 

The researchers began their work by considering how they might breach the blood-brain barrier. Daniell hypothesized that a molecule might be permitted to cross if it was attached to a carrier that is able to pass over, as a sort of molecular crossing guard. The protein cholera toxin B, or CTB, a non-toxic carrier currently approved for use in humans by the Food and Drug Administration, is used in this study to traverse the blood-brain barrier.

They next identified a protein that could clear the plaques that are found in the brains of Alzheimer’s patients. These plaques, which are believed to cause the dementia associated with the disease, are made up of tangles of amyloid beta (Aβ), a protein that is found in soluble form in healthy individuals. Noting that myelin basic protein (MBP) has been shown to degrade Aβ chains, the team decided to couple it with CTB to see if MBP would be permitted to cross.

“These tangles of beta amyloid are known to be the problem in Alzheimer’s,” says Daniell. “So our idea was to chop the protein back to their normal size so they wouldn’t form these tangles.”

To test this idea, the Penn-led team first exposed healthy mice to the CTB-MBP compound by feeding them capsules of freeze-dried leaves that had been genetically engineered to express the fused proteins, a method developed and perfected by Daniell over many years as a means of orally administering various drugs and vaccines. Adding a green-fluorescent protein to the CTB carrier, the researchers tracked the “glow” to see where the mice took up the protein. They found the glowing protein in both the brain and retina.

“When we found the glowing protein in the brain and the retina we were quite thrilled,” said Daniell. “If the protein could cross the barrier in healthy mice, we thought it was likely that it could cross in Alzheimer’s patients brains, because their barrier is somewhat impaired.”

When CTB was not part of the fused protein, they did not see this expression, suggesting that their carrier protein, the crossing guard, was an essential part of delivering their protein of interest.

To then see what MBP would do once it got to the brain, Daniell and colleagues exposed the CTB-MBP protein to the brains of mice bred to have an Alzheimer’s disease. They used a stain that binds to the brain plaques and found that exposure to the CTB-MBP compound resulted in reductions of staining up to 60 percent, indicating that the plaques were dissolving.

Gaining confidence that their compound was appropriately targeting the plaques, the researchers worked with the National Institutes of Health to obtain brain tissue from people who died of Alzheimer’s and performed the same type of staining. Their results showed a 47 percent decrease in staining in the inferior parietal cortex, a portion of the brain found to play an important role in the development of Alzheimer’s-associated dementia.

As a final step, the researchers fed the CTB-MBP-containing capsules to 15-month-old mice, the equivalent of 80 or more human years, bred to develop Alzheimer’s disease. After three months of feeding, the mice had reductions in Aβ plaques of up to 70 percent in the hippocampus and up to 40 percent in the cortex, whereas mice fed capsules that contained lettuce leaves without CTB-MBP added and mice that were not fed any capsules did not have any reduction in evidence of brain plaques.

Because Alzheimer’s patients have also been found to have plaques in their eyes, the researchers examined the eyes of the mice fed the protein. They found that, indeed, the Alzheimer’s-mice did have retinal plaques, but those fed the CBP-MBP compound had undetectable Aβ plaques in their retinae.

“Really no one knows whether the memory problems that people who have Alzheimer’s disease are due to the dementia or problems with their eyes,” Daniell said. “Here we show it may be both, and that we can dissolve the plaques through an oral route.”

Daniell hopes that this technique of delivering proteins across the blood-brain and blood-retina barriers could serve to treat a variety of diseases beyond Alzheimer’s. Several current clinical trials have failed because of an inability to deliver drugs to the brain.  Currently, treatments of some eye conditions must physically penetrate the retina with an injection, an approach that requires anesthesia and risks retinal detachment. Treatment with an ingestible capsule would be safer, easier, and more cost-effective.

As a next step, Daniell hopes to collaborate with Alzheimer’s experts at Penn to advance these studies and add a behavioral component to determine whether the CBP-MBP compound not only removes plaques but also improves the memory and functioning of mice with the Alzheimer’s disease.

A discovery by Emory Alzheimer’s Disease Research Center and Scripps Research Institute scientists could lead to drugs that slow Alzheimer’s disease progression.

