Powerful Function of Single Protein That Controls Neurotransmission Discovered

Scientists at Weill Cornell Medical College have discovered that the single protein -- alpha 2 delta -- exerts a spigot-like function, controlling the volume of neurotransmitters and other chemicals that flow between the synapses of brain neurons. The study, published online in Nature, shows how brain cells talk to each other through these signals, relaying thoughts, feelings and action, and this powerful molecule plays a crucial role in regulating effective communication.

In the study, the investigators also suggest how the widely used pain drug Lyrica might work. The alpha 2 delta protein is the target of this drug and the new work suggests an approach to how other drugs could be developed that effectively twist particular neurotransmitter spigots on and off to treat neurological disorders. The research findings surprised the research team, which includes scientists from University College London.

"We are amazed that any single protein has such power," says the study's lead investigator Dr. Timothy A. Ryan, professor of Biochemistry and associate professor of Biochemistry in Anesthesiology at Weill Cornell Medical College. "It is indeed rare to identify a biological molecule's function that is so potent, that seems to be controlling the effectiveness of neurotransmission."

The researchers found that alpha 2 delta determines how many calcium channels will be present at the synaptic junction between neurons. The transmission of chemical signals is triggered at the synapse by the entry of calcium into these channels, so the volume and speed of neurotransmission depends on the availability of these channels.

Researchers discovered that taking away alpha 2 delta from brain cells prevented calcium channels from getting to the synapse. "But if you add more alpha 2 delta, you can triple the number of channels at synapses," Dr. Ryan says. "This change in abundance was tightly linked to how well synapses carry out their function, which is to release neurotransmitters."

Before this study, it was known that Lyrica, which is used for neuropathic pain, seizures and fibromyalgia, binds to alpha 2 delta, but little was understood about how this protein works to control synapses.

Lifting up the Hood

Dr. Ryan is building what he calls a "shop manual" of neurological function, much of which centers on synaptic neurotransmission. In 2007 and 2008, he discovered crucial clues to how neurons repackage the chemicals used to signal across synapses. In 2011, Dr. Ryan discovered that distinct neurons differently tune the speed by which they package these chemicals. And in a recent study published April 29 in Nature Neuroscience, he described, for the first time, the molecular mechanisms at the synapse that control the release of dopamine, a crucial neurotransmitter.

"We are looking under the hood of these machines for the first time," he says. "Many neurological diseases are considered to arise from pathologies of synaptic function. The synapse is so complex; at least a few thousand genes control how they work. Repairing them through treatment requires that we understand how they work."

Dr. Ryan and his team often use two tools to conduct these studies -- they pin fluorescent tags on to molecules involved in synaptic function, and use ultra sensitive microscopy technology to watch these molecules up close and in real-time.

The researchers used the same toolkit to examine the function of calcium channels, which triggers neurotransmission. "At all synapses, the secretion of a neurotransmitter is driven by the arrival of an electric impulse, initiated by another neuron," Dr. Ryan says. When this impulse arrives at the nerve terminal it triggers the opening of calcium channels. The calcium that rushes in is the key trigger that drives a synapse to secrete its neurotransmitter.

"We have known for the past half century that calcium is a key controller of neurotransmission," he says. "Any small change in calcium influx has a big impact on neurotransmission."

Protein Acts like a Shipping Label

But the number of calcium channels at the synapse is not static. Neurons constantly replace worn out channels, and to do this, they build the channels in the neuron's cell body and then package them up and ship them to the nerve terminal. In some cases, that is a very long journey -- as much as a few feet, such as the distance between the brain and the base of the spinal cord or the length of a leg.

In the study, researchers tagged fluorescent proteins onto a gene that encodes protein that makes a calcium channel and delivered it to neurons. They then watched the progress of the newly formed channels as they made their way, from day four to day seven, from the bodies of neurons to the synapse.

They also manipulated the levels of alpha 2 delta, a suspected calcium channel partner, and discovered that when the protein was increased, more calcium channels were moved to the synapse. Less alpha 2 delta reduced the flow. "We discovered that alpha 2 delta made the decision of how many calcium channels should be shipped the length of the neuron to the synapse," Dr. Ryan says. "It's like the channels couldn't be transported without an alpha 2 delta shipping label."

The research team found however that alpha 2 delta must work in at least two steps. When they impaired a piece of alpha 2 delta that resembles proteins that are involved in how cells bind to each other, they found that this broken alpha 2 delta could still help get calcium channels shipped down to synapses. But once there, they no longer helped drive neurotransmitter release. "This means that not only does alpha 2 delta help to get calcium channels shipped out, but it also implies that something at the synapse has to sign-off on receiving the calcium channels, putting them in the right place for them to do their job," Dr. Ryan says.

The researchers suggest that Lyrica might work by interfering with this final step since the piece of alpha 2 delta they "broke" that prevents the signing-off resembles parts of proteins that allows them to stick to each other in a kind of handshake.

These findings suggest that future therapies designed to manipulate neurotransmission could try to target this handshaking process, Dr. Ryan says. To do this will require that researchers identify the missing partner in the handshake.

"We hope these exciting findings are providing a new direction in how to make better drugs to control communication between brain cells," Dr. Ryan says.

The study was funded by the National Institutes of Mental Health and the Welcome Trust. Co-authors of the study include Dr. Michael B. Hoppa from Weill Cornell Medical College, and Dr. Beatrice Lana, Dr. Wojciech Margas, and Dr. Annette C. Dolphin from University College London.

Source: NewYork-Presbyterian Hospital/Weill Cornell Medical Center/Weill Cornell Medical College [May 13, 2012]

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Could brain size determine whether you are good at maintaining friendships?

Researchers are suggesting that there is a link between the number of friends you have and the size of the region of the brain – known as the orbital prefrontal cortex – that is found just above the eyes. A new study, published today in the journal Proceedings of the Royal Society B, shows that this brain region is bigger in people who have a larger number of friendships. 

The research was carried out as part of the British Academy Centenary ‘Lucy to Language’ project, led by Professor Robin Dunbar of the University of Oxford in a collaboration with Dr Penny Lewis at The University of Manchester, Dr Joanne Powell and Dr Marta Garcia-Finana at Liverpool University, and Professor Neil Roberts at Edinburgh University. 

