Posts tagged neuroscience

ScienceDaily (Mar. 26, 2012) — Working with genetically engineered mice and the genomes of thousands of people with schizophrenia, researchers at Johns Hopkins say they now better understand how both nature and nurture can affect one’s risks for schizophrenia and abnormal brain development in general.

The green neurons have reduced DISC1 protein. Red neurons have less effective GABA. (Credit: Johns Hopkins Medicine)

The researchers reported in the March 2 issue of Cell that defects in a schizophrenia-risk genes and environmental stress right after birth together can lead to abnormal brain development and raise the likelihood of developing schizophrenia by nearly one and half times.

"Our study suggests that if people have a single genetic risk factor alone or a traumatic environment in very early childhood alone, they may not develop mental disorders like schizophrenia," says Guo-li Ming, M.D., Ph.D., professor of neurology and member of the Institute for Cell Engineering at the Johns Hopkins University School of Medicine. "But the findings also suggest that someone who carries the genetic risk factor and experiences certain kinds of stress early in life may be more likely to develop the disease."

Pinpointing the cause or causes of schizophrenia has been notoriously difficult, owing to the likely interplay of multiple genes and environmental triggers, Ming says. Searching for clues at the molecular level, the Johns Hopkins team focused on the interaction of two factors long implicated in the disease: Disrupted-in-Schizophrenia 1 (DISC1) protein, which is important for brain development, and GABA, a brain chemical needed for normal brain function.

To find how these factors impact brain development and disease susceptibility, the researchers first engineered mice to have reduced levels of DISC1 protein in one type of neuron in the hippocampus, a region of the brain involved in learning, memory and mood regulation. Through a microscope, they saw that newborn mouse brain cells with reduced levels of DISC1 protein had similar sized and shaped neurons as those from mice with normal levels of DISC1 protein. To change the function of the chemical messenger GABA, the researchers engineered the same neurons in mice to have more effective GABA. Those brain cells looked much different than normal neurons, with longer appendages or projections. Newborn mice engineered with both the more effective GABA and reduced levels of DISC1 showed the longest projections, suggesting, Ming said, that defects in both DISC1 and GABA together could change the physiology of developing neurons for the worse.

Meanwhile, other researchers at University of Calgary and at the National Institute of Physiological Sciences in Japan had shown in newborn mice that changes in environment and routine stress can impede GABA from working properly during development. In the next set of experiments, the investigators paired reducing DISC1 levels and stress in mice to see if it could also lead to developmental defects. To stress the mice, the team separated newborns from their mothers for three hours a day for ten days, then examined neurons from the stressed newborns and saw no differences in their size, shape and organization compared with unstressed mice. But when they similarly stressed newborn mice with reduced DISC1 levels, the neurons they saw were larger, more disorganized and had more projections than the unstressed mouse neurons. The projections, in fact, went to the wrong places in the brain.

Next, to see if their results in mice correlated to suspected human schizophrenia risk factors, the researchers compared the genetic sequences of 2,961 schizophrenia patients and healthy people from Scotland, Germany and the United States. Specifically, they determined if specific variations of DNA letters found in two genes, DISC1 and a gene for another protein, NKCC1, which controls the effect of GABA, were more likely to be found in schizophrenia patients than in healthy individuals. They paired 36 DNA “letter” changes in DISC1 and two DNA letter variations in NKCC1 — one DNA letter change per gene — in all possible combinations. Results showed that if a person’s genome contained one specific combination of single DNA letter changes, then that person is 1.4 times more likely than people without these DNA changes to develop schizophrenia. Having these single DNA letter changes in either one of these genes alone did not increase risk.

"Now that we have identified the precise genetic risks, we can rationally search for drugs that correct these defects," says Hongjun Song, Ph.D., co-author, professor of neurology and director of the Stem Cell Program at the Institute for Cell Engineering.

