Posts Tagged neuroscience

[WEB SITE] Half the brain encodes both arm movements

October 8, 2018, Society for Neuroscience
Half the brain encodes both arm movements

Patients implanted with electrocorticography arrays completed a 3D center-out reaching task. Electrode locations were based upon the clinical requirements of each patient and were localized to an atlas brain for display (A). B. Patients were seated in the semi-recumbent position and completed reaching movements from the center to the corners of a 50cm physical cube based upon cues from LED lights located at each target while hand positions and ECoG signals were simultaneously recorded. Each patient was implanted with electrodes in a single cortical hemisphere and performed the task with the arm contralateral (C) and ipsilateral (D) to the electrode array in separate recording sessions. Credit: Bundy et al., JNeuros(2018)

Individual arm movements are represented by neural activity in both the left and right hemispheres of the brain, according to a study of epilepsy patients published in JNeurosci. This finding suggests the unaffected hemisphere in stroke could be harnessed to restore limb function on the same side of the body by controlling a brain-computer interface.

The right side of the brain is understood to control the left side of the body, and vice versa. Recent evidence, however, supports a connection between the same side of the brain and body during .

Eric Leuthardt, David Bundy, and colleagues explored brain activity during such ipsilateral movements during a reaching task in four  whose condition enabled invasive monitoring of their brains through implanted electrodes. Using a machine learning algorithm, the researchers demonstrate successful decoding of speed, velocity, and position information of both left and right arm movements regardless of the location of the electrodes.

In addition to advancing our understanding of how the brain controls the body, these results could inform the development of more effective rehabilitation strategies following brain injury.

Half the brain encodes both arm movements

In the study a patient implanted with electrodes only on the left side of the brain was asked to make movements to 8 targets in 3D space with both their right and left arms. Using recordings from these electrodes, the authors were able to predict the hand speed, direction, and position for both arms showing that movements of both arms are encoded on one side of the brain. Credit: David Bundy and Eric Leuthardt

 Explore further: New research on the brain’s backup motor systems could open door to novel stroke therapies

More information: Unilateral, Three-dimensional Arm Movement Kinematics are Encoded in Ipsilateral Human Cortex, JNeurosci (2018). DOI: 10.1523/JNEUROSCI.0015-18.2018

via Half the brain encodes both arm movements

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[WEB SITE] Is There a Science to Psychotherapy?

Neuroscience findings suggest that psychotherapy alters the brain.

Since the decade of the brain, 1990-1999, neuroscience has captured enormous amounts of attention from both the scientific community and the general public. Many books and media reports describe the brain’s basic anatomy and function. There has been a proliferation of neuroscience institutes at universities. In laboratories all over the world, neuroscience has become one of the most exciting and productive branches of inquiry.

Yet not everyone is completely pleased with what neuroscience has to tell us. In particular, some decry neuroscience for trying to delegitimize the “mind.” Going back to the original Cartesian mind-body duality, these critics insist that neuroscience can only go so far by describing the function of neurons and neurotransmitters. What cannot be reached by science, they say, is that ineffable “mind” that constitutes the human spirit. For them, neuroscience is purely an attempt to reduce the complexities and wonders of human experience to brain scan images and electrical recordings from axons and dendrites.

In a new book, Neuroscience at the Intersection of Mind and Brain (Oxford University Press, 2018), one of us (Jack) attempts to allay fears that neuroscience will somehow reduce human experience and creativity to the “mere” workings of the physical brain. There is, in fact, nothing “reductive” about the physical brain. Rather, the brain is a gloriously complex, fascinating, and well-organized structure that constitutes, as neuroscientist Eric Kandel so eloquently put it, “the organ of the mind.”

Biologists versus Psychologists

As a resident in psychiatry in the late 1970s, Jack witnessed the emergence of psychopharmacology as the dominant discipline for academic psychiatry and lived through the often bitter battles between “biologists” and “psychologists.” This may be, in part, where the mistrust of neuroscience began. The biologists believed that their method of treating psychiatric illness—medication—was based on solid science and rejected psychotherapy as unscientific.  They also believed that neuroscience explained why the new psychiatric drugs worked and therefore promoted brain science as the basis for their discipline. Every lecture about depression or schizophrenia in those days began with a picture of a pre- and postsynaptic neuron forming a synapse across which neurotransmitters like serotonin, noradrenaline, and dopamine carried information. The new medications interact with receptors for these neurotransmitters and, it was taught at the time, this explains how they work to treat depression, anxiety, and psychosis.

 Andrew Rybalko/Shutterstock

Source: Andrew Rybalko/Shutterstock

It turns out that the picture of neurons everyone used back then was a vast oversimplification of what a synapse really looks like and that almost nothing we know about neurotransmitters and their receptors actually explains how psychiatric drugs work. But what really bothered the psychologists was the complete dismissal of psychotherapy by the biologists. Years of studying various types of psychotherapy convinced them that indeed they had science on their side. Furthermore, they objected to the biologists’ emphasis on inherited abnormalities as the sole basis for psychiatric illness. Psychologists had always been more interested in the ways that human experience, from birth onwards, shaped personality and behavior.

Over time, many (but thankfully not all) psychologists came to see neuroscience as the branch of science devoted to promoting pharmacology as the only treatment for psychiatric illness and to trying to prove that those illnesses were entirely due to inherited brain abnormalities. Biologists stood with nature; psychologists with nurture.