The study suggests that we need to employ a set of cognitive skills to maintain a number of friends (and the keyword is ‘friends’ as opposed to just the total number of people we know). These skills are described by social scientists as ‘mentalising’ or ‘mind-reading’– a capacity to understand what another person is thinking, which is crucial to our ability to handle our complex social world, including the ability to hold conversations with one another. This study, for the first time, suggests that our competency in these skills is determined by the size of key regions of our brains (in particular, the frontal lobe). 

Professor Dunbar, from the Institute of Cognitive and Evolutionary Anthropology, explained: “’Mentalising’ is where one individual is able to follow a natural hierarchy involving other individuals’ mind states. For example, in the play ‘Othello’, Shakespeare manages to keep track of five separate mental states: he intended that his audience believes that Iago wants Othello to suppose that Desdemona loves Cassio [the italics signify the different mind states]. Being able to maintain five separate individuals’ mental states is the natural upper limit for most adults.” 

The researchers took anatomical MR images of the brains of 40 volunteers at the Magnetic Resonance and Image Analysis Research Centre at the University of Liverpool to measure the size of the prefrontal cortex, the part of the brain used in high-level thinking. Participants were asked to make a list of everyone they had had social, as opposed to professional, contact with over the previous seven days. They also took a test to determine their competency in mentalising.  

Professor Dunbar said: “We found that individuals who had more friends did better on mentalising tasks and had more neural volume in the orbital frontal cortex, the part of the forebrain immediately above the eyes. Understanding this link between an individual’s brain size and the number of friends they have helps us understand the mechanisms that have led to humans developing bigger brains than other primate species. The frontal lobes of the brain, in particular, have enlarged dramatically in humans over the last half million years.” 

Dr Penny Lewis, from the School of Psychological Sciences at The University of Manchester, said: “Both the number of friends people had and their ability to think about other people’s feelings predicted the size of this same small brain area. This not only suggests that we’ve found a region which is critical for sociality, it also shows that the link between brain anatomy and social success is much more direct than previously believed.” 

Dr Joanne Powell, from the Department of Psychology, University of Liverpool, said: “Perhaps the most important finding of our study is that we have been able to show that the relationship between brain size and social network size is mediated by mentalising skills. What this tells us is that the size of your brain determines your social skills, and it is these that allow you to have many friends.” 

Dr Lewis added: “This research is particularly important because it provides the strongest support to date for the social brain hypothesis – that is, the idea that human brains evolved to accommodate the social demands of living in a big group. Cross-species comparisons between various monkey brains have already supported this, but our work is some of the first to show that people with larger social groups actually have more neural matter in this particular bit of cortex. It looks as though size really does matter when it comes to social success.” 

Source: University of Manchester [February 02, 2012]

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Why the brain is more reluctant to function as we age

New findings, led by neuroscientists at the University of Bristol and published this week in the journal Neurobiology of Aging, reveal a novel mechanism through which the brain may become more reluctant to function as we grow older. 

It is not fully understood why the brain's cognitive functions such as memory and speech decline as we age. Although work published this year suggests cognitive decline can be detectable before 50 years of age. The research, led by Professor Andy Randall and Dr Jon Brown from the University's School of Physiology and Pharmacology, identified a novel cellular mechanism underpinning changes to the activity of neurones which may underlie cognitive decline during normal healthy aging. 

The brain largely uses electrical signals to encode and convey information. Modifications to this electrical activity are likely to underpin age-dependent changes to cognitive abilities. 

The researchers examined the brain's electrical activity by making recordings of electrical signals in single cells of the hippocampus, a structure with a crucial role in cognitive function. In this way they characterised what is known as "neuronal excitability" — this is a descriptor of how easy it is to produce brief, but very large, electrical signals called action potentials; these occur in practically all nerve cells and are absolutely essential for communication within all the circuits of the nervous system. 

Action potentials are triggered near the neurone's cell body and once produced travel rapidly through the massively branching structure of the nerve cell, along the way activating the synapses the nerve cell makes with the numerous other nerve cells to which it is connected. 

The Bristol group identified that in the aged brain it is more difficult to make hippocampal neurones generate action potentials. Furthermore they demonstrated that this relative reluctance to produce action potential arises from changes to the activation properties of membrane proteins called sodium channels, which mediate the rapid upstroke of the action potential by allowing a flow of sodium ions into neurones. 

Professor Randall, Professor in Applied Neurophysiology said: "Much of our work is about understanding dysfunctional electrical signalling in the diseased brain, in particular Alzheimer's disease. We began to question, however, why even the healthy brain can slow down once you reach my age. Previous investigations elsewhere have described age-related changes in processes that are triggered by action potentials, but our findings are significant because they show that generating the action potential in the first place is harder work in aged brain cells. 

"Also by identifying sodium channels as the likely culprit for this reluctance to produce action potentials, our work even points to ways in which we might be able modify age-related changes to neuronal excitability, and by inference cognitive ability." 

Source: University of Bristol [February 01, 2012]

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Scientists decode how the brain hears words

US scientists said Wednesday they have found a way to decode how the brain hears words, in what researchers described as a major step toward one day helping people communicate after paralysis or stroke. 

These images courtesy of the Center for Vital Longevity, The University of Texas at Dallas, show positron emission tomography scans of the brains of healthy adults showing low (L) and high (R) levels of beta-amyloid protein. US scientists said Wednesday they have found a way to decode how the brain hears words [Credit: AFP]

By placing electrodes on the brains of research subjects and then having them listen to conversations, scientists were able to analyze the sound frequencies registered and figure out which words they were hearing. 

"We were focused on how the brain processes the sounds of speech," researcher Brian Pasley of the Helen Wills Neuroscience Institute at the University of California Berkeley told AFP. 

"Most of the information in speech is between one to 8,000 hertz. Essentially the brain analyzes those different sound frequencies in somewhat separate locations." 

By tracking how and where the brain registered sounds in the temporal lobe -- the center of the auditory system -- scientists were able to map out the words and then recreate them as heard by the brain. 

"When a particular brain site is being activated, we know that roughly corresponds to some sound frequency that the patient is actually listening to," Pasley said. 

"So we could map that out to an extent that would allow us to use that brain activity to resynthesize the sound from the frequencies we were guessing." 