A straightforward drug strategy against Alzheimer’s is to turn down the brain’s production of beta-amyloid, the key component of the disease’s characteristic plaques. A toxic fragment of a protein found in healthy brains, beta-amyloid accumulates in the brains of people affected by the disease.

The enzyme that determines how much beta-amyloid brain cells generate is called BACE (beta-secretase or beta-site APP cleaving enzyme). Yet finding drugs that inhibit that elusive enzyme has been far from straightforward.

Now researchers have identified a way to shut down production of beta-amyloid by diverting BACE to a different part of the cell and inhibiting its activity. The results were published this week in Journal of Neuroscience.

"This is an indirect but highly effective way of blocking BACE, which controls the chokepoint step in beta-amyloid production," says lead author Jeremy Herskowitz, PhD, instructor in neurology at Emory’s Alzheimer’s Disease Research Center.

"Jeremy has found a promising approach toward reducing beta-amyloid production and potentially modifying Alzheimer’s disease progression, something for which there is immense need," says senior author James Lah, MD, PhD, associate professor of neurology at Emory University School of Medicine and director of the Cognitive Neurology program. "Drugs that reduce beta-amyloid production would probably be mostly preventive. However, since amyloid-beta is toxic, such drugs could have some immediate effect on cognitive impairment."

In the paper, Herskowitz and his colleagues demonstrate that a specific inhibitor of the enzyme ROCK2 can cut beta-amyloid production in brain cells by more than 75 percent. Co-author Yangbo Feng, PhD, associate director of medicinal chemistry at Scripps Research Institute in Florida, previously discovered the ROCK2 inhibitor, called SR3677.

Alzheimer’s researchers were already interested in ROCK2 and a related enzyme, ROCK1, because of a connection with NSAIDs (non-steroid anti-inflammatory drugs) such as ibuprofen. Some NSAIDS can inhibit production of a particularly toxic form of beta-amyloid, and scientists believed NSAIDs were exerting their effects through the ROCKs.

Herskowitz first showed that in cultured cells, “knocking down” the ROCK2 gene reduced beta-amyloid production, but knocking down ROCK1 had the opposite effect.

"This says that anytime you’re hitting both ROCKs at once, the effects cancel each other out," he says.

The known drugs that affect the ROCKs seemed to affect both and thus have diminished effects. In contrast, SR3677 inhibits ROCK2 much more effectively than ROCK1, and it offered a way around the obstacle. Herskowitz found that by inhibiting ROCK2, SR3677 diverts BACE to a different part of the cell, where it is less likely to act on beta-amyloid’s parent protein.

He and ADRC colleagues found that ROCK2 levels are higher than usual in tissue samples from brains of patients with Alzheimer’s, including those with mild cognitive impairment, thought to be a precursor stage of the disease.

"There is plenty of ROCK2 in the brain, and its levels are elevated in Alzheimer’s patients, indicating that it’s an excellent drug target," Herskowitz says. "We are eager to pursue more extensive studies of this strategy in animal models of Alzheimer’s."

SR3677 can substantially inhibit beta-amyloid production in an animal model of Alzheimer’s, but so far, this effect has been observed when the drug is injected directly into the brain. More studies are required to learn if SR3677 or related drugs can pass the blood-brain barrier and thus be given by injection or orally, and what side effects could appear. ROCK inhibitors are also being investigated for treating other conditions such as glaucoma, hypertension and multiple sclerosis. 

Using a powerful gene-hunting technique for the first time in mammalian brain cells, researchers at Johns Hopkins report they have identified a gene involved in building the circuitry that relays signals through the brain. The gene is a likely player in the aging process in the brain, the researchers say. Additionally, in demonstrating the usefulness of the new method, the discovery paves the way for faster progress toward identifying genes involved in complex mental illnesses such as autism and schizophrenia — as well as potential drugs for such conditions. A summary of the study appears in the Dec. 12 issue of Cell Reports.