Source: Science Daily

ScienceDaily (Mar. 26, 2012) — Repeated stress triggers the production and accumulation of insoluble tau protein aggregates inside the brain cells of mice, say researchers at the University of California, San Diego School of Medicine in a new study published in the March 26 Online Early Edition of the Proceedings of the National Academy of Sciences.

Exposing mice to 14 days of repeated stress resulted in an accumulation of insoluble phosphorylated tau protein aggregates in brain cells, visualized in this electron micrograph. (Credit: Image courtesy of Robert Rissman, UC San Diego)

The aggregates are similar to neurofibrillary tangles or NFTs, modified protein structures that are one of the physiological hallmarks of Alzheimer’s disease. Lead author Robert A. Rissman, PhD, assistant professor of neurosciences, said the findings may at least partly explain why clinical studies have found a strong link between people prone to stress and development of sporadic Alzheimer’s disease (AD), which accounts for up to 95 percent of all AD cases in humans.

"In the mouse models, we found that repeated episodes of emotional stress, which has been demonstrated to be comparable to what humans might experience in ordinary life, resulted in the phosphorylation and altered solubility of tau proteins in neurons," Rissman said. "These events are critical in the development of NFT pathology in Alzheimer’s disease."

The effect was most notable in the hippocampus, said Rissman, a region of the brain linked to the formation, organization and storage of memories. In AD patients, the hippocampus is typically the first region of the brain affected by tau pathology and the hardest-hit, with substantial cell death and shrinkage.

Not all forms of stress are equally threatening. In earlier research, Rissman and colleagues reported that acute stress — a single, passing episode — does not result in lasting, debilitating long lasting changes in accumulation of phosphorylated tau. Acute stress-induced modifications in the cell are transient, he said, and on the whole, probably beneficial.

"Acute stress may be useful for brain plasticity and helping to facilitate learning. Chronic stress and continuous activation of stress pathways may lead to pathological changes in stress circuitry. It may be too much of a good thing." As people age, perhaps their neuronal circuits do too, he said, becoming less robust and perhaps less capable of completely rebounding from the effects of stress.

"Age is the primary, known risk factor for Alzheimer’s disease. It may be that as we age, our neurons just aren’t as plastic as they once were and some succumb."

The researchers observed that stress cues impacted two key corticotropin-releasing factor receptors, suggesting a target for potential therapies. Rissman noted drugs already exist and are in human trials (for other conditions) that modulate the activity of these receptors.

"You can’t eliminate stress. We all need to be able to respond at some level to stressful stimuli. The idea is to use an antagonist molecule to reduce the effects of stress upon neurons. The stress system can still respond, but the response in the brain and hippocampus would be toned down so that it doesn’t result in harmful, permanent damage."

The authors dedicate this work to long time mentor and colleague, Dr. Wylie Vale, whose years of pioneering work deciphering and describing the stress system were fundamental to this paper. Vale passed away earlier this year at the age of 70.

Source: Science Daily

ScienceDaily (Mar. 26, 2012) — Individuals with major depressive disorder (MDD) often undergo multiple courses of antidepressant treatment during their lives. This is because the disorder can recur despite treatment and because finding the right medication for a specific individual can take time.

While the relationship between prior treatment and the brain’s response to subsequent treatment is unknown, a new study by UCLA researchers suggests that how the brain responds to antidepressant medication may be influenced by its remembering of past antidepressant exposure.

Interestingly, the researchers used a harmless placebo as the key to tracking the footprints of prior antidepressant use.

Aimee Hunter, the study’s lead author and an assistant professor of psychiatry at UCLA’s Semel Institute for Neuroscience and Human Behavior, and colleagues showed that a simple placebo pill, made to look like actual medication for depression, can “trick” the brain into responding in the same manner as the actual medication.

The report was published online March 23 in the journal European Neuropsychopharmacology.

The investigators examined changes in brain function in 89 depressed persons during eight weeks of treatment, using either an antidepressant medication or a similar-looking placebo pill. They set out to compare the two treatments — medication versus placebo — but they also added a twist: They separately examined the data for subjects who had never previously taken an antidepressant and those who had.