One word the researchers mapped was "structure." The high-frequency "s" sound showed up as a certain pattern in the brain, while the lower harmonics of the "u" sound appeared as a different pattern. 

"There is to some extent a correspondence between these features of sound and the brain activity that they cause," and putting together the physical registry in the brain helped rebuild the words, Pasley explained. 

The work builds on previous research in ferrets, in which scientists read to the animals and recorded their brain activity. 

They were able to decode which words the creatures heard even though the ferrets themselves didn't understand the words. 

The next step for researchers is to figure out just how similar the process of hearing sounds may be to the process of imagining words and sounds. 

That information could one day help scientists determine what people want to say when they cannot physically speak. 

Some previous research has suggested there may be similarities, but much more work needs to be done, Pasley said. 

"This is huge for patients who have damage to their speech mechanisms because of a stroke or Lou Gehrig's disease and can't speak," co-author Robert Knight, a UC Berkeley professor of psychology and neuroscience, said in a statement. 

"If you could eventually reconstruct imagined conversations from brain activity, thousands of people could benefit." 

Participating researchers came from the University of Maryland, UC Berkeley and Johns Hopkins University in Baltimore, Maryland. 

The study appears in the January 31 edition of the open access journal PLoS Biology. 

Author: Kerry Sheridan | Source: AFP [February 01, 2012]

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Music training has biological impact on aging process

Age-related delays in neural timing are not inevitable and can be avoided or offset with musical training, according to a new study from Northwestern University. The study is the first to provide biological evidence that lifelong musical experience has an impact on the aging process. 

Measuring the automatic brain responses of younger and older musicians and non-musicians to speech sounds, researchers in the Auditory Neuroscience Laboratory discovered that older musicians had a distinct neural timing advantage. 

"The older musicians not only outperformed their older non-musician counterparts, they encoded the sound stimuli as quickly and accurately as the younger non-musicians," said Northwestern neuroscientist Nina Kraus. "This reinforces the idea that how we actively experience sound over the course of our lives has a profound effect on how our nervous system functions." 

Kraus, professor of communication sciences in the School of Communication and professor of neurobiology and physiology in the Weinberg College of Arts and Sciences, is co-author of "Musical experience offsets age-related delays in neural timing" published online in the journal Neurobiology of Aging. 

"These are very interesting and important findings," said Don Caspary, a nationally known researcher on age-related hearing loss at Southern Illinois University School of Medicine. "They support the idea that the brain can be trained to overcome, in part, some age-related hearing loss." 

"The new Northwestern data, with recent animal data from Michael Merzenich and his colleagues at University of California, San Francisco, strongly suggest that intensive training even late in life could improve speech processing in older adults and, as a result, improve their ability to communicate in complex, noisy acoustic environments," Caspary added. 

Previous studies from Kraus' Auditory Neuroscience Laboratory suggest that musical training also offset losses in memory and difficulties hearing speech in noise -- two common complaints of older adults. The lab has been extensively studying the effects of musical experience on brain plasticity across the life span in normal and clinical populations, and in educational settings. 

However, Kraus warns that the current study's findings were not pervasive and do not demonstrate that musician's have a neural timing advantage in every neural response to sound. "Instead, this study showed that musical experience selectively affected the timing of sound elements that are important in distinguishing one consonant from another." 

The automatic neural responses to speech sounds delivered to 87 normal-hearing, native English-speaking adults were measured as they watched a captioned video. "Musician" participants began musical training before age 9 and engaged consistently in musical activities through their lives, while "non-musicians" had three years or less of musical training.  

Source: Northwestern University [January 30, 2012]

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Making memories last

Memories in our brains are maintained by connections between neurons called "synapses". But how do these synapses stay strong and keep memories alive for decades? Neuroscientists at the Stowers Institute for Medical Research have discovered a major clue from a study in fruit flies: Hardy, self-copying clusters or oligomers of a synapse protein are an essential ingredient for the formation of long-term memory. 

Drosophila Orb2 plays an important role in the persistence of memory. Upon stimulation, Orb2 (shown in yellow) forms amyloid-like oligomers (shown in red), which are an essential ingredient for the formation of long-term memory [Credit: Illustration: Nicolle Rager Fuller, Sayo-Art]

The finding supports a surprising new theory about memory, and may have a profound impact on explaining other oligomer-linked functions and diseases in the brain, including Alzheimer's disease and prion diseases. 

"Self-sustaining populations of oligomers located at synapses may be the key to the long-term synaptic changes that underlie memory; in fact, our finding hints that oligomers play a wider role in the brain than has been thought," says Kausik Si, Ph.D., an associate investigator at the Stowers Institute, and senior author of the new study, which is published in the January 27, 2012 online issue of the journal Cell. 

Si's investigations in this area began nearly a decade ago during his doctoral research in the Columbia University laboratory of Nobel-winning neuroscientist Eric Kandel. He found that in the sea slug Aplysia californica, which has long been favored by neuroscientists for memory experiments because of its large, easily-studied neurons, a synapse-maintenance protein known as CPEB (Cytoplasmic Polyadenylation Element Binding protein) has an unexpected property. 

A portion of the structure is self-complementary and—much like empty egg cartons—can easily stack up with other copies of itself. CPEB thus exists in neurons partly in the form of oligomers, which increase in number when neuronal synapses strengthen. These oligomers have a hardy resistance to ordinary solvents, and within neurons may be much more stable than single-copy "monomers" of CPEB. They also seem to actively sustain their population by serving as templates for the formation of new oligomers from free monomers in the vicinity. 

CPEB-like proteins exist in all animals, and in brain cells they play a key role in maintaining the production of other synapse-strengthening proteins. Studies by Si and others in the past few years have hinted that CPEB's tendency to oligomerize is not merely incidental, but is indeed essential to its ability to stabilize longer-term memory. "What we've lacked till now are experiments showing this conclusively," Si says. 

In the new study, Si and his colleagues examined a Drosophila fruit fly CPEB protein known as Orb2. Like its counterpart in Aplysia, it forms oligomers within neurons. "We found that these Orb2 oligomers become more numerous in neurons whose synapses are stimulated, and that this increase in oligomers happens near synapses," says lead author Amitabha Majumdar, Ph.D., a postdoctoral researcher in Si's lab. 

