A typical symptom of Parkinson’s disease is tremor in patients. A group of scientists, including Professor Peter Tass from Forschungszentrum Jülich have succeeded in demonstrating the mechanisms which cause the so-called tremor: neuron clusters in the depths of the brain drive the tremor. This discovery supports Tass’ research activities aiming at developing a therapy for Parkinson’s disease. A new deep brain pacemaker is to bring cells out of the diseased mode for good.

Today’s article in the high-impact journal “Europhysics Letters” shows that the scientists from Forschungszentrum Jülich, a member of the Helmholtz Association, are on the right track. Their new deep brain pacemaker is to help Parkinson’s patients on a large scale for the first time in 2009. Communication between the networks of neurons is disturbed in people suffering from Parkinson’s disease. These “fire” their stimuli at the same time thus causing the typical tremor. The frequency measured here is 5 hertz (Hz), i.e. five oscillations per second. In Germany, there are officially around 150,000 Parkinson’s patients, although it is estimated that up to 450,000 people are affected.

To date, scientists have assumed that the 5-Hz rhythm deep in the brain resulted from nerve signals, which are transmitted from muscles in the limbs back to the brain. The scientific term for this response is “proprioceptive feedback”. The prevailing opinion of many scientists to date, however, is that the “cross fire” is not emitted by the brain. The reason for this assumption was that the measured frequency of the “proprioceptive feedback” and the frequency in a specific core region of the brain, in the thalamus and the basal ganglia, were not completely synchronous.

With a combination of several state-of-the-art analytical processes, the team has now succeeded in demonstrating that it is not only nerve signals from the muscles as feedback that drive the diseased 5-Hz rhythm in the brain. Headed by Prof. Volker Sturm, neurosurgeons in Cologne implanted electrodes in patients for the measurements, and scientists in Saratov, Russia, recalculated the obtained data together with scientists from Jülich. “Signals in the frequency domain of 5 Hz from the core region of the brain also drive the tremor”, explained Peter Tass. “The difference: the feedback from the limbs is a fast and easy stimulus transmission. The signals from the thalamus and the basal ganglia are, however, transmitted to certain loop-like neuron pathways of the brain and spinal cord. Therefore, the dynamics are more complicated and the pathway is longer.”

The Jülich medical scientist, mathematician and physicist believes that these new findings reinforce the theoretical basis of “his” deep brain pacemaker. This device influences the disturbed neurons in the core region of the brain and effectively removes their compulsion to “fire” at the same time. Tass’ new development disturbs this compulsory diseased mode by using very mild, targeted and desynchronized stimuli in different places. In this way, the rhythm becomes irregular and breaks down. Compared to conventional devices of this type, the Jülich deep brain pacemaker puts less strain on the patient and needs less energy. Moreover, the nerve tissue is stimulated in such a way that the neurons abandon their diseased strong synaptic networks and thus forget their compulsion to develop diseased rhythms.

The pacemaker consists of two electrodes that are carefully located at the dysregulated parts of the brain. The so-called stimulator provides the electrodes with energy and signals to stimulate the neurons in the brain. This device is implanted below the collarbone under the skin and thin wires also connect it with the electrodes under the skin.

Research involving large Middle Eastern families, sophisticated genetic analysis and groundbreaking neuroscience has implicated a half-dozen new genes in autism.  More importantly, it strongly supports the emerging idea that autism stems from disruptions in the brain’s ability to form new connections in response to experience – consistent with autism’s onset during the first year of life, when many of these connections are normally made.

Interestingly, not all the affected genes were actually deleted, but only prevented from turning on – offering hope that therapies could be developed to reactivate the genes.  The study, led by researchers at Children’s Hospital Boston and members of the Boston-based Autism Consortium, is the cover article in the July 11 issue of Science.

Autism genes have been difficult to identify because the disorder is complex, with a variety of causes stemming from many possible genes or combinations of genes.  In addition, since people with autism tend not to have children, most of the genes identified thus far aren’t inherited from a parent, but instead are mutated during embryonic development, making them hard to track through traditional linkage studies in families.

