Posts tagged science

A single dose of a commonly-prescribed attention deficit hyperactivity disorder (ADHD) drug helps improve brain function in cocaine addiction, according to an imaging study conducted by researchers from the Icahn School of Medicine at Mount Sinai. Methylphenidate (brand name Ritalin®) modified connectivity in certain brain circuits that underlie self-control and craving among cocaine-addicted individuals. The research is published in the current issue of JAMA Psychiatry, a JAMA network publication.

Previous research has shown that oral methylphenidate improved brain function in cocaine users performing specific cognitive tasks such as ignoring emotionally distracting words and resolving a cognitive conflict. Similar to cocaine, methylphenidate increases dopamine (and norepinephrine) activity in the brain, but, administered orally, takes longer to reach peak effect, consistent with a lower potential for abuse. By extending dopamine’s action, the drug enhances signaling to improve several cognitive functions, including information processing and attention.

“Orally administered methylphenidate increases dopamine in the brain, similar to cocaine, but without the strong addictive properties,” said Rita Goldstein, PhD, Professor of Psychiatry at Mount Sinai, who led the research while at Brookhaven National Laboratory (BNL) in New York. “We wanted to determine whether such substitutive properties, which are helpful in other replacement therapies such as using nicotine gum instead of smoking cigarettes or methadone instead of heroin, would play a role in enhancing brain connectivity between regions of potential importance for intervention in cocaine addiction.”

Anna Konova, a doctoral candidate at Stony Brook University, who was first author on this manuscript, added, ”Using fMRI, we found that methylphenidate did indeed have a beneficial impact on the connectivity between several brain centers associated with addiction.”

Dr. Goldstein and her team recruited 18 cocaine addicted individuals, who were randomized to receive an oral dose of methylphenidate or placebo. The researchers used functional magnetic resonance imaging (fMRI) to measure the strength of connectivity in particular brain circuits known to play a role in addiction before and during peak drug effects. They also assessed each subject’s severity of addiction to see if this had any bearing on the results.

Methylphenidate decreased connectivity between areas of the brain that have been strongly implicated in the formation of habits, including compulsive drug seeking and craving. The scans also showed that methylphenidate strengthened connectivity between several brain regions involved in regulating emotions and exerting control over behaviors—connections previously reported to be disrupted in cocaine addiction.

“The benefits of methylphenidate were present after only one dose, indicating that this drug has significant potential as a treatment add-on for addiction to cocaine and possibly other stimulants,” said Dr. Goldstein. “This is a preliminary study, but the findings are exciting and warrant further exploration, particularly in conjunction with cognitive behavioral therapy or cognitive remediation.”

(Source: newswise.com)

A chromosomal deletion is associated with changes in the brain’s white matter and delayed language acquisition in youngsters from Southeast Asia or with ancestral connections to the region, said an international consortium led by researchers at Baylor College of Medicine. However, many such children who can be described as late-talkers may overcome early speech and language difficulties as they grow.

The finding involved both cutting edge technology and two physicians with an eye for unusual clinical findings. Dr. Seema R. Lalani, a physician-scientist at BCM and Dr. Jill V. Hunter, professor of radiology at BCM and Texas Children’s Hospital, worked together to identify this genetic change responsible for expressive language delay and brain changes in children, predominantly from Southeast Asia.

Lalani, assistant professor of molecular and human genetics at BCM, is a clinical geneticist and also signs out diagnostic studies called chromosomal microarray analysis, a gene chip that helps identify abnormalities in specific genes and chromosomes, as part of her work at BCM’s Medical Genetics Laboratory.