The key was to show that the disruption of Orb2 oligomerization on its own impairs Orb2's function in stabilizing memory. Majumdar was able to do this by generating an Orb2 mutant that lacks the normal ability to oligomerize yet maintains a near-normal concentration in neurons. Fruit flies carrying this mutant form of Orb2 lost their ability to form long-term memories. "For the first 24 hours after a memory-forming stimulus, the memory was there, but by 48 hours it was gone, whereas in flies with normal Orb2 the memory persisted," Majumdar says. 

Si and his team are now following up with experiments to determine for how long Orb2 oligomers are needed to keep a memory alive. "We suspect that they need to be continuously present, because they are self-sustaining in a way that Orb2 monomers are not," says Si. 

The team's research also suggests some intriguing possibilities for other areas of neuroscience. This study revealed that Orb2 proteins in the Drosophila nervous system come in a rare, highly oligomerization-prone form (Orb2A) and a much more common, much less oligomerization-prone form (Orb2B). "The rare form seems to be the one that is regulated, and it seems to act like a seed for the initial oligomerization, which pulls in copies of the more abundant form," Si says. "This may turn out to be a basic pattern for functional oligomers." 

The findings may help scientists understand disease-causing oligomers too. Alzheimer's, Parkinson's and Huntington's disease, as well as prion diseases such as Creutzfeldt-Jakob disease, all involve the spread in the brain of apparently toxic oligomers of various proteins. One such protein, strongly implicated in Alzheimer's disease, is amyloid beta; like Orb2 it comes in two forms, the highly oligomerizing amyloid-beta-42 and the relatively inert amyloid-beta-40. Si's work hints at the possibility that oligomer-linked diseases are relatively common in the brain because the brain evolved to be relatively hospitable to CPEB proteins and other functional oligomers, and thus has fewer mechanisms for keeping rogue oligomers under control. 

Source: Stowers Institute for Medical Research [January 27, 2012]

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New Insights on Left Brain/Right Brain Paradigm

The left brain/right brain dichotomy has been prominent on the pop psychology scene since Nobel Laureate Roger Sperry broached the subject in the 1960s. The left is analytical while the right is creative, so goes the adage. 

And then there is the quasi-scientific obsession with "the face." Facial recognition technology and facial microexpressions are the stuff of television crime dramas, such as Person of Interest and Lie to Me. 

But Ming Meng, an assistant professor in the Department of Psychological and Brain Sciences at Dartmouth College, has brought these two together in a way that offers new insights into the organization of the brain with implications for autism. 

Meng and his colleagues have published their findings January 4 in the online edition of the Proceedings of the Royal Society B (Biological Sciences). 

Meng's novel approach is to combine functional magnetic resonance imaging (fMRI), computer vision, and psychophysics to take our understanding of brain function in a new direction. He was able to assign distinct complementary aspects of visual information processing to each side of the brain. Meng is interested in perception and considers vision its major domain. His research focuses on how the brain is organized to process visual information. 

The traditional approach to visual information processing has been to view it as an ordered sequence. In the early stages of processing, the right side of the brain was thought to process the left visual field and vice versa, whereas in later stages of processing the right and the left brain process the whole visual field in parallel. 

"I find such organization puzzling in terms of efficiency with both parts of the brain effectively processing the same thing—a waste of resources," says Meng. Instead, he proposes a division of labor with right side and left doing different things. 

Looking at how the brain processes faces is Meng's key to unlocking the mysteries of the left brain/right brain paradigm. 

The left and right fusiform gyri (spindle-shaped sections) of the temporal lobes were known to be the places where facial stimuli were processed, and Meng homed in here. "I wondered what the difference might be between the left brain and the right in processing the human face and this was the place to look," he says. 

But first he looked to computer-generated images for his experimental materials. Meng felt that fMRI measurement of his test subjects' reactions only to images of faces versus non-faces offered too coarse a distinction. 

"We needed to study the full spectrum, the stimuli that makes an image look like a face but not necessarily a face. These results would show the subtle differences between the left and right side of the brain as they dealt with this range of images," he explains. A computer algorithm generated the desired range of images that he then showed to his test subjects while taking fMRI measurements of their brain activity. 

Using psychophysics as behavioral testing tools, Meng analyzed the spectrum from random non-faces to genuine faces. 

"We were able to systematically quantify the face-semblance of each of our stimuli (images). This is important because otherwise we would only have an oversimplified 'black-white' distinction between faces and non-faces, which would not be particularly useful to differentiate the functional roles of the left and right hemispheres," Meng explains. 

"Only with the psychophysical face-semblance ratings, we've found that the left is involved in the graded analysis of the visual stimuli. Our results suggest the left side of the brain is processing the external physical input which resolves into a 'grey scale' while the right brain is underlying the final decision of whether or not it is a face." 

Application of Meng's tripartite methodology that has shown the differences in the left brain/right brain picture could provide a template for studying patients with face processing deficits, as well as a new frame of reference for autism. 

Faces constitute a particular challenge for autistic children. They typically avoid eye contact, diverting their gaze from another person's face. Meng suggests that, "the underlying reason for their problems with social interaction may be correlated to their problems with face perception." 

Knowing the organization of face processing mechanisms in normal individuals provides a good starting point for exploring how this organization might be different in people with autism. 

Author: Joseph Blumberg | Source: Dartmouth College [January 04, 2012]

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Deep brain stimulation shows promising results for unipolar and bipolar depression

A new study shows that deep brain stimulation (DBS) is a safe and effective intervention for treatment-resistant depression in patients with either unipolar major depressive disorder (MDD) or bipolar ll disorder (BP). The study was published Online First by Archives of General Psychiatry, one of the JAMA/Archives journals. 

The study was led by Helen S. Mayberg, MD, professor in the Departments of Psychiatry and Behavioral Sciences and Neurology at Emory University School of Medicine, with co-investigators Paul E. Holtzheimer, MD, lead psychiatrist and now associate professor and director of the Mood Disorders Service, Dartmouth Medical School, and neurosurgeon Robert E. Gross, MD, PhD, associate professor in the Departments of Neurosurgery and Neurology at Emory. Gross served as chief neurosurgeon for the study. 