This fear of neuroscience’s aims is entirely misplaced. Over the last several decades, neuroscience has, in fact, focused a great deal of attention on the biology of experience, elucidating the ways in which what happens to us in life affects the structure and function of the brain. Every time we see, hear, smell, or touch something, learn a new fact, or have a new experience, genes are activated in the brain, new proteins are synthesized, and neural pathways communicate the new information to multiple brain regions.

Neuroscience is not, therefore, synonymous with psychopharmacology, nor does it invalidate the complexities of human experience. It has shown, for example, that early life interactions between a parent and child shape how the brain will function for the rest of a person’s life.

This has tremendous implications for understanding the mechanism of action of psychotherapy if we accept the idea that psychotherapy itself is a form of life experience and therefore capable of changing brain function at molecular, cellular, and structural levels. Here are two examples that illustrate ways in which neuroscience informs psychotherapy.

CBT and the Prefrontal to Amygdala Connection

It is now clear that the expression of conditioned fear is dependent upon an intact, functioning amygdala. Scientists have shown that the amygdala, located in a primitive part of the brain often referred to as the limbic cortex, reciprocally inhibits and is inhibited by a more evolutionarily advanced part of the brain, the medial prefrontal cortex (mPFC). Thus, under circumstances of heightened fear, the amygdala shuts down the ability of the mPFC to exert reason over emotion and initiates a cascade of fearful responses that include increased heart rate and blood pressure and freezing in place. When the mPFC is able to reassert its capacity for logic and reason, it can, in turn, inhibit the amygdala and reduce and extinguish fear.

Cognitive behavioral therapy (CBT) is an evidence-based intervention that is the first-line treatment for most anxiety disorders and for mild, moderate, and in many cases even severe depression. Because the automatic, irrational fears and avoidance behaviors manifested by patients with anxiety disorders and depression resemble the behavior of rodents in Pavlovian fear conditioning experiments, scientists have wondered if CBT works, at least in part, by strengthening the prefrontal cortex to amygdala pathway, thereby reducing amygdala activity. Indeed, many studies have shown that anxious and depressed patients have reduced activity in this pathway and exaggerated amygdala responses to fearful stimuli. Studies have also shown that successful CBT for social anxiety disorder decreases amygdala activation.

Most recently, a group of scientists from Oxford, Harvard, and Berkeley showed clearly that stimulation of the prefrontal cortex in human volunteers both reduced amygdala activation and fear. Maria Ironside and colleagues selected 18 women with high levels of trait anxiety and randomized them to receive either transcranial direct current stimulation (tDCS) to the prefrontal cortex or sham tDCS. The subjects underwent functional magnetic resonance imaging (fMRI) of the brain and performed an attentional load task that tests vigilance to threat. Real, but not sham, tDCS increased activity in the prefrontal cortex, decreased activity in the amygdala, and decreased threat responses.

This study is one example of preclinical and clinical neuroscience coming together to suggest a biological mechanism for the efficacy of a psychosocial intervention. We know that the cognitive portion of CBT strengthens a patient’s ability to assert reason over irrational thoughts and fears and that this decreases amygdala activity in some studies. We know clearly from animal studies that stimulating the prefrontal cortex reduces amygdala activation and potentiates fear extinction. Now we also know that in a group of anxious people, direct stimulation of the prefrontal cortex does exactly the same thing as it does in animal studies and, in addition, reduces anxiety. With this plausible hypothesis for how CBT works, scientists can now push further to see if brain imaging can ultimately help select patients with particularly weak prefrontal to amygdala pathway strength who might be prime candidates for CBT and then to track how they are doing in therapy objectively by repeating the brain imaging studies to see if and when that pathway is strengthened.

Psychoanalysis and Reconsolidation

CBT has been proven effective by many high-quality clinical trials and therefore is a prime candidate for biological studies, but can the same be said for such widely used but not empirically-validated treatments as psychoanalysis and psychoanalytic psychotherapy? In 2011, Jack and his colleague, Columbia psychiatrist and psychoanalyst Steven Roose, proposed that another aspect of fear conditioning—reconsolidation of fear memories—may explain one biological mechanism of action for how psychoanalysis works. In rats, when a conditioned fear memory is reactivated, it temporarily becomes labile and can be completely erased by blocking the biological mechanisms that permit reconsolidation of the memory. Could it be that in psychoanalytic therapies, the patient undergoes a process of reactivating distressing early memories that, once made conscious through the psychoanalytic process, can be manipulated by the therapist’s interpretations? According to this hypothesis, those now altered memories can then be reconsolidated into permanent memory in a less disturbing format.

The theory has been considered since then by many scientists and psychoanalytic theorists and a number of experiments show that the phenomena of labile reactivated memories and blockade of reconsolidation do indeed occur in humans. Blocking reconsolidation of reactivated memories has been shown to be effective in experiments attempting to help addicts overcome the powerful tendency to succumb to subtle cues and resume taking drugs even after successful rehabilitation. Here again, information gained from the basic neuroscience laboratory and from clinical neuroscience studies may help us understand how one aspect of psychoanalysis works to change the brain in ways that are helpful to people suffering with mental illness.

It is not necessary to invoke an ineffable “mind” to explain our unique human characteristics. Understanding the complexity of the human brain is sufficient to reveal how we are able to take what we experience and transform it into scientific theories, poetry, and philosophical ideas. Neuroscience is not superficial or reductionistic and it is not at all in the sole service of psychopharmacology and the genetic explanation for mental disorders. This becomes clear as we recognize the tremendous contributions neuroscientists have made to elucidating basic mechanisms that allow experiences to change the physical structure and function of the brain on a second-by-second basis. Everything we experience during life is translated into events that occur in the brain.