"I got intrigued when I kept seeing this small (genomic) change in children from a large sample of more than 15,000 children referred for chromosomal microarray analysis at Baylor College of Medicine. These children were predominantly Burmese refugees or of Vietnamese ancestry living in the United States. It started with two children whom I evaluated at Texas Children’s Hospital and soon realized that there was a pattern of early language delay and brain imaging abnormalities in these individuals carrying this deletion from this part of the world. Within a period of two to three years, we found 13 more families with similar problems, having the same genetic change. There were some children who obviously were more affected than the others and had cognitive and neurological problems, but many of them were identified as late-talkers who had better non-verbal skills compared to verbal performance," said Lalani. Hunter, helped in determining the specific pattern of white matter abnormalities in the MRI (magnetic resonance imaging) scans in children and their parents carrying this deletion. Most of the children either came from Southeast Asia or were the offspring of people from that area. (White matter is the paler material in the brain that consists of nerve fibers covered with myelin sheaths.)

Now, in a report that appears online in the American Journal of Human Genetics, Lalani, Hunter and an international group of collaborators identify a genomic deletion on chromosome 2 that is associated with bright white spots that show up in an MRI in the white matter of the brain . The chromosomal deletion removes a portion of a gene known as TM4SF20 that encodes a protein that spans the cellular membrane. They do not know yet what the function of the protein is. They found this genetic change in children from 15 unrelated families mainly from Southeast Asia.

"This deletion could be responsible for early childhood language delay in a large number of children from this part of the world," says Lalani.

She credits Dr. Wojciech Wiszniewski, an assistant professor of molecular and human genetics at BCM with doing much of the work. Wiszniewski has an interest in genomic disorders and is working under the mentorship of Dr. James R. Lupski, vice chair of the department of molecular and human genetics.

Lupski said, “Professor Lalani has made a stunning discovery in that she provides evidence that population-specific intragenic CNV (copy number variation – a deletion or duplication of the chromosome) can contribute to genetic susceptibility of even common complex disease such as speech delay in children.”

"In a way, this is a good news story," said Hunter. There is evidence from family studies that some of these children may do quite well in the future, said Lalani.

Lalani elaborates. “This is a genetic change that is present in 2 percent of Vietnamese Kinh population (an ethnic group that makes up 90 percent of the population in that country),” she said. “In the 15 families we have identified, all children have early language delay. Some are diagnosed with autism spectrum disorder, and if you do a brain MRI study, you find white matter changes in about 70 percent of them. We have found this change in children who are Vietnamese, Burmese, Thai, Indonesian, Filipino and and Micronesian. It is very likely that children from other Southeast Asian countries within this geographical distribution also carry this genetic change.”

Because these are all within a geographic location, she suspects that there is an ancient founder effect, meaning that at some point in the distant past, the gene deletion occurred spontaneously in an individual, who then passed it on to his or her children and to succeeding generations.

"It is important to follow these children longitudinally to see how these late-talkers develop as they grow," said Lalani. "We have also seen this deletion in children whose parents clearly were late-talkers themselves, but overcame the earlier problems to become doctors and professionals. The variability within the deletion carriers is fascinating and brings into question genetic and environmental modifiers that contribute to the extent of disease in these children.

Language delays mean that they may speak only two or three words at age 2, in comparison to other children who would generally have between 75-100 word vocabulary by this age. While there is evidence that children with this deletion may catch up, it is unclear if they continue to have better non-verbal skills than verbal skills. It is also unclear how the specific brain changes correlate with communication disorders in these children.

In fact, when doctors check the parents of these children, they often find similar white matter changes in the parent carrying the deletion. “Young parents in their 30s should not have age-related white matter changes in the brain and these changes should definitely not be present in healthy children,” said Lalani. Hunter said they are not sure how the gene variation relates to the changes in brain white matter and how all of these result in delay in language.

(Source: eurekalert.org)

Insights into how the brain compensates for temporary hearing loss during infancy, such as that commonly experienced by children with glue ear, have been revealed in a research study in ferrets. The Wellcome Trust-funded study could point to new therapies for glue ear and has implications for the design of hearing aid devices.

Normally, the brain works out where sounds are coming from by relying on information from both ears located on opposite sides of the head, such as differences in volume and time delay in sounds reaching the two ears. The shape of the outer ear also helps us to interpret the location of sounds by filtering sounds from different directions - so-called ‘spectral cues’.

This ability to identify where sounds are coming from not only helps us to locate the path of moving objects but also helps us to separate different sound sources in noisy environments.