"Depression is a serious and debilitating medical illness," says Mayberg. "When we found that the potential for effective and sustained antidepressant response with DBS for patients with otherwise treatment resistant major depressive disorder was high, the next step was to determine if patients with intractable bipolar depression could also be successfully treated." 

An earlier study by Mayberg done in Toronto in collaboration with scientists at Toronto Western Hospital, University Health Network and Emory, was the first to show such results for patients with treatment-resistant major depressive disorder. Mayberg conducted this new expanded trial at Emory to include patients with bipolar ll disorder. 

Bipolar spectrum disorder, sometimes referred to as manic-depression, is characterized by bouts of mania or hypomania alternating between episodes of depression. Although people with bipolar ll disorder do not have full manic episodes, depressive episodes are frequent and intense, and there is a high risk of suicide. A major challenge in treating bipolar depression is that many antidepressant medications may cause patients to "switch" into a hypomanic or manic episode. 

DBS uses high-frequency electrical stimulation targeted to a predefined area of the brain specific to the particular neuropsychiatric disorder. Here, each study participant was implanted with two thin wire electrodes, one on each side of the brain. The other end of each wire was connected under the skin of the patient's neck to a pulse generator implanted in the chest – similar to a pacemaker – that directs the electrical current. 

Study participants received single-blind stimulation for four weeks (patients did not know if the DBS system was on or off), followed by active stimulation for 24 weeks. Patients were evaluated for up to two years following onset of active stimulation. Seventeen patients were enrolled in the study. 

A significant decrease in depression and increase in function were associated with continuing stimulation. Remission and response rates were 18 percent and 41 percent after 24 weeks; 36 percent and 36 percent after one year and 58 percent and 92 percent after two years of active stimulation. Patients who achieved remission did not experience a spontaneous relapse. Efficacy was similar for Major Depressive Disorder and Bi-Polar patients, and no participant experienced a manic or hypomanic episode. 

Mayberg and her colleagues continue to refine this intervention. Current studies include demographic, clinical and imaging predictors of response and remission, and introduction of psychotherapeutic rehabilitation. Why and how this treatment works is the primary focus of ongoing research. 

"Most of these patients have been in a depressed state for many years and are disabled and isolated," says Holtzheimer. "As their depression improves, they need a process to help them achieve full recovery that includes integration back into society. 

"We hope to optimize the rate of improvement for these patients by using a model of care that provides psychotherapeutic rehabilitation built on evidence-based psychotherapy but tailored to the specific individual's situation."  

Source: Emory University [January 02, 2012]

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Computers implanted in brain could help paralyzed

It sounds like science fiction, but scientists around the world are getting tantalizingly close to building the mind-controlled prosthetic arms, computer cursors and mechanical wheelchairs of the future. 

Cochlear implants work under the same premise as brain devices being developed [Credit: Kendra Luck/The Chronicle]

Researchers already have implanted devices into primate brains that let them reach for objects with robotic arms. They've made sensors that attach to a human brain and allow paralyzed people to control a cursor by thinking about it. 

In the coming decades, scientists say, the field of neural prosthetics - of inventing and building devices that harness brain activity for computerized movement - is going to revolutionize how people who have suffered major brain damage interact with their world. 

"Medicine has not taken neural prosthetics very seriously until recently," said Dr. Edward Chang, a UCSF neurosurgeon and co-director of the Center for Neural Engineering and Prostheses at UC Berkeley and UCSF. "But it's become clear in the last five to 10 years that there are some practical applications." 

Jose Carmena, a neuro-engineer at UC Berkeley and Chang's co-director, puts his thoughts more succinctly: "There's going to be an explosion in neural prosthetics." 

The joint UC Berkeley and UCSF center started a year ago to take advantage of the neurology expertise in San Francisco and the engineering skills across the bay. 

Such devices that allow the brain to control a device aren't entirely new. Aside from some small steps made at other institutions - the brain-controlled computer cursor, for example - there's the cochlear implant, the first neural prosthetic tool developed and the only one that's ever seen wide use. 

The cochlear implant, which was invented at UCSF in the 1970s, intercepts sounds as electrical signals and then sends those signals directly to the brain, bypassing the damaged nerves that caused hearing loss. The devices being developed today work under the same premise but are much more complex. 

Over the past decade, scientists have made leaps of progress in learning how to read and decode the millions of electronic impulses that fire between neurons in the brain, controlling how our bodies move and how we see, feel and relate to the world around us. 

Imagine, for example, the neural effort required just to pick up a glass of red wine, Carmena said. 

Vast amount of details 

It's not enough just to prompt the right muscles to move an arm. Millions of signals in the brain help us determine where our own arm is in relation to our body, so our hand doesn't grope wildly for the glass. Our brains sense that it's a delicate glass that must be picked up carefully, pinched between fingers. The neurons control how fast our arm moves, making sure the wine doesn't slop over the edges. 

That's an astronomical amount of communication happening, all in fractions of a second, without our even being aware of it. In fact, it's more communication than our best smart-phone technology can handle. 

"We don't have existing electronics to be able to process in real time dozens of channels from the brain," Chang said. "It turns out we need a lot of information from the brain to work." 

The neural prosthetic devices that are just in their infancy now work by connecting a device inserted into the brain directly to a computer. The signals from the brain, in the form of electrical impulses, travel through a cable to the computer, where they are decoded into instructions for some kind of action, like moving a cursor. 

But for a neural prosthetic device to actually be useful, it would have to be transplanted near or in the brain and transmit wireless signals to a device like a robotic arm. It would need to be able to last forever - or at least a lifetime - on batteries that never have to be changed and won't damage the brain. 

Scientists say the actual technology is only one problem. 

"Some of the problems are purely technical, like how do you record from hundreds and hundreds of neurons at the same time," said Philip Sabes, a neuroscientist at the Keck Center for Integrative Neuroscience at UCSF. 

Other problems are going to require an even deeper understanding of how the brain works. Scientists don't yet know what parts of the brain would be best suited for implanting a device to read electrical signals - or even whether an implanted device would work better than one that's attached to the brain's surface. 

It's possible that a surface device could collect enough information to be useful in controlling a neural prosthesis with much less risk to the patient. 

'Sense of ownership' 

But it may be that scientists need to implant a device into the brain to collect enough of the brain signals, especially for creating a prosthetic device that feels natural - a robotic arm, perhaps, that can sense hot and cold, or the difference between a wine glass and a coffee mug. 