Christopher Walsh, MD, PhD, chief of genetics at Children’s Hospital Boston, approached the problem by studying Middle Eastern families.  In traditional Arab societies, it is common for cousins to marry, increasing the likelihood that offspring will inherit rare mutations.  Middle Eastern families also tend to have many children, making them ideal for mapping genes.

“To map a gene for autism in American families, averaging two to three kids per family, you would need to pool many families,” says Walsh, who is also a Howard Hughes Medical Institute investigator at Beth Israel Deaconess Medical Center (BIDMC).  “In larger families, one family alone may be enough to definitively localize a gene.”

The Homozygosity Mapping Collaborative for Autism (HMCA) recruited 104 families with a high incidence of autism from the Arabic Middle East, Turkey and Pakistan; 88 of these families have cousin marriages.  Local clinicians were rigorously trained in administering standardized autism research assessments.  Walsh’s team later flew to sites in Turkey, Dubai, Kuwait and Saudi Arabia to confirm the diagnoses.

Using a technique called homozygosity mapping Walsh and colleagues compared the DNA of family members with and without autism, searching for recessive mutations—those that cause disease only when a child inherits two copies.

“We check each set of chromosomes from beginning to end, looking for one place where the child has two identical pieces of DNA on both chromosomes,” Walsh explains.  “Eventually we find a spot where all affected children have two identical chunks of DNA, and where unaffected children have something different.”

Just over 6 percent of the 88 families showed rare, inherited deletions within DNA regions linked to autism.  These affected DNA regions varied among families, further indication of autism’s large variety of genetic causes.  In all, the technique identified five chromosome deletions affecting at least six identifiable genes (C3orf58, NHE9, PCDH10, contactin-3 [CNTN3], RNF8, and genes encoding a cluster of cellular sodium channels).

One of the genes, NHE9, was also found to be mutated in European and American children with autism (particularly those with both autism and seizures).

Experience-dependent learning: A common thread

The genes discovered are diverse in function, but all seem to be part of a fundamental molecular network that orchestrates the refinement and maturation of brain connections, or synapses, in response to input from the outside world.  It is the refinement of these synaptic connections that is the basis of learning and memory, suggesting that autism at its heart may represent molecular defects of learning.

“This network can be disrupted in a myriad of ways, and may be one mechanism that people with a variety of autism-linked mutations share,” says Michael Greenberg, PhD, a coauthor on the paper and director of the Neurobiology Program at Children’s Hospital Boston.

Normally, as a neuron (brain cell) receives an incoming message at the synapse, a network of reactions is sparked that extends all the way to its nucleus.  Greenberg and his colleagues had long been mapping this network, and had previously found that it activates at least 300 genes.  These genes then communicate back to the neuron’s surface, telling the cell to make a new synapse, strengthen the synapse that’s already there, eliminate a synapse, or make a different kind of synapse.  This give-and-take system is how the brain builds its circuitry; neuroscientists call it “experience-dependent learning.”

Working independently of Walsh, Greenberg and his colleagues had already identified three of the same genes found in the Middle Eastern patients (c3orf58, NHE9, and PCDH10) while looking for genes that turn on or off in neurons as part of this network – either in response to synaptic activity or through so-called transcription factors that are activated by synaptic activity.

The work bolsters a growing body of evidence that autism may represent a disruption of the brain’s ability to modify its synaptic connections in response to experience.

“Taken together, our findings suggest that experience-dependent learning could be relevant to autism, and that autism might result from the deregulation of any one of a number of genes that are part of the same signaling pathway,” Greenberg says.

Can normal function be revived?

Interestingly, only one chromosome deletion found in the Middle Eastern families actually removed a gene – in most cases, what was lost was a region adjacent to the gene that contains its “on/off” switches.  This has important implications for therapy, because it suggests that autism mutations don’t always remove a gene altogether, but only inhibit its activity in certain contexts, says Eric Morrow, MD, PhD, of Massachusetts General Hospital, who is co-first author of the paper with Seung-Yun Yoo, PhD.  “This means that we would not need to replace the gene, if we could only figure out how to reactivate it, perhaps with medications,” says Morrow, who also holds appointments at BIDMC and Children’s.