Psychotherapy is a form of life experience that changes the way the brain works, often ameliorating abnormalities caused by adverse experience and stressful life events. So yes, there is a science to psychotherapy, one that can be readily understood by learning about some of the fundamental and fascinating ways our brains work. Neuroscience at the Intersection of Mind and Brain tries to do just that.

via Is There a Science to Psychotherapy? | Psychology Today UK

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[WEB SITE] Virtual Reality Reduces Pain and Increases Performance During Exercise – Neuroscience News

Summary: Researchers report virtual reality can help to lower pain levels and increase performance when undertaking physical activity. Participants using VR reported a pain intensity 10% lower than those not using the technology when performing isometric bicep curls.

Source: University of Kent.

The research, led by PhD candidate Maria Matsangidou from EDA, set out to determine how using VR while exercising could affect performance by measuring a raft of criteria: heart rate, including pain intensity, perceived exhaustion, time to exhaustion and private body consciousness.

To do this they monitored 80 individuals performing an isometric bicep curl set at 20% of the maximum weight they could lift, which they were then asked to hold for as long as possible. Half of the group acted as a control group who did the lift and hold inside a room that had a chair, a table and yoga mat on the floor.

The VR group were placed in the same room with the same items. They then put on a VR headset and saw the same environment, including a visual representation of an arm and the weight (see image below). They then carried out the same lift and hold as the non-VR group.

The results showed a clear reduction in perception of pain and effort when using VR technology. The data showed that after a minute the VR group had reported a pain intensity that was 10% lower than the non-VR group.

Furthermore the time to exhaustion for the VR group was around two minutes longer than those doing conventional exercise. The VR group also showed a lower heart rate of three beats per minute than the non-VR group.

Results from the study also showed no significant effect of private body consciousness on the positive impact of VR. Private body consciousness is the subjective awareness each of us has to bodily sensations.

the vr system

Previous research has shown that individuals who have a high private body consciousness tend to better understand their body and as a result perceive higher pain when exercising. However, the study’s findings revealed that VR was effective in reducing perceived pain and that private body consciousness did not lessen this effect.

As such, the improvements shown by the VR group suggest that it could be a possible way to encourage less active people to exercise by reducing the perceived pain that exercise can cause and improving performance, regardless of private body consciousness.

Lead researcher Maria Matsangidou said: ‘It is clear from the data gathered that the use of VR technology can improve performance during exercise on a number of criteria. This could have major implications for exercise regimes for everyone, from occasional gym users to professional athletes.’

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE

 

Dr Jim Ang from EDA and Dr Alex Mauger from the School of Sport and Exercise Sciences at Kent were also involved in the research.

Source: Dan Worth – University of Kent
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is credited to Maria Matsangidou.
Original Research: Abstract for “Is your virtual self as sensational as your real? Virtual Reality: The effect of body consciousness on the experience of exercise sensations” by Maria Matsangidou, Chee Siang Ang, Alexis R. Mauger, Jittrapol Intarasirisawat, Boris Otkhmezuri, and Marios N. Avraamides in Psychology of Sports and Exercise. Published July 18 2018.
doi:10.1016/j.psychsport.2018.07.004

CITE THIS NEUROSCIENCENEWS.COM ARTICLE
University of Kent”Virtual Reality Reduces Pain and Increases Performance During Exercise.” NeuroscienceNews. NeuroscienceNews, 1 October 2018.
<http://neurosciencenews.com/virtual-reality-pain-exercise-9941/&gt;.

Abstract

Is your virtual self as sensational as your real? Virtual Reality: The effect of body consciousness on the experience of exercise sensations

Objectives
Past research has shown that Virtual Reality (VR) is an effective method for reducing the perception of pain and effort associated with exercise. As pain and effort are subjective feelings, they are influenced by a variety of psychological factors, including one’s awareness of internal body sensations, known as Private Body Consciousness (PBC). The goal of the present study was to investigate whether the effectiveness of VR in reducing the feeling of exercise pain and effort is moderated by PBC.

Design and methods
Eighty participants were recruited to this study and were randomly assigned to a VR or a non-VR control group. All participants were required to maintain a 20% 1RM isometric bicep curl, whilst reporting ratings of pain intensity and perception of effort. Participants in the VR group completed the isometric bicep curl task whilst wearing a VR device which simulated an exercising environment. Participants in the non-VR group completed a conventional isometric bicep curl exercise without VR. Participants’ heart rate was continuously monitored along with time to exhaustion. A questionnaire was used to assess PBC.

Results
Participants in the VR group reported significantly lower pain and effort and exhibited longer time to exhaustion compared to the non-VR group. Notably, PBC had no effect on these measures and did not interact with the VR manipulation.

Conclusions
Results verified that VR during exercise could reduce negative sensations associated with exercise regardless of the levels of PBC.

 

via Virtual Reality Reduces Pain and Increases Performance During Exercise – Neuroscience News

 

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[VIDEO] Your Brain on Depression: Neuroscience, Animated – YouTube

Depression is a multifaceted and insidious disorder, nearly as complex as the brain itself. As research continues to suggest, the onset of depression can be attributed to an interplay of the many elements that make us human—namely, our genetics, the structure and chemistry of our brains, and our lived experience. Second only, perhaps, to the confounding mechanics of anesthesia, depression is the ultimate mind-body problem; understanding how it works could unlock the mysteries of human consciousness.