(Image: A mouse neuron with synapses shown: Red dots mark excitatory synapses, while green dots mark so-called inhibitory synapses. Credit: Kamal Sharma/Johns Hopkins University School of Medicine)

“We have been looking for a way to sift through large numbers of genes at the same time to see whether they affect processes we’re interested in,” says Richard Huganir, Ph.D., director of the Johns Hopkins University Solomon H. Snyder Department of Neuroscience and a Howard Hughes Medical Institute investigator, who led the study. “By adapting an automated process to neurons, we were able to go through 800 genes to find one needed for forming synapses — connections — among those cells.”

Although automated gene-sifting techniques have been used in other areas of biology, Huganir notes, many neuroscience studies instead build on existing knowledge to form a hypothesis about an individual gene’s role in the brain. Traditionally, researchers then disable or “knock out” the gene in lab-grown cells or animals to test their hypothesis, a time-consuming and laborious process.

In this study, Huganir’s group worked to test many genes all at once using plastic plates with dozens of small wells. A robot was used to add precise allotments of cells and nutrients to each well, along with molecules designed to knock out one of the cells’ genes — a different one for each well.

“The big challenge was getting the neurons, which are very sensitive, to function under these automated conditions,” says Kamal Sharma, Ph.D., a research associate in Huganir’s group. The team used a trial-and-error approach, adjusting how often the nutrient solution was changed and adding a washing step, and eventually coaxed the cells to thrive in the wells. In addition, Sharma says, they fine-tuned an automated microscope used to take pictures of the circuitry that had formed in the wells and calculated the numbers of synapses formed among the cells.

The team screened 800 genes in this way and found big differences in the well of cells with a gene called LRP6 knocked out. LRP6 had previously been identified as a player in a biochemical chain of events known as the Wnt pathway, which controls a range of processes in the brain. Interestingly, Sharma says, the team found that LRP6 was only found on a specific kind of synapse known as an excitatory synapse, suggesting that it enables the Wnt pathway to tailor its effects to just one synapse type.

“Changes in excitatory synapses are associated with aging, and changes in the Wnt pathway in later life may accelerate aging in general. However, we do not know what changes take place in the synaptic landscape of the aging brain. Our findings raise intriguing questions: Is the Wnt pathway changing that landscape, and if so, how?” says Sharma. “We’re interested in learning more about what other proteins LRP6 interacts with, as well as how it acts in different types of brain cells at different developmental stages of circuit development and refinement.”

Another likely outcome of the study is wider use of the gene-sifting technique, he says, to explore the genetics of complex mental illnesses. The automated method could also be used to easily test the effects on brain cells of a range of molecules and see which might be drug candidates.

While the human brain is in a resting state, patterns of neuronal activity which are associated to specific memories may spontaneously reappear. Such recurrences contribute to memory consolidation – i.e. to the stabilization of memory contents. Scientists of the DZNE and the University of Bonn are reporting these findings in the current issue of The Journal of Neuroscience. The researchers headed by Nikolai Axmacher performed a memory test on a series of persons while monitoring their brain activity by functional magnetic resonance imaging (fMRI). The experimental setup comprised several resting states including a nap inside a neuroimaging scanner. The study indicates that resting periods can generally promote memory performance.

Depending on one’s mood and activity different regions are active in the human brain. Perceptions and thoughts also influence this condition and this results in a pattern of neuronal activity which is linked to the experienced situation. When it is recalled, similar patterns, which are slumbering in the brain, are reactivated. How this happens, is still largely unknown.

The prevalent theory of memory formation assumes that memories are stored in a gradual manner. At first, the brain stores new information only temporarily. For memories to remain in the long term, a further step is required. „We call it consolidation“, Dr. Nikolai Axmacher explains, who is a researcher at the Department of Epileptology of the University of Bonn and at the Bonn site of the DZNE. “We do not know exactly how this happens. However, studies suggest that a process we call reactivation is of importance. When this occurs, the brain replays activity patterns associated with a particular memory. In principle, this is a familiar concept. It is a fact that things that are actively repeated and practiced are better memorized. However, we assume that a reactivation of memory contents may also happen spontaneously without there being an external trigger.”