"You want the arm to feel like it's a part of you, not this thing you're picking up," Sabes said. "It will increase the sense of ownership of the device." 

A major part of Chang's research is determining what devices would actually be useful to patients. He knows that some scientists are studying exoskeletons that may allow paralyzed people to walk someday, but he wonders if that's a truly feasible device. 

Patients may be better served by a simple computer cursor that is highly responsive to their minds and doesn't require intense, focused concentration to move, Chang said. For a person who is completely paralyzed, just being able to send and read e-mails may be life changing. 

"Controlling a robotic body, that's the dream. But it's not my dream," Chang said. "I'm not sure that kind of thing is the most useful for people. I want to find out what are the things that are going to be most useful for people, and it may be as simple as communication." 

Author: Erin Allday | Source: San Francisco Chronicle [December 27, 2011]

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Scientists succeed in making the spinal cord transparent

In the event of the spinal cord injury, the long nerve cell filaments, the axons, may become severed. For quite some time now, scientists have been investigating whether these axons can be stimulated to regenerate. Such growth takes place on a scale of only a few millimetres. To date, changes like this could be determined only by cutting the tissue in question into wafer-thin slices and examining these under a microscope. 

A spinal cord as if made of glass: The new method enables scientists to see nerve cell in the intact cellular network Credit:© MPI of Neurobiology / Erturk]

However, the two-dimensional sections provide only an inaccurate picture of the spatial distribution and progression of the cells. Together with an international team, scientists at the Max Planck Institute for Neurobiology in Martinsried have now developed a new method by virtue of which single nerve cells can be both examined in intact tissue and portrayed in all three dimensions. 

The spinal cord is the most important pathway for relaying information from the skin, muscles and joints to the brain and back again. Damage to nerve cells in this region usually results in irreversible paralysis and loss of sensation. For many years, scientists have been doing their best to ascertain why nerve cells refuse to regenerate. They search for ways to stimulate these cells to resume their growth. 

To establish whether a single cell is growing, the cell must be visible in the first place. Up to now, the procedure has been to cut the area of the spinal cord required for examination into ultra-thin slices. These are then examined under a microscope and the position and pathway of each cell is reconstructed. In exceptional cases, scientists could go to the trouble of first digitizing each slice and then reassembling the images, one by one, to produce a virtual 3D model. 

However, this is a very time-consuming endeavour, requiring days and sometimes even weeks to process the results of just one examination. Even worse, mistakes can easily creep in and falsify the results: The appendages of individual nerve cells might get squashed during the process of slicing, and the layers might be ever so slightly misaligned when set on top of each other. 

As Frank Bradke explains: "Although this might not seem dramatic to begin with it prevents us from establishing the length and extent of growth of single cells." Bradke and his team at the Max Planck Institute of Neurobiology have investigated the regeneration of nerve cells following injuries to the spinal cord. Since July he has been working at the German Centre for Neurodegenerative Diseases (DZNE) in Bonn. "However, since changes on this crucial scale are precisely what we need to see, we worked meticulously until we came up with a better technique", he continues. 

The new technique is based on a method known as ultramicroscopy, which was developed by Hans Ulrich Dodt from the Technical University of Vienna. The Max Planck neurobiologists and an international team of colleagues have now taken this technique a step further. 

The principle is relatively straightforward. Spinal cord tissue is opaque due to the fact that the water and the proteins contained in it refract light differently. Thus, the scientists removed the water from a piece of tissue and replaced it by an emulsion that refracts light in exactly the same way as the proteins. This left them with a completely transparent piece of tissue. 

"It's the same effect as if you were to spread honey onto textured glass", Ali Erturk, the study's first author adds. The opaque pane becomes crystal clear as soon as the honey has compensated for the surface irregularities. 

The new method is a leap forward in regeneration research. By using fluorescent dyes to stain individual nerve cells, scientists can now trace their path from all angels in an otherwise transparent spinal cord section. This enables them to ascertain once and for all whether or not these nerve cells recommenced their growth following injury to the spine – an essential prerequisite for future research. 

"The really great thing is the fact that this method can also be easily applied to other kinds of tissue", Frank Bradke relates. For example, the blood capillary system or the way a tumour is embedded in tissue could be portrayed and analysed in 3D. 

Source: Max-Planck-Gesellschaft [December 25, 2011]

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Sea snails help scientists explore a possible way to enhance memory

Efforts to help people with learning impairments are being aided by a species of sea snail known as Aplysia californica. The mollusk, which is used by researchers to study the brain, has much in common with other species including humans. Research involving the snail has contributed to the understanding of learning and memory. 

At The University of Texas Health Science Center at Houston (UTHealth), neuroscientists used this animal model to test an innovative learning strategy designed to help improve the brain's memory and the results were encouraging. It could ultimately benefit people who have impairments resulting from aging, stroke, traumatic brain injury or congenital cognitive impairments. 

The proof-of-principle study was published on the Nature Neuroscience website on Dec. 25. The next steps in the research may involve tests in other animal models and eventually humans. 

The strategy was used to identify times when the brain was primed for learning, which in turn facilitated the scheduling of learning sessions during these peak periods. The result was a significant increase in memory. 

"We found that memory could be enhanced appreciably," said John H. "Jack" Byrne, Ph.D., senior author and chair of the Department of Neurobiology and Anatomy at the UTHealth Medical School. 

Building on earlier research that identified proteins linked to memory, the investigators created a mathematical model that tells researchers when the timing of the activity of these proteins is aligned for the best learning experience. 

Right now, the scheduling of learning sessions is based on trial and error and is somewhat arbitrary. If the model proves effective in follow-up studies, it could be used to identify those periods when learning potential is highest. 

"When you give a training session, you are starting several different chemical reactions. If you give another session, you get additional effects. The idea is to get the sessions in sync," Byrne said. "We have developed a way to adjust the training sessions so they are tuned to the dynamics of the biochemical processes." 

Two groups of snails received five learning sessions. One group received learning sessions at irregular intervals as predicted by a mathematical model. Another group received training sessions in regular 20-minute intervals. 

Five days after the learning sessions were completed, a significant increase in memory was detected in the group that was trained with a schedule predicted by a computer. But, no increase was detected in the group with the regular 20-minute intervals. 