Emma Allen, a visual artist, and Dr. Daisy Thompson-Lake, a clinical neuroscientist, are fascinated by the physical processes that underlie mental health conditions. Together, they created Adam, a stop-motion animation composed of nearly 1,500 photographs. The short film illuminates the neuroscience of depression while also conveying its emotive experience.

“It was challenging translating the complicated science into an emotional visual story with scenes that would flow smoothly into each other,” Allen told The Atlantic.

“One of the most complex issues we had to deal with,” added Thompson-Lake, “is that there no single neuroscientific explanation for depression…While scientists agree that there are biological and chemical changes within the brain, the actual brain chemistry is very unique to the individual—although, of course, we can see patterns when studying large numbers of patients.” As a result, Allen and Thompson-Lake attempted a visual interpretation of depression that does not rely too heavily on any one explanation.

The film’s first sequence depicts the brain’s vast network of neuronal connections. Neurons communicate via synapses, across which electrical and chemical signals are exchanged. In a depressed patient’s brain, some of these processes are inefficient or dysfunctional, as the animation illustrates. Next, we see a positron emission tomography (PET) scan of a depressed brain, demarcated by darkened areas. Finally, the animation shows activity in the hippocampus and the frontal lobe. Abnormalities in the activity of both of these areas of the brain have been implicated in depression by recent research.

For Allen, one of the main objectives in creating Adam was to help dispel the notion that depression is a character flaw. “A common misconception is that the person is at fault for feeling this way, and that to ask for help is a weakness or embarrassing,” Allen said. “But depression has a physical component that needs treating.”

“The shame surrounding mental health still exists,” Allen continued. “In fact, in the case of Kate Spade, it was reported that she was concerned about the stigma her brand might face if this were made public.”

And who, exactly, is Adam? “Daisy lost a friend to suicide,” said Allen, “so the film is named in his memory.”

“Adam” was directed by animator Emma Allen and neuroscientist Daisy Thompson-Lake. It is part of The Atlantic Selects, an online showcase of short films from independent creators, curated by The Atlantic.

 

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[WEB SITE] Christiana Care Health System opens first Epilepsy Monitoring Unit in Delaware

 

To increase access to advanced neurological care, Christiana Care Health System has opened the first Epilepsy Monitoring Unit (EMU) in the First State.

Specially outfitted private hospital rooms in the Transition Neuro Unit at Christiana Hospital provide state-of-the-art equipment for video and audio monitoring. In the rooms, brain waves are tracked with electroencephalography (EEG) and electrical activity in the heart is recorded with electrocardiography (EKG), helping clinicians understand what is happening during a seizure. To further enhance safety, nurses assist patients whenever they are out of their bed. And patients wear mobility vests that connect to a stationary lift, a system that allows patients to move around a room – and prevents them from falling if they have a seizure. This is one of the few EMUs in the U.S. that uses a patient lift to prevent falls.

Epilepsy is a central nervous system disorder, in which brain activity becomes abnormal, leading to seizures or periods of unusual behavior, sensations or loss of awareness. The U.S. Centers for Disease Control and Prevention report that there are 3.4 million Americans with epilepsy and there is a growing incidence of the disease among the adult population in Delaware, especially among people 60 and older.

“Our community deserves the very best in neurological care,” said Valerie Dechant, M.D., physician leader, Neuroscience Service Line, and medical director, Neurocritical Care and Acute Neurologic Services. “Our new Epilepsy Monitoring Unit will enable us to serve the complex neurologic needs of our adult patients.”

Christiana Care’s EMU is part of a larger effort to establish an epilepsy center of excellence, so adults of any age can receive the highest quality routine and specialty care for seizure disorders.

“We want to help patients who believe they have been over-diagnosed or under-diagnosed so they can see improvement in their lives,” said Neurologist John R. Pollard, M.D., medical director of the new EMU.

While most patients with epilepsy are successfully treated by a general neurologist or epileptologist, a significant number of patients have persistent fainting or seizure episodes – or they have unwanted side effects from medications. This new facility enables physicians to work more closely with these patients to understand their seizures and determine appropriate treatment.

“Typically, these patients visit an EMU where they may stay for several days so they can be safely taken off medications, inducing seizures that are recorded and studied so a proper diagnosis and treatment can be planned,” said Christy L. Poole, RN, BSN CRNI CCRC, a neurosciences program manager. Visiting an EMU to induce a seizure could be a source of anxiety for patients and their families.

“Our staff works with patients and families to reduce any fear by providing information on what to expect, stressing procedures that enhance patient safety and making the stay as pleasant as possible,” said Susan Craig, MSN, RNIII-BC, epilepsy clinical nurse practice coordinator.

via Christiana Care Health System opens first Epilepsy Monitoring Unit in Delaware

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[WEB SITE] Human brains make new nerve cells — and lots of them — well into old age.

Previous studies have suggested neurogenesis tapers off or stops altogether

BY
LAUREL HAMERS, APRIL 5, 2018
nerve cells in hippocampi

NEURON NURSERY  Roughly the same number of new nerve cells (dots) exist in the hippocampus of people in their 20s (three hippocampi shown, top row) as in people in their 70s (bottom). Blue marks the dentate gyrus, where new nerve cells are born.
M. BOLDRINI/COLUMBIA UNIV.

Your brain might make new nerve cells well into old age.