The researchers focused on the prefrontal cortex, an area of the brain thought to be involved in planning complex cognitive behavior, personality expression, decision-making and moderating social behavior, all things depressed people wrestle with.

Brain changes were assessed using electroencephalograph (EEG) measures developed at UCLA by study co-authors Dr. Ian Cook, UCLA’s Miller Family Professor of Psychiatry, and Dr. Andrew Leuchter, a professor of psychiatry and director of the Laboratory of Brain, Behavior and Pharmacology at UCLA’s Semel Institute. The EEG measure, recorded from scalp electrodes, is linked to blood flow in the cerebral cortex, which suggests the level of brain activity.

The antidepressant medication given during the study appeared to produce slight decreases in prefrontal brain activity, regardless of whether subjects had received prior antidepressant treatment during their lifetime or not. (A decrease in brain activity is not necessarily a bad thing, the researchers note; with depression, too much activity in the brain can be as bad as too little.)

However, the researchers observed striking differences in the power of placebo, depending on subjects’ prior antidepressant use. Subjects who had never been treated with an antidepressant exhibited large increases in prefrontal brain activity during placebo treatment. But those who had used antidepressant medication in the past showed slight decreases in prefrontal activity — brain changes that were indistinguishable from those produced by the actual drug.

"The brain’s response to the placebo pill seems to depend on what happened previously — on whether or not the brain has ever ‘seen’ antidepressant medication before," said Hunter, who is a member of the placebo research team at the Laboratory of Brain, Behavior and Pharmacology. "If it has seen it before, then the brain’s signature ‘antidepressant-exposure’ response shows up."

According to Hunter, the effect looks conspicuously like a classical conditioning phenomenon, wherein prior exposure to the actual drug may have produced the specific prefrontal brain response and subsequent exposure to the cues surrounding drug administration — the relationship with the doctor or nurse, the medical treatment setting, the act of taking a prescribed pill and so forth — came to elicit a similar brain response through ‘conditioning’ or ‘associative learning.’

While medication can have a powerful effect on our physiology, said Hunter, “the behaviors and cues in the environment that are associated with taking medication can come to elicit their own effects. One’s personal treatment history is one of the many factors that influence the overall effects of treatment.”

Still, she noted, there are other possible explanations, and further research is needed to tease out changes in brain function that are related to antidepressant exposure, compared with brain changes that are related to clinical improvement during treatment.

Source: Science Daily

ScienceDaily (Mar. 26, 2012) — Smoking alters the impact of a schizophrenia risk gene. Scientists from the universities of Zurich and Cologne demonstrate that healthy people who carry this risk gene and smoke process acoustic stimuli in a similarly deficient way as patients with schizophrenia. Furthermore, the impact is all the stronger the more the person smokes.

Schizophrenia has long been known to be hereditary. However, as a melting pot of disorders with different genetic causes is concealed behind manifestations of schizophrenia, research has still not been able to identify the main gene responsible to this day.

In order to study the genetic background of schizophrenia, the frequency of particular risk genes between healthy and ill people has mostly been compared until now. Pharmacopyschologist Professor Boris Quednow from University Hospital of Psychiatry, Zurich, and Professor Georg Winterer’s workgroup at the University of Cologne have now adopted a novel approach. Using electroencephalography (EEG), the scientists studied the processing of simple acoustic stimuli (a sequence of similar clicks). When processing a particular stimulus, healthy people suppress the processing of other stimuli that are irrelevant to the task at hand. Patients with schizophrenia exhibit deficits in this kind of stimulus filtering and thus their brains are probably inundated with too much information. As psychiatrically healthy people also filter stimuli with varying degrees of efficiency, individual stimulus processing can be associated with particular genes.

Smokers process stimuli less effectively

In a large-scale study involving over 1,800 healthy participants from the general population, Boris Quednow and Georg Winterer examined how far acoustic stimulus filtering is connected with a known risk gene for schizophrenia: the so-called “transcription factor 4” gene (TCF4). TCF4 is a protein that plays a key role in early brain development. As patients with schizophrenia often smoke, the scientists also studied the smoking habits of the test subjects.