The computer sorted through 10,000 different permutations in order to determine a schedule that would enhance memory. 

To confirm their findings, researchers analyzed nerve cells in the brain of snails and found greater activity in the ones receiving the enhanced training schedule, said Byrne, the June and Virgil Waggoner Chair of Neurobiology and Anatomy at UTHealth. 

"This study shows the feasibility of using computational methods to assist in the design of training schedules that enhance memory," Byrne said.  

Source: University of Texas Health Science Center at Houston [December 25, 2011]

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Understanding the mechanical biology of life's bonds

When he was 10 years old, Julio Fernandez took a correspondence course in electronics and earned a certificate for putting together a doorbell. Today, the Columbia professor of biological sciences builds and takes apart proteins, the building blocks of the body which, when they bond improperly, may cause disease. 

Traditionally, scientists study proteins in a test tube, a method that Fernandez believes does not offer an accurate enough picture of complex body biochemistry. “In a test tube how would you know what’s happening to something that requires mechanical force to extend and relax?” he says, referring to the stretching and contracting that happens to proteins when they bond with one another in the body. “You have to study proteins and biological molecules in an environment as close to their native condition as possible.” 

To that end, Fernandez has spent his career developing a new field—mechanical biology—to understand organic substances with tools from physics, engineering and computer science. His team in the Northwest Corner building builds its own equipment, engineers its own proteins and writes its own computer programs to analyze the data. Though the students each have academic specialties, many have picked up expertise on the job in other disciplines. 

In a paper published in the October edition of Nature Chemistry, Fernandez’s team made the first direct observation of how disulfide bonds reshuffle within a protein. Disulfide bonds play a central role in controlling the elasticity of tissues. They used an atomic force microscope, a device developed by physicists in the 1980s to study items such as computer chips at the nanoscale, but adapted by his team to examine biological substances. 

“Think of a protein as a rope tied up in a knot that is held together by a disulfide bond,” explains Pallav Kosuri, a Ph.D. student on Fernandez’s team. “Someone breaks the disulfide bond and the knot can now unfurl. We’re watching knots unfurl in a single protein molecule.” The team placed proteins on the examining surface of the atomic force microscope, which is fitted with a sensitive tip that is more than a thousand times sharper than the thickness of a human hair. The tip is attached to the protein, and a laser is used to record the exact position of the tip as the knot unfurls—or when the protein bonds reshuffle. 

Disulfide bonds occur in nearly 30 percent of proteins; because they’re so prevalent, scientists believe their interactions may be clues to unraveling a broad range of illnesses, from infectious disease to cancer. Viruses, for example, interact with human cells through proteins that contain disulfide bonds. Marfan Syndrome is a disorder in which fibrillin, a disulfide-bonded protein in connective tissue, malfunctions. Symptoms may include extraordinarily stretchy skin, and in heart tissue, a faulty elasticity that can affect healthy blood flow. 

As a physics student at the University of Chile, Fernandez met a group of neuroscientists from Los Angeles studying a squid native to the shores of that South American country. They lured Fernandez to the UCLA School of Medicine, where he received his Ph.D. in physiology and was a post-doctoral research fellow. Following appointments at the Max Planck Institute, the University of Pennsylvania’s School of Medicine and the Mayo Foundation, Fernandez came to Columbia in 2002. 

His lab is currently at work studying how muscle elasticity works. They’re also trying to understand the elasticity of the main receptor implicated in HIV infection—another protein with disulfide bonds. “We’re trying to revolutionize protein biochemistry from the point of view of mechanical forces,” he says. 

Author: Beth Kwon | Source: Columbia University [December 21, 2011]

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How the brain cell works

University of Miami biology professor Akira Chiba is leading a multidisciplinary team to develop the first systematic survey of protein interactions within brain cells. The team is aiming to reconstruct genome-wide in situ protein-protein interaction networks (isPIN) within the neurons of a multicellular organism. Preliminary data were presented at the American Society for Cell Biology annual meeting, December 3 through 7, 2011, in Denver, Colorado. 

At the core of the new imaging technology is the phenomenon known as FRET that occurs only when two fluorescently tagged molecules come within the distance of eight nanometer or less. Detecting the FRET serves as a proxy for the two proteins X and Y associating with each other within a living cell [Credit: A. Chiba/University of Miami]

"This work brings us closer to understanding the mechanics of molecules that keep us functioning," says Chiba, principal investigator of this project. "Knowing how our cells work will improve medicine. Most importantly, we will gain a better understanding of what life is at the molecular level." 

Neurons are the cells that are mainly responsible for signaling in the brain. Like all other cells, each neuron produces millions of individual proteins that associate with one another and form a complex communication network. Until recently, observing these protein-protein interactions had not been possible due to technical difficulties. Individual proteins are small and typically less than 10 nm (nanometer) in diameter. Yet, this nano-scale distance was considered to be off-limits even with super-resolution microscopy. 

Now, Chiba and his collaborators have developed a novel methodology to examine interaction of individual proteins in the fruit fly – the model organism of choice for this project. The researchers are creating genetically engineered insects that are capable of expressing over 500 fluorescently-tagged assorted proteins, two at a time. The fluorescent tags make it possible to visualize the exact spot where a given pair of proteins associates with each other. 

The team utilizes a custom- built 3D FLIM (fluorescent lifetime imaging microscopy) system to quantify this association event within the cells of a live animal. FLIM shows the location and time of such protein interaction, providing the data that allow creation of a point-by-point map of protein-protein interactions. 

The pilot phase of this multidisciplinary project is being funded by the National Institutes of Health. It employs advanced genetics, molecular imaging technology and high-performance computation, among other fields. "Collaborating fluorescent chemistry, laser optics and artificial intelligence, my team is working in the 'jungle' of the molecules of life within the living cells," Chiba says. "This is a new kind of ecology played out at the scale of nanometers—creating a sense of deja vu 80 years after the birth of modern ecology." 

At present, the researchers still need to extrapolate from data obtained in test tubes. In the future, they will begin to visualize directly how the individual proteins interact with one another in their 'native environment,' which are the cells in our body.  