Healthy people in their 70s have just as many young nerve cells, or neurons, in a memory-related part of the brain as do teenagers and young adults, researchers report in the April 5 Cell Stem Cell. The discovery suggests that the hippocampus keeps generating new neurons throughout a person’s life.

The finding contradicts a study published in March, which suggested that neurogenesis in the hippocampus stops in childhood (SN Online: 3/8/18). But the new research fits with a larger pile of evidence showing that adult human brains can, to some extent, make new neurons. While those studies indicate that the process tapers off over time, the new study proposes almost no decline at all.

Understanding how healthy brains change over time is important for researchers untangling the ways that conditions like depression, stress and memory loss affect older brains.

When it comes to studying neurogenesis in humans, “the devil is in the details,” says Jonas Frisén, a neuroscientist at the Karolinska Institute in Stockholm who was not involved in the new research. Small differences in methodology — such as the way brains are preserved or how neurons are counted — can have a big impact on the results, which could explain the conflicting findings. The new paper “is the most rigorous study yet,” he says.

Researchers studied hippocampi from the autopsied brains of 17 men and 11 women ranging in age from 14 to 79. In contrast to past studies that have often relied on donations from patients without a detailed medical history, the researchers knew that none of the donors had a history of psychiatric illness or chronic illness. And none of the brains tested positive for drugs or alcohol, says Maura Boldrini, a psychiatrist at Columbia University. Boldrini and her colleagues also had access to whole hippocampi, rather than just a few slices, allowing the team to make more accurate estimates of the number of neurons, she says.

To look for signs of neurogenesis, the researchers hunted for specific proteins produced by neurons at particular stages of development. Proteins such as GFAP and SOX2, for example, are made in abundance by stem cells that eventually turn into neurons, while newborn neurons make more of proteins such as Ki-67. In all of the brains, the researchers found evidence of newborn neurons in the dentate gyrus, the part of the hippocampus where neurons are born.

Although the number of neural stem cells was a bit lower in people in their 70s compared with people in their 20s, the older brains still had thousands of these cells. The number of young neurons in intermediate to advanced stages of development was the same across people of all ages.

Still, the healthy older brains did show some signs of decline. Researchers found less evidence for the formation of new blood vessels and fewer protein markers that signal neuroplasticity, or the brain’s ability to make new connections between neurons. But it’s too soon to say what these findings mean for brain function, Boldrini says. Studies on autopsied brains can look at structure but not activity.

Not all neuroscientists are convinced by the findings. “We don’t think that what they are identifying as young neurons actually are,” says Arturo Alvarez-Buylla of the University of California, San Francisco, who coauthored the recent paper that found no signs of neurogenesis in adult brains. In his study, some of the cells his team initially flagged as young neurons turned out to be mature cells upon further investigation.

But others say the new findings are sound. “They use very sophisticated methodology,” Frisén says, and control for factors that Alvarez-Buylla’s study didn’t, such as the type of preservative used on the brains.

via Human brains make new nerve cells — and lots of them — well into old age | Science News

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[WEB SITE] New Brain Maps With Unmatched Detail May Change Neuroscience

A technique based on genetic bar codes can easily map the connections of individual brain cells in unprecedented numbers. Unexpected complexity in the visual system is only the first secret it has revealed.

Illustration for mapping the cortex

A new technology for tracing the precise pathways of neural connections in the brain works with numbers of cells that were unimaginable until recently.

Sitting at the desk in his lower-campus office at Cold Spring Harbor Laboratory, the neuroscientist Tony Zador turned his computer monitor toward me to show off a complicated matrix-style graph. Imagine something that looks like a spreadsheet but instead of numbers it’s filled with colors of varying hues and gradations. Casually, he said: “When I tell people I figured out the connectivity of tens of thousands of neurons and show them this, they just go ‘huh?’ But when I show this to people …” He clicked a button onscreen and a transparent 3-D model of the brain popped up, spinning on its axis, filled with nodes and lines too numerous to count. “They go ‘What the _____!’”

What Zador showed me was a map of 50,000 neurons in the cerebral cortex of a mouse. It indicated where the cell bodies of every neuron sat and where they sent their long axon branches. A neural map of this size and detail has never been made before. Forgoing the traditional method of brain mapping that involves marking neurons with fluorescence, Zador had taken an unusual approach that drew on the long tradition of molecular biology research at Cold Spring Harbor, on Long Island. He used bits of genomic information to imbue a unique RNA sequence or “bar code” into each individual neuron. He then dissected the brain into cubes like a sheet cake and fed the pieces into a DNA sequencer. The result: a 3-D rendering of 50,000 neurons in the mouse cortex (with as many more to be added soon) mapped with single cell resolution.

This work, Zador’s magnum opus, is still being refined for publication. But in a paper recently published byNature, he and his colleagues showed that the technique, called MAPseq (Multiplexed Analysis of Projections by Sequencing), can be used to find new cell types and projection patterns never before observed. The paper also demonstrated that this new high-throughput mapping method is strongly competitive in accuracy with the fluorescent technique, which is the current gold standard but works best with small numbers of neurons.

Photo of Tony Zador in his Cold Spring Harbor Laboratory office.

Tony Zador, a neurophysiologist at Cold Spring Harbor Laboratory, realized that genome sequencing techniques could scale up to tame the astronomical numbers of neurons and interconnections in the brain.