A memory test inside the scanner
Axmacher and his team tested this hypothesis in an experiment that involved ten healthy participants with an average age of 24 years. They were shown a series of pictures, which displayed – among other things – frogs, trees, airplanes and people. Each of these pictures was associated with a white square as a label at a different location. The subjects were asked to memorize the position of the square. At the end of the experiment all images were shown again, but this time without the label. The study participants were then asked to indicate with a mouse cursor where the missing mark was originally located. Memory performance was measured as the distance between the correct and the indicated position.

“This is an associative task. Visual and spatial perceptions have to be linked together”, the researcher explains. “Such tasks involve several brain regions. These include the visual cortex and the hippocampus, which takes part in many memory processes.”

Brain activity was recorded by fMRI during the entire experiment, which lasted several hours and included resting periods and a nap inside the neuroimaging scanner.

Recurrent brain patterns increased the accuracy
For data processing a pattern recognition algorithm was trained to look for similarities between neuronal patterns observed during initial encoding and patterns appearing at later occasions. “This method is complex, but quite effective”, Axmacher says. “Analysis showed that neuronal activity associated with images that were shown initially did reappear during subsequent resting periods and in the sleeping phase.”

Memory performance correlated with the replay of neuronal activity patterns. “The more frequently a pattern had reappeared, the more accurate test participants could label the corresponding image”, Axmacher summarizes the findings. “These results support our assumption that neural patterns can spontaneously reappear and that they promote the formation of long-lasting memory contents. There was already evidence for this from animal studies. Our experiment shows that this phenomenon also happens in humans.”

Memory performance benefits from resting periods
The study indicates that resting periods can generally foster memory performance. “Though, our data did not show whether sleeping had a particular effect. This may be due to the experimental setup, which only allowed for a comparatively short nap”, Axmacher reckons. “By contrast, night sleep is considered to be beneficial for the consolidation of memory contents. But it usually takes many hours and includes multiple transitions between different stages of sleep. However, other studies suggest that even short naps may positively affect memory consolidation.”

An objective look at memory contents
It is up to speculation whether the recurring brain patterns triggered conscious memories or whether they remained below the threshold of perception. “I think it is reasonable to assume that during resting periods the test participants let their mind wander and that they recalled images they had just seen before. But this is a matter of subjective perception of the test participants. That’s something we did not look at because it is not essential for our investigation“, Axmacher says. “The strength of our approach lies rather in the fact that we look at memory contents from the outside, in an objective manner. And that we can evaluate them by pattern recognition. This opens ways to many questions of research. For example, brain patterns that reoccur spontaneously are also of interest in the context of experimental dream research.”

Even with today’s technology, it still takes both a male and a female to make a baby. But is it important for both parents to raise that child? Many studies have outlined the value of a mother, but few have clearly defined the importance of a father, until now. New findings from the Research Institute of the McGill University Health Centre (RI-MUHC) show that the absence of a father during critical growth periods, leads to impaired social and behavioural abilities in adults. This research, which was conducted using mice, was published today in the journal Cerebral Cortex. It is the first study to link father absenteeism with social attributes and to correlate these with physical changes in the brain.

“Although we used mice, the findings are extremely relevant to humans,” says senior author Dr. Gabriella Gobbi, a researcher of the Mental Illness and Addiction Axis at the RI-MUHC and an associate professor at the Faculty of Medicine at McGill University. “We used California mice which, like in some human populations, are monogamous and raise their offspring together.” 

“Because we can control their environment, we can equalize factors that differ between them,” adds first author, Francis Bambico, a former student of Dr. Gobbi at McGill and now a post-doc at the Centre for Addiction and Mental Health (CAMH) in Toronto. “Mice studies in the laboratory may therefore be clearer to interpret than human ones, where it is impossible to control all the influences during development.”

Dr. Gobbi and her colleagues compared the social behaviour and brain anatomy of mice that had been raised with both parents to those that had been raised only by their mothers. Mice raised without a father had abnormal social interactions and were more aggressive than counterparts raised with both parents. These effects were stronger for female offspring than for their brothers. Females raised without fathers also had a greater sensitivity to the stimulant drug, amphetamine. 