Glue ear, or otitis media, is a relatively common condition caused by a build-up of fluid in the middle ear that causes temporary hearing loss. By age 10, eight out of ten children will have experienced one or more episodes of glue ear. It usually resolves itself, but more severe cases can require interventions such as the insertion of tubes (commonly known as grommets) to drain the fluid and restore hearing.

If the loss of hearing is persistent, however, it can lead to impairments in later life, even after normal hearing has returned. These impairments include ‘lazy ear’, or amblyaudia, which leaves people struggling to locate sounds or pick out sounds in noisy environments such as classrooms or restaurants.

Researchers at the University of Oxford used removable earplugs to introduce intermittent, temporary hearing loss in one ear in young ferrets, mimicking the effects of glue ear in children. The team then tested their ability to localise sounds as adults and measured activity in the brain to see how the loss of hearing affected their development.

The results show that animals raised with temporary hearing loss were still able to localise sounds accurately while wearing an earplug in one ear. They achieved this by becoming more dependent on the unchanged spectral cues from the outer part of the unaffected ear. When the plug was removed and hearing returned to normal, the animals were just as good at localising sounds as those who had never experienced hearing loss.

Professor Andrew King, a Wellcome Trust Principal Research Fellow at the University of Oxford who led the study, explains: “Our results show that, with experience, the brain is able to shift the strategy it uses to localise sounds depending on the information that is available at the time.

"During periods of hearing loss in one ear - when the spatial cues provided by comparing the sounds at each ear are compromised - the brain becomes much more reliant on the intact spectral cues that arise from the way sounds are filtered by the outer ear. But when hearing is restored, the brain returns to using information from both ears to work out where sounds are coming from."

The results contrast with previous studies that looked at the effects of enduring hearing loss - rather than recurring hearing loss - on brain development. These earlier studies found that changes in the brain that result from loss of hearing persisted even when normal hearing returned.

The new findings suggest that intermittent experience of normal hearing is important for preserving sensitivity to those cues and could offer new strategies for rehabilitating people who have experienced hearing loss in childhood. In addition, the finding that spectral cues from the outer ear are an important source of information during periods of hearing loss has important implications for the design of hearing aids, particularly those that sit behind the ear.

"Recurring periods of hearing loss are extremely common during childhood. These findings will help us to find better ways of rehabilitating those affected, which should limit the number who go on to develop more serious hearing problems in later life," adds Professor King.

The study is published today in the journal ‘Current Biology’.

(Source: wellcome.ac.uk)

A study from Karolinska Institutet shows, that our imagination may affect how we experience the world more than we perhaps think. What we imagine hearing or seeing ‘in our head’ can change our actual perception. The study, which is published in the scientific journal Current Biology, sheds new light on a classic question in psychology and neuroscience - about how our brains combine information from the different senses.

"We often think about the things we imagine and the things we perceive as being clearly dissociable," says Christopher Berger, doctoral student at the Department of Neuroscience and lead author of the study. "However, what this study shows is that our imagination of a sound or a shape changes how we perceive the world around us in the same way actually hearing that sound or seeing that shape does. Specifically, we found that what we imagine hearing can change what we actually see, and what we imagine seeing can change what we actually hear."

The study consists of a series of experiments that make use of illusions in which sensory information from one sense changes or distorts one’s perception of another sense. Ninety-six healthy volunteers participated in total. In the first experiment, participants experienced the illusion that two passing objects collided rather than passed by one-another when they imagined a sound at the moment the two objects met. In a second experiment, the participants’ spatial perception of a sound was biased towards a location where they imagined seeing the brief appearance of a white circle. In the third experiment, the participants’ perception of what a person was saying was changed by their imagination of a particular sound.

According to the scientists, the results of the current study may be useful in understanding the mechanisms by which the brain fails to distinguish between thought and reality in certain psychiatric disorders such as schizophrenia. Another area of use could be research on brain computer interfaces, where paralyzed individuals’ imagination is used to control virtual and artificial devices.