The project was born from Zador’s frustration during his “day job” as a neurophysiologist, as he wryly referred to it. He studies auditory decision-making in rodents: how their brain hears sounds, processes the audio information and determines a behavioral output or action. Electrophysiological recordings and the other traditional tools for addressing such questions left the mathematically inclined scientist unsatisfied. The problem, according to Zador, is that we don’t understand enough about the circuitry of the neurons, which is the reason he pursues his “second job” creating tools for imaging the brain.

The current state of the art for brain mapping is embodied by the Allen Brain Atlas, which was compiled from work in many laboratories over several years at a cost upward of $25 million. The Allen Atlas is what’s known as a bulk connectivity atlas because it traces known subpopulations of neurons and their projections as groups. It has been highly useful for researchers, but it cannot distinguish subtle differences within the groups or neuron subpopulations.

If we ever want to know how a mouse hears a high-pitched trill, processes that the sound means a refreshing drink reward is available and lays down new memories to recall the treat later, we will need to start with a map or wiring diagram for the brain. In Zador’s view, lack of knowledge about that kind of neural circuitry is partly to blame for why more progress has not been made in the treatment of psychiatric disorders, and why artificial intelligence is still not all that intelligent.

Justus Kebschull, a Stanford University neuroscientist, an author of the new Nature paper and a former graduate student in Zador’s lab, remarked that doing neuroscience without knowing about the circuitry is like “trying to understand how a computer works by looking at it from the outside, sticking an electrode in and probing what we can find. … Without ever knowing the hard drive is connected to the processor and the USB pod provides input to the whole system, it’s difficult to understand what’s happening.”

Inspiration for MAPseq struck Zador when he learned of another brain mapping technique called Brainbow. Hailing from the lab of Jeff Lichtman at Harvard University, this method was remarkable in that it genetically labeled up to 200 individual neurons simultaneously using different combinations of fluorescent dyes. The results were a tantalizing, multicolored tableau of neon-colored neurons that displayed, in detail, the complex intermingling of axons and neuron cell bodies. The groundbreaking work gave hope that mapping the connectome — the complete plan of neural connections in the brain — was soon to be a reality. Unfortunately, a limitation of the technique in practice is that through a microscope, experimenters could resolve only about five to 10 distinct colors, which was not enough to penetrate the tangle of neurons in the cortex and map many neurons at once.

That’s when the lightbulb went on in Zador’s head. He realized that the challenge of the connectome’s huge complexity might be tamed if researchers could harness the increasing speed and dwindling costs of high-throughput genomic sequencing techniques. “It’s what mathematicians call reducing it to a previously solved problem,” he explained.

Video: Tony Zador explains the new MAPseq technology and its potential for unlocking the secrets hidden in details of the brain’s connectivity.

In MAPseq, researchers inject an animal with genetically modified viruses that carry a variety of known RNA sequences, or “bar codes.” For a week or more, the viruses multiply inside the animal, filling each neuron with some distinctive combination of those bar codes. When the researchers then cut the brain into sections, the RNA bar codes can help them track individual neurons from slide to slide.

Zador’s insight led to the new Nature paper, in which his lab and a team at University College London led by the neuroscientist Thomas Mrsic-Flogel used MAPseq to trace the projections of almost 600 neurons in the mouse visual system. (Editor’s note: Zador and Mrsic-Flogel both receive funding from the Simons Foundation, which publishes Quanta.)

Six hundred neurons is a modest start compared with the tens of millions in the brain of a mouse. But it was ample for the specific purpose the researchers had in mind: They were looking to discern whether there is a structure to the brain’s wiring pattern that might be informative about its function. A currently popular theory is that in the visual cortex, an individual neuron gathers a specific bit of information from the eye — about the edge of an object in the field of view, or a type of movement or spatial orientation, for example. The neuron then sends a signal to a single corresponding area in the brain that specializes in processing that type of information.

Gif of brain scan 1

Gif of brain scan 2Gif of brain scan 3

These images offer an example of how MAPseq can determine the wiring of multitudes of neurons. The small colored dots in the first image represent the positions of the cell bodies of 50,000 neurons in the cortex of a mouse. In the second image, the axon projections from just two of those neurons to endpoints elsewhere in the brain are shown. In the third image, the pathways from many more of the neurons are superimposed.

To test this theory, the team first mapped a handful of neurons in mice in the traditional way by inserting a genetically encoded fluorescent dye into the individual cells. Then, with a microscope, they traced how the cells stretched from the primary visual cortex (the brain area that receives input from the eyes) to their endpoints elsewhere in the brain. They found that the neurons’ axons branched out and sent information to many areas simultaneously, overturning the one-to-one mapping theory.

Next, they asked if there were any patterns to these projections. They used MAPseq to trace the projections of 591 neurons as they branched out and innervated multiple targets. What the team observed was that the distribution of axons was structured: Some neurons always sent axons to areas A, B and C but never to D and E, for example.

These results suggest the visual system contains a dizzying level of cross-connectivity and that the pattern of those connections is more complicated than a one-to-one mapping. “Higher visual areas don’t just get information that is specifically tailored to them,” Kebschull said. Instead, they share many of the same inputs, “so their computations might be tied to each other.”

Nevertheless, the fact that certain cells do project to specific areas also means that within the visual cortex there are specialized cells that have not yet been identified. Kebschull said this map is like a blueprint that will enable later researchers to understand what these cells are doing. “MAPseq allows you to map out the hardware. … Once we know the hardware we can start to look at the software, or how the computations happen,” he said.