The findings also support the use of behavioral therapies in autism, which expose children to a rich environment and highly repetitive activities that may help turn on the genes and strengthen synaptic connections, Morrow adds.

“This publication a big event in the world of autism research,” says Clarence Schutt, PhD, Scientific Advisor to the Nancy Lurie Marks Family Foundation, which funded work by both the Walsh and Greenberg labs.  “To have discovered a connection between autism and activity-related gene expression at the synapse will put this field at the center of neuroscience.”

One of the characteristics of type 2 diabetes is insulin resistance, which refers to the inability of cells in the body to respond appropriately to the hormone insulin.  Among the cells in the body that normally respond to insulin are nerves in a region of the brain known as the hypothalamus.  New data, generated in rats, by Hiraku Ono and colleagues, at Albert Einstein College of Medicine, New York, has provided insight into a molecular pathway in the hypothalamus that contributes to the development of insulin resistance.

Insulin plays a key role in controlling the amount of glucose in the body through its ability to make cells, such as liver and fat cells, take up glucose from the blood and store it for future use.  Insulin also prevents liver cells from releasing stored glucose, partly through its effects in the hypothalamus.  In the study, if rats were fed a high-fat diet for a short period of time the ability of insulin to prevent liver cells releasing stored glucose was reduced.  This was associated with both a decrease in insulin-induced signaling and an increase in activation of a protein known as SK6 in the hypothalamus.  The importance of SK6 activation in the hypothalamus in suppressing the ability of insulin to prevent glucose release from liver cells was confirmed by two sets of experiments.  First, it was shown that enforced SK6 activation in the hypothalamus had the same effects as feeding rats a high-fat diet; second, blocking the effects of SK6 activation restored the ability of insulin to prevent glucose release from liver cells, even when rats were fed a high-fat diet.  These data lead the authors to speculate that the earliest stages of diet-induced insulin resistance might be prevented by inhibition of S6K in the hypothalamus.

Neuroscientists at Georgetown University Medical Center have solved a mystery that lies at the heart of human learning, and they say the solution may help explain some forms of mental retardation as well as provide clues to overall brain functioning.

Researchers have long puzzled over why a gene known as brain-derived neurotrophic factor (BDNF), which is crucial to the ability of neurons in the hippocampus to grow and connect to each other – forming the basis of memory and learning – produces two different transcripts, which then each fabricate identical proteins.

In the July 11 issue of Cell, the scientists report the answer, and it has to do with transportation.  They found that the longer of the two transcripts (messenger RNAs, or mRNAs) include extra sequences that “motor” molecules attach to, in order to move the information far away from the nucleus of the cell and toward the long, tree-like branches of the nerve cell known as dendrites.  There, protein-synthesizing machines use that mRNA to produce protein that helps small protrusions (called dendritic spines) on these dendrites grow.

The shorter of the mRNAs are also moved from the nucleus into the cytoplasm of the neuron, but they do not need to be transported to dendrites.  These transcripts produce an identical protein, but in this case, investigators believe they help the axon, the long cable-like body of a neuron, grow.

Learning occurs when both axons and dendritic spines grow and touch each other, forming connections, and existing connections are strengthened.  The scientists’ findings provide a critical understanding of how dendritic spines grow and mature, but this understanding may be more broadly applied.

That’s because as exciting as the findings are for understanding the function – and dysfunction of BDNF as it relates to human learning, they also are relevant for other genes and proteins, says the study’s lead investigator, Baoji Xu, Ph.D., an assistant professor in the Department of Pharmacology at Georgetown.

“The fascinating thing is that many genes produce multiple transcripts for the same protein – and no one has known why,” he says.  “So what we found here is likely very applicable to other genes.  It reveals a mechanism for differential regulation of subcellular functions of proteins.”