“The behavioural deficits we observed are consistent with human studies of children raised without a father,” says Dr. Gobbi, who is also a psychiatrist at the MUHC. “These children have been shown to have an increased risk for deviant behaviour and in particular, girls have been shown to be at risk for substance abuse. This suggests that these mice are a good model for understanding how these effects arise in humans.” 

In pups deprived of fathers, Dr. Gobbi’s team also identified defects in the mouse prefrontal cortex, a part of the brain that helps control social and cognitive activity, which is linked to the behaviourial deficits.

“This is the first time research findings have shown that paternal deprivation during development affects the neurobiology of the offspring,” says Dr. Gobbi. These results should incite researchers to look more deeply into the role of fathers during critical stages of growth and suggest that both parents are important in children’s mental health development.

A UW-Madison research team reports today that the brain can produce and release estrogen — a discovery that may lead to a better understanding of hormonal changes observed from before birth throughout the entire aging process.

The new research shows that the hypothalamus can directly control reproductive function in rhesus monkeys and very likely performs the same action in women.

Scientists have known for about 80 years that the hypothalamus, a region in the brain, is involved in regulating the menstrual cycle and reproduction. Within the past 40 years, they predicted the presence of neural estrogens, but they did not know whether the brain could actually make and release estrogen.

Most estrogens, such as estradiol, a primary hormone that controls the menstrual cycle, are produced in the ovaries. Estradiol circulates throughout the body, including the brain and pituitary gland, and influences reproduction, body weight, and learning and memory. As a result, many normal functions are compromised when the ovaries are removed or lose their function after menopause.

"Discovering that the hypothalamus can rapidly produce large amounts of estradiol and participate in control of gonadotropin-releasing hormone neurons surprised us," says Ei Terasawa, professor of pediatrics at the UW School of Medicine and Public Health and senior scientist at the Wisconsin National Primate Research Center. "These findings not only shift the concept of how reproductive function and behavior is regulated but have real implications for understanding and treating a number of diseases and disorders."

For diseases that may be linked to estrogen imbalances, such as Alzheimer’s disease, stroke, depression, experimental autoimmune encephalomyelitis and other autoimmune disorders, the hypothalamus may become a novel area for drug targeting, Terasawa says. “Results such as these can point us in new research directions and find new diagnostic tools and treatments for neuroendocrine diseases.”

The study, published today in the Journal of Neuroscience, “opens up entirely new avenues of research into human reproduction and development, as well as the role of estrogen action as our bodies age,” reports the first author of the paper, Brian Kenealy, who earned his Ph.D. this summer in the Endocrinology and Reproductive Physiology Program at UW-Madison. Kenealy performed three studies. In the first experiment, a brief infusion of estradiol benzoate administered into the hypothalamus of rhesus monkeys that had surgery to remove their ovaries rapidly stimulated GnRH release. The brain took over and began rapidly releasing this estrogen in large pulsing surges.

In the second experiment, mild electrical stimulation of the hypothalamus caused the release of both estrogen and GnRH (thus mimicking how estrogen could induce a neurotransmitter-like action). Third, the research team infused letrazole, an aromatase inhibitor that blocks the synthesis of estrogen, resulting in a lack of estrogen as well as GnRH release from the brain. Together, these methods demonstrated how local synthesis of estrogen in the brain is important in regulating reproductive function.

The reproductive, neurological and immune systems of rhesus macaques have proven to be excellent biomedical models for humans over several decades, says Terasawa, who focuses on the neural and endocrine mechanisms that control the initiation of puberty. “This work is further proof that these animals can teach us about so many basic functions we don’t fully understand in humans.”

Leading up to this discovery, Terasawa said, recent evidence had shown that estrogen acting as a neurotransmitter in the brain rapidly induced sexual behavior in quails and rats. Kenealy’s work is the first evidence of this local hypothalamic action in primates, and in those that don’t even have ovaries.

"The discovery that the primate brain can make estrogen is key to a better understanding of hormonal changes observed during every phase of development, from prenatal to puberty, and throughout adulthood, including aging," Kenealy says.