MAPseq’s competitive edge in speed and cost for such investigations is considerable: According to Zador, the technique should be able to scale up to handle 100,000 neurons within a week or two for only $10,000 — far faster than traditional mapping would be, at a fraction of the cost.

Such advantages will make it more feasible to map and compare the neural pathways of large numbers of brains. Studies of conditions such as schizophrenia and autism that are thought to arise from differences in brain wiring have often frustrated researchers because the available tools don’t capture enough details of the neural interconnections. It’s conceivable that researchers will be able to map mouse models of these conditions and compare them with more typical brains, sparking new rounds of research. “A lot of psychiatric disorders are caused by problems at the circuit level,” said Hongkui Zeng, executive director of the structured science division at the Allen Institute for Brain Science. “Connectivity information will tell you where to look.”

High-throughput mapping also allows scientists to gather lots of neurological data and look for patterns that reflect general principles of how the brain works. “What Tony is doing is looking at the brain in an unbiased way,” said Sreekanth Chalasani, a molecular neurobiologist at the Salk Institute. “Just as the human genome map has provided a scaffolding to test hypotheses and look for patterns in [gene] sequence and function, Tony’s method could do the same” for brain architecture.

The detailed map of the human genome didn’t immediately explain all the mysteries of how biology works, but it did provide a biomolecular parts list and open the way for a flood of transformative research. Similarly, in its present state of development, MAPseq cannot provide any information about the function or location of the cells it is tagging or show which cells are talking to one another. Yet Zador plans to add this functionality soon. He is also collaborating with scientists studying various parts the brain, such as the neural circuits that underlie fear conditioning.

“I think there are insights to be derived from connectivity. But just like genomes themselves aren’t interesting, it’s what they enable that is transformative. And that’s why I’m excited,” Zador said. “I’m hopeful it’s going to provide the scaffolding for the next generation of work in the field.”

This article was reprinted on Wired.com.

 

via New Brain Maps With Unmatched Detail May Change Neuroscience | Quanta Magazine

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[WEB SITE] Vagus nerve stimulation accelerates motor skill recovery after stroke

Researchers at The University of Texas at Dallas have demonstrated a method to accelerate motor skill recovery after a stroke by helping the brain reorganize itself more quickly.

In a preclinical study, the scientists paired vagus nerve stimulation (VNS) with a physical therapy task aimed at improving the function of an upper limb in rodents. The results showed a doubled long-term recovery rate relative to current therapy methods, not only in the targeted task but also in similar muscle movements that were not specifically rehabbed. Their work was recently published in the journal Stroke.

A clinical trial to test the technique in humans is underway in Dallas and 15 other sites across the country.

Dr. Michael Kilgard, associate director of the Texas Biomedical Device Center (TxBDC) and Margaret Forde Jonsson Professor of Neuroscience in the School of Behavioral and Brain Sciences, led the research team with Dr. Seth Hays, the TxBDC director of preclinical research and assistant professor of bioengineering in the Erik Jonsson School of Engineering and Computer Science, and postdoctoral researcher Eric Meyers PhD’17.

“Our experiment was designed to ask this new question: After a stroke, do you have to rehabilitate every single action?” Kilgard said. “If VNS helps you, is it only helping with the exact motion or function you paired with stimulation? What we found was that it also improves similar motor skills as well, and that those results were sustained months beyond the completion of VNS-paired therapy.”

Kilgard said the results provide an important step toward creating guidelines for standardized usage of VNS for post-stroke therapy.

“This study tells us that if we use this approach on complicated motor skills, those improvements can filter down to improve simpler movements,” he said.

Building Stronger Cell Connections

When a stroke occurs, nerve cells in the brain can die due to lack of blood flow. An arm’s or a leg’s motor skills fail because, though the nerve cells in the limb are fine, there’s no longer a connection between them and the brain. Established rehab methods bypass the brain’s damaged area and enlist other brain cells to handle the lost functions. However, there aren’t many neurons to spare, so the patient has a long-lasting movement deficit.

The vagus nerve controls the parasympathetic nervous system, which oversees elements of many unconscious body functions, including digestion and circulation. Electrical stimulation of the nerve is achieved via an implanted device in the neck. Already used in humans to treat depression and epilepsy, VNS is a well-documented technique for fine-tuning brain function.

The UT Dallas study’s application of VNS strengthens the communication path to the neurons that are taking over for those damaged by stroke. The experiments showed a threefold-to-fivefold increase in engaged neurons when adding VNS to rehab.

“We have long hypothesized that VNS is making new connections in the brain, but nothing was known for sure,” Hays said. “This is the first evidence that we are driving changes in the brain in animals after brain injury. It’s a big step forward in understanding how the therapy works — this reorganization that we predicted would underlie the benefits of VNS.”

In anticipation of the technique’s eventual use in humans, the team is working on an at-home rehab system targeting the upper limbs.

“We’ve designed a tablet app outlining hand and arm tasks for patients to interact with, delivering VNS as needed,” Meyers said. “We can very precisely assess their performance and monitor recovery remotely. This is all doable at home.”

Expanding the Possibilities for Therapy

The researchers are motivated in part by an understanding of the practical limitations of current therapeutic options for patients.

“If you have a stroke, you may have a limited time with a therapist,” Hays said. “So when we create guidelines for a therapist, we now know to advise doing one complex activity as many times as possible, as opposed to a variety of activities. That was an important finding — it was exciting that not only do we improve the task that we trained on, but also relatively similar tasks. You are getting generalization to related things, and you’re getting sustained improvement months down the line.”