In this study, Xu and his research team, which included investigators from the National Institute of Child Health and Human Development (NICHHD), Emory University, and the University of Colorado, looked at why a neuron needs two “species” of BDNF mRNAs.

The gene produces a growth factor that makes neurons grow, and is vital to initial development of the brain; mice born without BDNF have developmental deficits and soon die.  BDNF is also secreted by neurons in adult brains when needed, and that is usually when synaptic junctions between neurons require strengthening, a condition known as “synaptic plasticity” that underlies memory and learning.  “If BDNF is deleted in an adult animal’s brain, the animal will struggle to learn new tasks,” Xu says.

Scientists had found that protein translation occurs in dendrites, and they believed that this protein production was important for synaptic plasticity, “but it has been difficult to study local protein synthesis only in dendrites,” Xu says.  “When you change protein synthesis in dendrites, you also affect protein production in other parts of the neuron.”

To solve that problem, Xu and the scientists managed to create mouse mutants in which the long BDNF mRNA variant is converted to the shorter mRNA form.  They found that in these mice, dendritic spines form normally, but do not mature properly and aren’t “pruned” as they need to be.  “This process is important for the normal function of the brain.  Without it, the mice can’t refine neuronal connections in response to learning,” he says.

Some people diagnosed with mental retardation suffer from the same problem, Xu adds.  “At a certain stage of development, maturation of dendritic spines is frozen.  For example, in Fragile X Syndrome, there are too many immature dendritic spines.

“What we see in our mutant mouse and in Fragile X is similar,” he says.  “If we could find a way to increase BDNF synthesis in dendrites, it may be helpful to people with mental retardation.

“That, of course, is just a theory, but now that we understand the function of these two different mRNAs, we can begin to explore what issues their dysfunction causes in humans,” Xu says.

Individuals who are obese are at increased risk of many diseases, including type 2 diabetes and heart disease.  As 75%-95% of previously obese individuals regain their lost weight, many researchers are interested in developing treatments to help individuals maintain their weight loss.  A new study, by Michael Rosenbaum and colleagues, at Columbia University Medical Center, New York, has provided new insight into the critical interaction between the hormone leptin and the brain’s response to weight loss.

Leptin levels fall as obese individuals lose weight.  So, the authors set out to see whether changes in leptin levels altered activity in the regions of the brain known to have a role in regulating food intake.  They observed that activity in these regions of the brain in response to visual food-related cues changed after an obese individual successfully lost weight.  However, these changes in brain activity were not observed if the obese individual who had successfully lost weight was treated with leptin.  These data are consistent with the idea that the decrease in leptin levels that occurs when an individual loses weight serves to protect the body against the loss of body fat.  Further, both the authors and, in an accompanying commentary, Rexford Ahima, at the University of Pennsylvania School of Medicine, Philadelphia, suggest that leptin therapy after weight loss might improve weight maintenance by overriding this fat-loss defense.

Researchers have determined that there are hundreds of biological differences between the sexes when it comes to gene expression in the cerebral cortex of humans and other primates.  These findings, published June 20th in the open-access journal PloS Genetics, indicate that some of these differences arose a very long time ago and have been preserved through evolution.  These conserved differences constitute a signature of sex differences in the brain.

Many more obvious gender differences have been preserved throughout primate evolution; examples include average body size and weight, and genitalia design.  This study, believed to be the first of its kind, focuses on gene expression within the cerebral cortex.  The cerebral cortex is involved in many of the more complex functions in both humans and other primates, including memory, attentiveness, thought processes and language.

The researchers measured gene expression in the brains of male and female primates from three species: humans, macaques, and marmosets.  To measure activity of specific genes, the products of genes (RNA) obtained from the brain of each animal were hybridized to microarrays containing thousands of DNA clones coding for thousands of genes.  The authors also investigated DNA sequence differences among primates for genes showing different levels of expression between the sexes.

“Knowledge about gender differences is important for many reasons.  For example, this information may be used in the future to calculate medical dosages, as well as for other treatments of diseases or damage to the brain,” says team leader Professor Elena Jazin, at Uppsala University, Sweden.