Source: University of Miami [December 21, 2011]

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Timing is key in the proper wiring of the brain

After birth, the developing brain is largely shaped by experiences in the environment. However, neurobiologists at Yale and elsewhere have also shown that for many functions the successful wiring of neural circuits depends upon spontaneous activity in the brain that arises before birth independent of external influences. 

Now Yale researchers have shown in research published online Dec. 18 in the journal Nature Neuroscience that the timing of this activity is crucial to the development of vision — and perhaps to other key neural processes that have been implicated in autism and other neurodevelopmental disorders. 

“This spontaneous activity is not dependent upon external sensory stimuli,” said Michael Crair, the William Ziegler III Associate Professor of Neurobiology and associate professor of ophthalmology and visual science and senior author of the paper. “We want to know where this activity comes from and how does it work.” 

Yale researchers tried to interfere with this spontaneous activity in neonatal mice through a technique called optogenetics – or the manipulation of brain cells genetically engineered to be activated by light. The Yale team showed that proper wiring of connections between the eye and brain depended upon exactly when this spontaneous activity occurs.  When the researchers simultaneously induced retinal activity in both eyes of a neonatal mouse, they found the visual connections did not develop properly. However, when they induced activity first in one eye and then the other, neural connections were unaffected or even enhanced. 

Crair said that rhythmic spontaneous activity has been implicated in proper development of many brain areas, including the cortex, cerebellum, and spinal cord. He said it is possible that a disruption in the timing of this spontaneous activity could play a role in a host of developmental disorders. 

“The genes thought to be involved in autism involve the formation and function of brain synapses and neural circuits, and that is exactly what is getting messed up when we interfere with brain activity early in development,” Crair said. 

Author: Bill Hathaway | Source: Yale University [December 18, 2011]

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Scientists provide potential explanation for mechanisms of associative memory

Researchers from the University of Bristol have discovered that a chemical compound in the brain can weaken the synaptic connections between neurons in a region of the brain important for the formation of long-term memories. The findings, published in the Journal of Neuroscience, may also provide a potential explanation for the loss of memory associated with Alzheimer's. 

Acetylcholine, a neurotransmitter, is released in the brain and is known to play an important role in normal brain functions such as sleep, attention, and learning and memory. Until now the mechanisms by which this transmitter controls such processes were not well understood. 

The findings, led by researchers from the University's MRC Centre for Synaptic Plasticity in the School of Physiology and Pharmacology, highlight the mechanisms by which acetylcholine controls communication between neurons located in the prefrontal cortex and may help in understanding how higher cognitive processing is controlled in this important brain area. 

Professor of Cellular Neuroscience, Zafar Bashir and his team have demonstrated how electrical stimulation of the prefrontal cortex leads to the release of acetylcholine from synaptic terminals and the subsequent weakening of synaptic connections between neurons. 

When acetylcholine is released it binds to specific receptors and starts a molecular cascade which triggers physiological alterations in how prefrontal cortical neurons are 'wired' together. The findings suggest that the persistent weakening of synaptic connections between neurons induced by the endogenous release of acetylcholine in the prefrontal cortex may underlie the formation of new associative memories. 

The authors speculate that the memory impairments associated with Alzheimer's dementia may result, in part, from a loss of synaptic plasticity in the prefrontal cortex related to the depletion of brain acetylcholine that occurs in the disease. 

Dr Douglas Caruana, who carried out the experiments, said: "Disruptions in cholinergic signaling in the prefrontal cortex are known to affect how the brain encodes lasting associations between objects and places, and a depletion of brain acetylcholine levels in the cortex is a classic hallmark of Alzheimer's dementia'." 

Professor Bashir added: "Acetylcholinesterase inhibitors are the most widely used medication to treat individuals with Alzheimer's dementia and the enhancement of synaptic plasticity by acetylcholinesterase inhibition that we now demonstrate may be a way in which these drugs provide clinical efficacy." 

Source: University of Bristol [December 13, 2011]

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How We Decide

Until now, most psychology and neural imaging research have focused on how humans learn behavior through trial and error. 

However, Carnegie Mellon University neuroscientists Matthew M. Walsh and John R. Anderson have found that this view is incomplete. 

In their study published in the Proceedings of the National Academy of Sciences (PNAS), Walsh and Anderson show how the brain uses both instruction and experience to select actions. 

This identification of separate neural systems that control behavior also suggests that damage to one may not impair the other. 

"With most decisions that we make, we have access to both experience and instruction sources of information, so it is overly simplistic to just consider one," said Walsh, a doctoral student in the Department of Psychology within CMU's Dietrich College of Humanities and Social Sciences. 

"By tapping different neural learning systems, we can facilitate learning in patient populations. For example, Parkinson's disease is associated with a loss of dopamine and an impaired ability to learn from experience. Consequently, Parkinson's patients may more readily learn from instruction than experience." 

For the study, Walsh and Anderson used electroencephalography (EEG) to measure participants' neural activity during experiments designed to explore how instruction influences trial and error learning.   

The participants were shown two symbols that were assigned different reward values. Their goal was to maximize their reward by selecting the symbol that was more likely to be rewarded within each pair. 

One group received a description of the rewards before choosing, while the other group only received feedback about whether their choices were rewarded. 

The results showed that participants who did not receive instruction gradually learned from experience. Participants who did receive instruction performed perfectly from the beginning. 

Walsh and Anderson focused their analyses on the feedback-related negativity (FRN), a neural signal of reward learning. 

In striking contrast to their behavior, the FRN only developed once participants experienced outcomes in both conditions of the experiment. Thus, while instruction governed behavior, experience controlled the FRN. 

"Little research to this point has looked at how instruction engages behavior," said Walsh. 

"Our work shows that different systems in the brain control behavior, and that one system may learn from experience while the other controls responses." 

Anderson, the R.K. Mellon University Professor of Psychology and Computer Science, has spent the past three decades combining cognitive psychology research with computer science to understand how the brain works, how people learn and how computer-based instructional systems can be used as educational aids. 

For his trailblazing contributions, he received the 2011 Benjamin Franklin Medal in Computer and Cognitive Science. 

"These results highlight a striking dissociation between behavioral and neural responses. While instruction may immediately control behavior, certain neural responses must be learned from experience. Although some theories anticipate such a dissociation, this is the most direct evidence to date," said Anderson. 

Source: Carnegie Mellon University [December 12, 2011]

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