"This is the first set of experiments to definitively establish that the sensory signals generated by one’s imagination are strong enough to change one’s real-world perception of a different sensory modality", says Professor Henrik Ehrsson, the principle investigator behind the study.

(Source: ki.se)

A protein secreted with insulin travels through the bloodstream and accumulates in the brains of individuals with type 2 diabetes and dementia, in the same manner as the amyloid beta (Αβ) plaques that are associated with Alzheimer’s disease, a study by researchers with the UC Davis Alzheimer’s Disease Center has found.

The study is the first to identify deposits of the protein, called amylin, in the brains of people with Alzheimer’s disease, as well as combined deposits of amylin and Aβ plaques, suggesting that amylin is a second amyloid as well as a new biomarker for age-related dementia and Alzheimer’s.

“We’ve known for a long time that diabetes hurts the brain, and there has been a lot of speculation about why that occurs, but there has been no conclusive evidence until now,” said UC Davis Alzheimer’s Disease Center Director Charles DeCarli.

“This research is the first to provide clear evidence that amylin gets into the brain itself and that it forms plaques that are just like the amyloid beta that has been thought to be the cause of Alzheimer’s disease,” DeCarli said. “In fact, the amylin looks like the amyloid beta protein, and they both interact. That’s why we’re calling it the second amyloid of Alzheimer’s disease.”

 ”Amylin deposition in the brain: A second amyloid in Alzheimer’s disease?” is published online today in the Annals of Neurology.

Type 2 diabetes is a chronic metabolic disorder that increases the risk for cerebrovascular disease and dementia, a risk that develops years before the onset of clinically apparent diabetes. Its incidence is far greater among people who are obese and insulin resistant.

Amylin, or islet amyloid polypeptide, is a hormone produced by the pancreas that circulates in the bloodstream with insulin and plays a critical role in glycemic regulation by slowing gastric emptying, promoting satiety and preventing post-prandial spikes in blood glucose levels. Its deposition in the pancreas is a hallmark of type 2 diabetes.

When over-secreted, some proteins have a higher propensity to stick to one another, forming small aggregates, called oligomers, fibrils and amyloids. These types of proteins are called amyloidogenic and include amylin and Aβ. There are about 28 amyloidogenic proteins, each of which is associated with diseases.                

The study was conducted by examining brain tissue from individuals who fell into three groups: those who had both diabetes and dementia from cerebrovascular or Alzheimer’s disease; those with Alzheimer’s disease without diabetes; and age-matched healthy individuals who served as controls.

The research found numerous amylin deposits in the gray matter of the diabetic patients with dementia, as well as in the walls of the blood vessels in their brains, suggesting amylin influx from blood circulation. Surprisingly, the researchers also found amylin in the brain tissue of individuals with Alzheimer’s who had not been diagnosed with diabetes; they postulate that these individuals may have had undiagnosed insulin resistance. They did not find amylin deposits in the brains of the healthy control subjects.

“We found that the amylin deposits in the brains of people with dementia are both independent of and co-located with the Aβ, which is the suspected cause of Alzheimer’s disease,” said Florin Despa, assistant professor-in-residence in the UC Davis Department of Pharmacology. “It is both in the walls of the blood vessels of the brain and also in areas remote from the blood vessels.

“It is accumulating in the brain and we found signs that amylin is killing neurons similar to Aβ,” he continued. “And that might be the answer to the question of ‘What makes obese and type 2 diabetes patients more prone to developing dementia?’”

The researchers undertook the investigation after Despa and his colleagues found that amylin accumulates in the blood vessels and muscle of the heart. From this evidence, he hypothesized that the same thing might be happening in the brain. To test the hypothesis he received a pilot research grant through the Alzheimer’s Disease Center.

The research was conducted using tissue from the brains of individuals over 65 donated to the UC Davis Alzheimer’s Disease Center: 15 patients with Alzheimer’s disease and type 2 diabetes; 14 Alzheimer’s disease patients without diabetes; and 13 healthy controls. A series of tests, including Western blot, immunohistochemistry and ELISA (enzyme-linked immunosorbent assay) were used to test amylin accumulation in specimens from the temporal cortex.