The data collected shows that psychiatrically healthy carriers of the TCF4 gene also filter stimuli less effectively — like people who suffer from schizophrenia. It turned out that primarily smokers who carry the risk gene display a less effective filtering of acoustic impressions. This effect was all the more pronounced the more the people smoked. Non-smoking carriers of the risk gene, however, did not process stimuli much worse. “Smoking alters the impact of the TCF4 gene on acoustic stimulus filtering,” says Boris Quednow, explaining this kind of gene-environment interaction. “Therefore, smoking might also increase the impact of particular genes on the risk of schizophrenia.”

The results could also be significant for predicting schizophrenic disorders and for new treatment approaches, says Quednow and concludes: “Smoking should also be considered as an important cofactor for the risk of schizophrenia in future studies.” A combination of genetic (e.g. TCF4), electrophysiological (stimulus filtering) and demographic (smoking) factors could help diagnose the disorder more rapidly or also define new, genetically more uniform patient subgroups.

Source: Science Daily

ScienceDaily (Mar. 26, 2012) — Though autism is often not diagnosed until the age of three, some children begin to show signs of developmental delay before they turn a year old. While not all infants and toddlers with delays will develop autism spectrum disorders (ASD), experts point to early detection of these signs as key to capitalizing on early diagnosis and intervention, which is believed to improve developmental outcomes.

According to Dr. Rebecca Landa, director of the Center for Autism and Related Disorders at the Kennedy Krieger Institute in Baltimore, Md., parents need to be empowered to identify the warning signs of ASD and other communication delays.

"We want to encourage parents to become good observers of their children’s development so that they can see the earliest indicators of delays in a baby’s communication, social and motor skills," says Dr. Landa, who also cautions that some children who develop ASD don’t show signs until after the second birthday or regress after appearing to develop typically.

For the past decade, Dr. Landa has followed infant siblings of children with autism to identify red flags of the disorder in their earliest form. Her research has shown that diagnosis is possible in some children as young as 14 months and sparked the development of early intervention models that have been shown to improve outcomes for toddlers showing signs of ASD as young as one and two years old.

Dr. Landa recommends that as parents play with their infant (6 — 12 months), they look for the following signs that have been linked to later diagnosis of ASD or other communication disorders:

1. Rarely smiles when approached by caregivers 2. Rarely tries to imitate sounds and movements others make, such as smiling and laughing, during simple social exchanges 3. Delayed or infrequent babbling 4. Does not respond to his or her name with increasing consistency from 6 — 12 months 5. Does not gesture to communicate by 10 months 6. Poor eye contact 7. Seeks your attention infrequently 8. Repeatedly stiffens arms, hands, legs or displays unusual body movements such as rotating the hands on the wrists, uncommon postures or other repetitive behaviors 9. Does not reach up toward you when you reach to pick him or her up 10. Delays in motor development, including delayed rolling over, pushing up and crawling

"If parents suspect something is wrong with their child’s development, or that their child is losing skills, they should talk to their pediatrician or another developmental expert," says Dr. Landa. "Don’t adopt a ‘wait and see’ perspective. We want to identify delays early in development so that intervention can begin when children’s brains are more malleable and still developing their circuitry."

Source: Science Daily

March 26, 2012

A meta-analysis of previously published studies found that the ratio of blood plasma amyloid-β (Aβ) peptides Aβ42:Aβ40 was significantly associated with development of Alzheimer disease and dementia, according to a report published Online First by Archives of Neurology.

"Plasma levels of amyloid-β (Aβ) peptides have been a principal focus of the growing literature on blood-based biomarkers, but studies to date have varied in design, assay methods, and sample size, making it difficult to readily interpret the overall data," the authors write as background in the study.

Alain Koyama, S.M., then of Harvard School of Public Health and Brigham and Women’s Hospital, Boston, now with the University of California, San Francisco, and colleagues conducted a meta-analysis of 13 previously published studies to examine the association between plasma amyloid-β and development of dementia, Alzheimer disease (AD) and cognitive decline.