In a new paper published in the current issue of Neuron, McLean Hospital and Harvard Medical School researchers report that increased activity in the medial prefrontal cortex (mPFC) of the brain is linked to decreased activity in the amygdala, the portion of the brain used in the creation of memories of events that scared those exposed.

According to author Vadim Bolshakov, PhD, director of the Cellular Neurobiology Laboratory at McLean and professor at Harvard Medical School, this finding is significant in that it could lead to better methods to prevent PTSD.

"A single exposure to something traumatic or scary can be enough to create a fear memory—causing someone to expect and be afraid in similar situations in the future," said Bolshakov. "What we’re seeing is that we may one day be able to prevent those fear memories."

Bolshakov and his colleagues tested their theory using animal models. Dividing the mice into two groups, some were taught to fear an auditory stimulus while in others fear memory was extinguished Increased activation of mPFC in extinguished animals led to inhibition of the amygdala and significant decreases in fear responses.

"For example, if a sound ended with an extremely loud shriek, a subject would come to expect that scary noise at the end of the sound," explained Bolshakov. "What we found was when we suppressed the fear memory by decreasing activity in the amygdala, the subjects were not afraid of the end of the auditory stimulus any longer."

Bolshakov notes that this work could have serious implications for the treatment of a number of conditions including PTSD.

"While there is still a great deal of research that needs to be done before our work can be translated to clinical trials, what we are showing has the potential to ensure that individuals exposed to trauma were not haunted by the conditions surrounding their initial stressor."

Fear, at the right level, can increase alertness and protect against dangers. Disproportionate fear, on the other hand, can disrupt the sensory perception, be disabling, reduce happiness and therefore become a danger in itself.  Anxiety disorders are therefore a psychiatric condition that should not be underestimated. In these disorders, the fear is so strong that there is tremendous psychological strain and living a normal life appears to be impossible. Researchers at the MedUni Vienna have now found a possible explanation as to how social phobias and fear can be triggered in the brain: a missing inhibitory connection or missing “brake” in the brain.

Inside the brain, the amygdala and the orbitofrontal cortex in the frontal lobe form an important control circuit for regulating the emotions. This control circuit is termed the brain’s emotional control centre. Whereas in healthy subjects, this circuit has “negative feedback” and “calmness” was identified, scientists used functional magnetic resonance imaging (MRI) on people with social phobias and found the opposite to be true: an important inhibitory connection is different in these patients, which may explain why they are unable to control their fears.

In collaboration with the Centre for Medical Physics and Biomedical Technology and the University Department of Psychiatry and Psychotherapy at the MedUni Vienna, the research team lead by Christian Windischberger was also able to discover through its recent study at the MedUni Vienna’s High Field MR Centre of Excellence how the areas of the brain that are involved with processing emotions are able to influence each other.

The study participants were shown a series of “emotional faces” while undergoing functional magnetic resonance imaging. fMRI is a non-invasive method which uses radio waves and magnetic fields to measure changes in the levels of oxygen in the blood and therefore neuronal activity in individual regions of the brain. An analysis method developed at University College London was used to provide new perspectives on the data obtained.

Breaking the circle of fear
When emotional facial expressions were shown - from laughing to crying, from happiness to anger - neuronal activity was triggered in the brain. The result: on a purely external basis, the test subjects looked no different, but the healthy subjects were kept calm thanks to their automatic “brake”, despite the emotional nature of the images. For the social phobics, on the other hand, the photographs put their brains into “overdrive”, triggering very strong neuronal activity. This was demonstrated very clearly using the new analysis method: “We have the opportunity not only to localise brain activity and compare it between groups, but we can now also make statements regarding functional connections within the brain. In psychiatric conditions especially, we can assume that there are not complete failures of these connections going on, but rather imbalances in complex regulatory processes,” says Ronald Sladky, the study’s primary author.

This better understanding of the neuronal mechanisms involved will now be used to develop new approaches to treatment. The aim is to understand what effect medications and psycho-therapeutic support have on the networks involved in order to help patients break out of their circles of fear.