In contrast with the healthy brains, the brain tissue infiltrated with amylin showed increased interstitial spaces, cavities within the tissue, sponginess, and blood vessels bent around amylin accumulation sites.

Despa said that the finding may offer a therapeutic target for drug development, either by increasing the rate of amylin elimination through the kidneys, or by decreasing its rate of oligomerization and deposition in diabetic patients.

"If we’re smart about the treatment of pre-diabetes, a condition that promotes increased amylin secretion, we might be able to reduce the risk of complications, including Alzheimer’s and dementia,” Despa said.

(Source: ucdmc.ucdavis.edu)

In a perspective piece appearing today in the journal Science, researchers at University of Rochester Medical Center (URMC) point to a newly discovered system by which the brain removes waste as a potentially powerful new tool to treat neurological disorders like Alzheimer’s disease. In fact, scientists believe that some of these conditions may arise when the system is not doing its job properly. 

“Essentially all neurodegenerative diseases are associated with the accumulation of cellular waste products,” said Maiken Nedergaard, M.D., D.M.Sc., co-director of the URMC Center for Translational Neuromedicine and author of the article. “Understanding and ultimately discovering how to modulate the brain’s system for removing toxic waste could point to new ways to treat these diseases.”   

The body defends the brain like a fortress and rings it with a complex system of gateways that control which molecules can enter and exit. While this “blood-brain barrier” was first described in the late 1800s, scientists are only now just beginning to understand the dynamics of how these mechanisms function. In fact, the complex network of waste removal, which researchers have dubbed the glymphatic system, was only first disclosed by URMC scientists last August in the journal Science Translational Medicine.  

The removal of waste is an essential biological function and the lymphatic system – a circulatory network of organs and vessels – performs this task in most of the body. However, the lymphatic system does not extend to the brain and, consequently, researchers have never fully understood what the brain does its own waste. Some scientists have even speculated that these byproducts of cellular function where somehow being “recycled” by the brain’s cells.  

One of the reasons why the glymphatic system had long eluded comprehension is that it cannot be detected in samples of brain tissue. The key to discovering and understanding the system was the advent of a new imaging technology called two-photon microscopy which enables scientists to peer deep within the living brain. Using this technology on mice, whose brains are remarkably similar to humans, Nedergaard and her colleagues were able to observe and document what amounts to an extensive, and heretofore unknown, plumbing system responsible for flushing waste from throughout the brain. 

The brain is surrounded by a membrane called the arachnoid and bathed in cerebral spinal fluid (CSF). CSF flows into the interior of the brain through the same pathways as the arteries that carry blood. This parallel system is akin to a donut shaped pipe within a pipe, with the inner ring carrying blood and the outer ring carrying CSF. The CSF is draw into brain tissue via a system of conduits that are controlled by a type support cells in the brain known as glia, in this case astrocytes. The term glymphatic was coined by combining the words glia and lymphatic.

The CSF is flushed through the brain tissue at a high speed sweeping excess proteins and other waste along with it. The fluid and waste are exchanged with a similar system that parallels veins which carries the waste out of the brain and down the spine where it is eventually transferred to the lymphatic system and from there to the liver, where it is ultimately broken down.

While the discovery of the glymphatic system solved a mystery that had long baffled the scientific community, understanding how the brain removes waste – both effectively and what happens when this system breaks down – has significant implications for the treatment of neurological disorders.

One of the hallmarks of Alzheimer’s disease is the accumulation in the brain of the protein beta amyloid. In fact, over time these proteins amass with such density that they can be observed as plaques on scans of the brain. Understanding what role the glymphatic system plays in the brain’s inability to break down and remove beta amyloid could point the way to new treatments. Specifically, whether certainly key ‘players’ in the glymphatic system, such as astrocytes, can be manipulated to ramp up the removal of waste.

“The idea that ‘dirty brain’ diseases like Alzheimer may result from a slowing down of the glymphatic system as we age is a completely new way to think about neurological disorders,” said Nedergaard. “It also presents us with a new set of targets to potentially increase the efficiency of glymphatic clearance and, ultimately, change the course of these conditions.”