The 13 studies included in the analysis had a total of 10,303 participants, and were published between 1995 and 2011. The studies also included measurement of at least one relevant plasma amyloid-β species (Aβ40, Aβ42, or Aβ42: Aβ40 ratio) and reported an effect estimate for dementia, AD or cognitive decline.

The authors found that lower Aβ42: Aβ40 ratios were significantly associated with development of Alzheimer disease and dementia, with most studies in the analysis reporting similar findings. Plasma levels of Aβ40 and Aβ42 alone, however, were not significantly associated with either outcome.

"In conclusion, despite the limitations of existing research and heterogeneity across the studies considered, this systematic review and meta-analysis suggests that the ratio of plasma Aβ42: Aβ40 may have value in predicting the risk for later development of dementia or AD and merits further investigation."

More information: Arch Neurol. Published online March 26, 2012. doi:10.1001/archneurol.2011.1841

Provided by JAMA and Archives Journals

Source: medicalxpress.com

March 26, 2012

Dr. Judith Edersheim, co-founder and co-director of the Center for Law, Brain and Behavior at Massachusetts General Hospital, explores how neuroscience can enhance the pursuit of justice.

Dr. Judith Edersheim of the Center for Law, Brain and Behavior delivered the 13th annual Francine and Michael Saferstein Memorial Lecture in Forensic Science on Tuesday. Photo by Dominick Reuter.

“If neuroscience could shed light on mental states, it might be able to illuminate whether someone meant the crime or intended to harm someone,” Edersheim told approximately 200 students, faculty, staff and community members who filled Northeastern’s Raytheon Amphitheater on Tuesday for the 13th annual Francine and Michael Saferstein Memorial Lecture in Forensic Science.

The lecture series — which is co-sponsored by the Barnett Institute of Chemical and Biological Analysis and the School of Criminology and Criminal Justice — was established by forensic scientist Richard Saferstein in memory of his wife and child, who were killed in 1978 when a bomb discharged inside the family’s garage.

Barry Karger — the James L. Waters Chair in Analytical Chemistry in Northeastern’s College of Science and director of the Barnett Institute of Chemical and Biological Analysis — introduced Edersheim by praising her for “performing a broad range of psychiatric evaluations in criminal and civil forensic settings.”

Edersheim, who holds both an MD and JD, said “neurolaw” is similar to  “neuropolitics” and “neuromarketing,” in that the field tries to incorporate both neuroscience and psychology into a more established practice.

One’s genetic composition as well as the electrical activity and physical structure of the working brain, she explained, can all be explored to shed light on the question of criminal responsibility.

But Edersheim added a note of caution in taking this approach: If biology single-handedly determines behavior, then the very notion of free will becomes compromised. Technological, procedural, constitutional and deterministic limitations, she said, must all be considered when applying neuroscience to the law.

“The science has to be respected in the community and it has to be peer reviewed,” Edersheim said. “It has to be reliable, reproducible and there have to be known error rates. Judges are gatekeepers and they should keep evidence out that doesn’t meet those tests.”

Edersheim also addressed the constitutionality of neurolaw. If brain scans are examples of involuntary search and seizure or if they force defendants to unwillingly incriminate themselves, then the procedure, she said, could be in violation of the Fourth and Fifth amendments, respectively.

“Thoughts may be subject to constitutional protection,” Edersheim explained, adding that the law and the brain “live in different worlds.”

The law, she said, gives us a set of rules we must abide by, but we must decide as a society whether neurobiological explanations of human behavior should matter when determining criminality.

Edersheim said the Center for Law, Brain and Behavior has an “operational philosophy for the faithful translation of law into neuroscience,” meaning that courtroom use of neurological and biological data should be limited to instances when the science is inextricably and causally linked to a behavior.