In addition to the results mentioned above, the researchers also report on evolutionary speeds in genes that have been identified as male or female-oriented.  This could provide clues about the power of natural selection processes during the evolution of primates.

Lead author Björn Reinius notes that the study does not determine whether these differences in gene expression are in any way functionally significant.  Such questions remain to be answered by future studies.

Soon after an individual becomes infected with HIV the virus infects cells in the brain and spinal cord (the central nervous system [CNS]).  Although this causes no immediate problems, during the late-stages of disease it can cause dementia and encephalitis (acute inflammation of the brain that can cause death).  Monkeys infected with a relative of HIV (SIV) also sometimes develop CNS damage and provide a good model of CNS disease in individuals infected with HIV.  Insight into the mechanisms of CNS damage in SIV-infected monkeys has now been provided by a team of researchers at The Scripps Research Institute, La Jolla, who developed an approach to identify molecular changes in the fluid bathing the CNS (the CSF).  The researchers, who were led by Howard Fox and Gary Siuzdak, hope that similar approaches could be used to provide new information about other neurodegenerative and neuropsychiatric disorders.

In the study, an approach known as global metabolomics was used to assess the levels of molecules known as metabolites in the CSF before and after SIV-induced encephalitis was manifest.  The level of a number of metabolites, including some known as fatty acids and phospholipids, was observed to increase during infection.  Consistent with this, a protein known to be important in the generation of fatty acids was found to be increased in the brain of monkeys with SIV-induced encephalitis.  Further studies will be required to determine the precise role of the increased level of each metabolite, but it should be noted that many of them are known to induce receptor signaling and thereby might be able to further modulate CNS function.

A study by Indiana University researchers found a strong connection between the cognitive function of their elderly study participants and their postural stability — or balance. The study, which is in line with recent findings by other researchers involving the brain and balance, also found a brief questionnaire designed to probe cognitive function effective at identifying people with poorer balance. Falls are one of the most common causes of injury and death among the elderly. Motor control experts at Indiana University’s School of Health, Physical Education and Recreation are searching for a way to alert the elderly to when they become more at risk for falls before the falls occur — ideally developing a screening technique that can be conducted by physicians or other health care providers. Koichi Kitano, a doctoral student in the School of HPER’s Department of Kinesiology and lead author of the study, said the questionnaire used for their study could be conducted and scored by physicians and possibly other health care professionals. Patients could complete the questionnaire in around 15 minutes. “It’s an accessible, easy tool to identify people with risk,” he said. Kitano said IU researchers want to continue their research with larger numbers of people and more diverse populations — the current study involved 28 residents ranging in age from 80 to 90. Researchers at the School of HPER are also looking into stretches and exercises that could help the elderly improve their balance. Kitano said, however, that cognitive exercises might be even more effective.

A study released today reveals a cellular mechanism involved in alcohol dependence. The study, in the May 28 issue of The Journal of Neuroscience, shows that gabapentin, a drug used to treat chronic pain and epilepsy, reduces alcohol intake in alcohol-dependent rats by normalizing chemical communication between neurons, which is altered by chronic alcohol abuse.

The central amygdala, a part of the brain involved in emotions such as stress and fear, is important in regulating alcohol consumption. Most central amygdala neurons communicate via a chemical signal known as GABA, which is an inhibitory neurotransmitter. Alcohol dependence has been associated with the strengthening of inhibitory synapses in this brain region.

Gabapentin (known commercially as Neurontin) is structurally similar to GABA and increases GABA neurotransmission. In alcoholics, gabapentin has been shown to effectively treat alcohol withdrawal and reduce alcohol consumption and cravings following detoxification. However, how gabapentin acts in the brain to combat alcohol dependence has been unclear.

The study’s authors, led by Marisa Roberto, PhD, at the The Scripps Research Institute, made rats dependent on alcohol by chronically exposing them to ethanol in an aerosol or in their food. They then tested how much alcohol the rats voluntarily drank and examined neural signaling in the central amygdala.