The power of the brain lies in its trillions of intercellular connections, called synapses, which together form complex neural “networks.” While neuroscientists have long sought to map these complex connections to see how they influence specific brain functions, traditional techniques have yet to provide the desired resolution. Now, by using an innovative brain-tracing technique, scientists at the Gladstone Institutes and the Salk Institute have found a way to untangle these networks. Their findings offer new insight into how specific brain regions connect to each other, while also revealing clues as to what may happen, neuron by neuron, when these connections are disrupted.

In the latest issue of Neuron, a team led by Gladstone Investigator Anatol Kreitzer, PhD, and Salk Investigator Edward Callaway, PhD, combined mouse models with a sophisticated tracing technique—known as the monosynaptic rabies virus system—to assemble brain-wide maps of neurons that connect with the basal ganglia, a region of the brain that is involved in movement and decision-making. Developing a better understanding of this region is important as it could inform research into disorders causing basal ganglia dysfunction, including Parkinson’s disease and Huntington’s disease.

“Taming and harnessing the rabies virus—as pioneered by Dr. Callaway—is ingenious in the exquisite precision that it offers compared with previous methods, which were messier with a much lower resolution,” explained Dr. Kreitzer, who is also an associate professor of neurology and physiology at the University of California, San Francisco, with which Gladstone is affiliated. “In this paper, we took the approach one step further by activating the tracer genetically, which ensures that it is only turned on in specific neurons in the basal ganglia. This is a huge leap forward technologically, as we can be sure that we’re following only the networks that connect to particular kinds of cells in the basal ganglia.”

At Gladstone, Dr. Kreitzer focuses his research on the role of the basal ganglia in Parkinson’s and other neurological disorders. Last year, he and his team published research that revealed clues to the relationship between two types of neurons found in the region—and how they guide both movement and decision-making. These two types, called direct-pathway medium spiny neurons (dMSNs) and indirect-pathway medium spiny neurons (iMSNs), act as opposing forces. dMSNs initiate movement, like the gas pedal, and iMSNs inhibit movement, like the brake. The latest research from the Kreitzer lab further found that these two types are also involved in behavior, specifically decision-making, and that a dysfunction of dMSNs or iMSNs is associated with addictive or depressive behaviors, respectively. These findings were important because they provided a link between the physical neuronal degeneration seen in movement disorders, such as Parkinson’s, and some of the disease’s behavioral aspects. But this study still left many questions unanswered.

“For example, while that study and others like it revealed the roles of dMSNs and iMSNs in movement and behavior, we knew very little about how other brain regions influenced the function of these two neuron types,” said Salk Institute Postdoctoral Fellow Nicholas Wall, PhD, the paper’s first author. “The monosynaptic rabies virus system helps us address that question.”

The system, originally developed in 2007 and refined by Wall and Callaway for targeting specific cell types in 2010, uses a modified version of the rabies virus to “infect” a brain region, which in turn targets neurons that are connected to it. When the system was applied in genetic mouse models, the team could see specifically how sensory, motor, and reward structures in the brain connected to MSNs in the basal ganglia. And what they found was surprising.

“We noticed that some regions showed a preference for transmitting to dMSNs versus iMSNs, and vice versa,” said Dr. Kreitzer. “For example, neurons residing in the brain’s motor cortex tended to favor iMSNs, while neurons in the sensory and limbic systems preferred dMSNs. This fine-scale organization, which would have been virtually impossible to observe using traditional techniques, allows us to predict the distinct roles of these two neuronal types.”

“These initial results should be treated as a resource not only for decoding how this network guides the vast array of very distinct brain functions, but also how dysfunctions in different parts of this network can lead to different neurological conditions,” said Dr. Callaway. “If we can use the rabies virus system to pinpoint distinct network disruptions in distinct types of disease, we could significantly improve our understanding of these diseases’ underlying molecular mechanisms—and get even closer to developing solutions for them.”