Provided by Northeastern University

Source: medicalxpress.com

ScienceDaily (Mar. 26, 2012) — A new study, using brain imaging technology, reveals structural adaptations in short-track speed skaters’ brains which are likely to explain their extraordinary balance and co-ordination skills.

Short track speed skaters. (Credit: © sarah besson / Fotolia)

The work by Im Joo Rhyu from the Korea University College of Medicine, and colleagues, is published online in Springer’s journal Cerebellum.

The cerebellum in the brain plays an essential role in balance control, coordinated movement, and visually guided movement, which are key abilities required for short-track speed skaters as they glide on perfectly smooth ice, cornering and passing at high speeds. Previous studies have shown that damage to the cerebellum results in impaired balance and coordination. In addition, structural changes in the brain have been documented following training of complex motor skills, in both jugglers and basketball players for instance. Are these changes sports-specific?

To assess the effect of short-track speed skating training on the relative structure and size of the two brain hemispheres, the authors analyzed brain MRI scans of 16 male professional short-track speed skaters. They compared them to scans of 18 non-skaters, who did not engage in regular exercise.

They found that skaters had larger right hemispheres of the cerebellum and vermian lobules VI-VII (the lobes connecting the left and right parts of the cerebellum) than non-skaters. These results suggest that the specialized abilities of balance and coordination in skaters are associated with a certain amount of flexibility in the structure of the right hemisphere of the cerebellum and vermian VI-VII.

Why do the structural changes occur to the right side of the cerebellum? Gliding on smooth ice requires specialized abilities to control dynamic balance and coordination. During cornering at high speed, short-track speed skaters turn only to the left while maintaining balance on their right foot. Standing on the right foot activates the right lobes of the cerebellum.

In addition, learning a visually guided task is thought to occur in the right side of the brain. Therefore the larger volume of the right hemisphere of the cerebellum in these skaters is likely to be associated with the type of movements which the sport requires, for strong visual guidance while cornering and passing.

The authors conclude: “Short-track speed skaters’ specialized abilities of balance and coordination stimulate specific structural changes in the cerebellum, following extensive training. These changes reflect the effects of extraordinary abilities of balance and coordination on the right region of the brain.”

Source: Science Daily

March 26, 2012 by Bob Yirka

(Medical Xpress) — A research team made up of people from a wide variety of biological sciences has found that mice fed a diet high in fat tend to see an increase in the number of neurons created in the hypothalamus, a region of the brain associated with regulating energy use in the body. The team, as they describe in their paper published in Nature Neuroscience, write that the increase in neurons occurs in a part of the hypothalamus called the median eminence, which lies outside the blood-brain barrier.

Hypothalamic proliferative zone. For more details, Nature Neuroscience (2012) doi:10.1038/nn.3079

Suspecting that something unusual goes on with the hypothalamus and the median eminence in particular, when mice eat more fat, the research team put a group of mice on a diet very high in it. In the lab, mice are usually fed a diet that is approximately thirty five percent fat, which keeps them from gaining weight. In this study, the fat content was raised to sixty percent, which of course caused the mice to get fat. But, the team found, it also caused the creation of new brain cells in the median eminence to increase, from one to five percent.

Next the researchers forced the mouse brains to stop creating new brain cells while continuing to feed the mice the high fat diet. And surprisingly, the mice weight gain slowed and the mice demonstrated more energy. Adding to the good news was the fact that the median eminence lies outside of the blood-brain area (a separation of blood and brain fluid that prevents many materials in blood from reaching brain cells) meaning that the possibility of developing a therapy based on this research to help humans lose weight might be possible.

The researchers are quick to point out however, that there is no evidence yet that increased neuron production occurs in people who eat extra amounts of fat, or even in any other animal. They also say they don’t yet understand why new neuron growth occurs when mice are fed a high fat diet, but speculate that it may have something to do with detecting chemicals in the bloodstream and responding by sending signals to the rest of the hypothalamus.

More information: Tanycytes of the hypothalamic median eminence form a diet-responsive neurogenic niche, Nature Neuroscience (2012) doi:10.1038/nn.3079

Source: medicalxpress.com