The study authors found that gabapentin reduced alcohol intake in rats chronically exposed to alcohol, but not in rats that were chronically unexposed. Gabapentin reduced alcohol intake in alcohol-dependent rats whether it was given systemically or infused directly into the central amygdala, supporting the importance of the central amygdala in alcohol dependence.

“What I find to be important about this paper is that gabapentin’s effect on alcohol consumption is only seen in alcohol-dependent rats,” said Julie Blendy, PhD, at the University of Pennsylvania, an expert unaffiliated with the study. “For me, this speaks volumes to the addiction field, in that therapeutic targets for addiction—which have been few and far between—may be missed when examined in animal studies that use only minor exposures of alcohol,” said Blendy.

Gabapentin corrected the cellular effects of chronic alcohol exposure. Both gabapentin and alcohol increase GABA neurotransmission in the central amygdala of non-alcohol-dependent rats, but in alcohol-dependent rats, gabapentin reduced it, suggesting that altered GABA neurotransmission is key to alcohol dependence.

In the study, gabapentin and chronic alcohol exposure both affected GABA B (GABAB) receptors. The authors believe that alcohol abuse alters the function of these receptors, and gabapentin may be able to counteract alcohol dependence by regulating their function.

“This study provides important mechanistic insights,” said Robert Messing, MD, at the Ernest Gallo Clinic and Research Center at the University of California at San Francisco, an expert also uninvolved with the study. “Because gabapentin is well tolerated, this paper provides a strong rationale for large clinical trials testing whether gabapentin is an effective treatment for alcoholism in both detoxified and actively drinking alcoholics,” Messing said.

A monkey has successfully fed itself with fluid, well-controlled movements of a human-like robotic arm by using only signals from its brain, researchers from the University of Pittsburgh School of Medicine report in the journal Nature. This significant advance could benefit development of prosthetics for people with spinal cord injuries and those with “locked-in” conditions such as Lou Gehrig’s disease, or amyotrophic lateral sclerosis.“Our immediate goal is to make a prosthetic device for people with total paralysis,” said Andrew Schwartz, Ph.D., senior author and professor of neurobiology at the University of Pittsburgh School of Medicine. “Ultimately, our goal is to better understand brain complexity.”

Previously, work has focused on using brain-machine interfaces to control cursor movements displayed on a computer screen. Monkeys in the Schwartz lab have been trained to command cursor movements with the power of their thoughts.

“Now we are beginning to understand how the brain works using brain-machine interface technology,” said Dr. Schwartz. “The more we understand about the brain, the better we’ll be able to treat a wide range of brain disorders, everything from Parkinson’s disease and paralysis to, eventually, Alzheimer’s disease and perhaps even mental illness.”

Using this technology, monkeys in the Schwartz lab are able to move a robotic arm to feed themselves marshmallows and chunks of fruit while their own arms are restrained. Computer software interprets signals picked up by probes the width of a human hair. The probes are inserted into neuronal pathways in the monkey’s motor cortex, a brain region where voluntary movement originates as electrical impulses. The neurons’ collective activity is then evaluated using software programmed with a mathematic algorithm and then sent to the arm, which carries out the actions the monkey intended to perform with its own limb. Movements are fluid and natural, and evidence shows that the monkeys come to regard the robotic device as part of their own bodies.

The primary motor cortex, a part of the brain that controls movement, has thousands of nerve cells, called neurons, which fire together as they contribute to the generation of movement. Because of the massive number of neurons that fire at the same time to control even the simplest of actions, it would be impossible to create probes that capture the firing pattern of each. Pitt researchers developed a special algorithm that uses limited information from about 100 neurons to fill in the missing signals.

“In our research, we’ve demonstrated a higher level of precision, skill and learning,” explained Dr. Schwartz. “The monkey learns by first observing the movement, which activates his brain cells as if he were doing it. It’s a lot like sports training, where trainers have athletes first imagine that they are performing the movements they desire.”