For stroke patients, the opportunity to benefit from this technology may not be far off.

“A clinical trial that started here at UTD is now running nationwide, including at UT Southwestern,” Kilgard said. “They are recruiting patients. People in Dallas can enroll now — which is only fitting, because this work developed here, down to publishing this in a journal of the American Heart Association, which is based here in Dallas. This is a homegrown effort.

“The ongoing clinical trial is the last step in getting approved as an established therapy,” Kilgard said. “We’re hopefully within a year of having this be standard practice for chronic stroke.”

 

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[WEB SITE] Largest-ever study to examine anatomical alterations in the brains of epilepsy patients

Largest-ever study to examine anatomical alterations in the brains of epilepsy patients 

An international research consortium used neuroimaging techniques to analyze the brains of more than 3,800 volunteers in different countries. The largest study of its kind ever conducted set out to investigate anatomical similarities and differences in the brains of individuals with different types of epilepsy and to seek markers that could help with prognosis and treatment.

Epilepsy’s seizure frequency and severity, as well as the patient’s response to drug therapy, vary with the part of the brain affected and other poorly understood factors. Data from the scientific literature suggests that roughly one-third of patients do not respond well to anti-epileptic drugs. Research has shown that these individuals are more likely to develop cognitive and behavioral impairments over the years.

The new study was conducted by a specific working group within an international consortium called ENIGMA, short for Enhancing NeuroImaging Genetics through Meta-Analysis, established to investigate several neurological and psychiatric diseases. Twenty-four cross-sectional samples from 14 countries were included in the epilepsy study.

Altogether, the study included data for 2,149 people with epilepsy and 1,727 healthy control subjects (with no neurological or psychiatric disorders). The Brazilian Research Institute for Neuroscience and Neurotechnology (BRAINN), which participated in the multicenter study, was the center with the largest sample, comprising 291 patients and 398 controls. Hosted in Brazil, at the State University of Campinas (UNICAMP), BRAINN is a Research, Innovation and Dissemination Center (RIDC http://cepid.fapesp.br/en/home/) supported by the Sao Paulo Research Foundation – FAPESP.

“Each center was responsible for collecting and analyzing data on its own patients. All the material was then sent to the University of Southern California’s Imaging Genetics Center in the US, which consolidated the results and performed a meta-analysis,” said Fernando Cendes, a professor at UNICAMP and coordinator of BRAINN.

A differential study

All volunteers were subjected to MRI scans. According to Cendes, a specific protocol was used to acquire three-dimensional images. “This permitted image post-processing with the aid of computer software, which segmented the images into thousands of anatomical points for individual assessment and comparison,” he said.

According to the researcher, advances in neuroimaging techniques have enabled the detection of structural alterations in the brains of people with epilepsy that hadn’t been noticed previously.

Cendes also highlighted that this is the first epilepsy study built on a really large number of patients, which allowed researchers to obtain more robust data. “There were many discrepancies in earlier studies, which comprised a few dozen or hundred volunteers.”

The patients included in the study were divided into four subgroups: mesial temporal lobe epilepsy (MTLE) with left hippocampal sclerosis, MTLE with right hippocampal sclerosis, idiopathic (genetic) generalized epilepsy, and a fourth group comprising various less common subtypes of the disease.

The analysis covered both patients who had had epilepsy for years and patients who had been diagnosed recently. According to Cendes, the analysis – whose results were published in the international journal Brain – aimed at the identification of atrophied brain regions in which the cortical thickness was smaller than in the control group.

First analysis

The researchers first analyzed data from the four patient subgroups as a whole and compared them with the controls to determine whether there were anatomical alterations common to all forms of epilepsy. “We found that all four subgroups displayed atrophy in areas of the sensitive-motor cortex and also in some parts of the frontal lobe,” Cendes said.

“Ordinary MRI scans don’t show anatomical alterations in cases of genetic generalized epilepsy,” Cendes said. “One of the goals of this study was to confirm whether areas of atrophy also occur in these patients. We found that they do.”

This finding, he added, shows that in the case of MTLE, there are alterations in regions other than those in which seizures are produced (the hippocampus, parahippocampus, and amygdala). Brain impairment is, therefore, more extensive than previously thought.

Cendes also noted that a larger proportion of the brain was compromised in patients who had had the disease for longer. “This reinforces the hypothesis that more brain regions atrophy and more cognitive impairment occurs as the disease progresses.”

The next step was a separate analysis of each patient subgroup in search of alterations that characterize each form of the disease. The findings confirmed, for example, that MTLE with left hippocampal sclerosis is associated with alterations in different neuronal circuits from those associated with MTLE with right hippocampal sclerosis.

“Temporal lobe epilepsy occurs in a specific brain region and is therefore termed a focal form of the disease. It’s also the most common treatment-refractory subtype of epilepsy in adults,” Cendes said. “We know it has different and more severe effects when it involves the left hemisphere than the right. They’re different diseases.”

“These two forms of the disease are not mere mirror-images of each other,” he said. “When the left hemisphere is involved, the seizures are more intense and diffuse. It used to be thought that this happened because the left hemisphere is dominant for language, but this doesn’t appear to be the only reason. Somehow, it’s more vulnerable than the right hemisphere.”

In the GGE group, the researchers observed atrophy in the thalamus, a central deep-lying brain region above the hypothalamus, and in the motor cortex. “These are subtle alterations but were observed in patients with epilepsy and not in the controls,” Cendes said.

Genetic generalized epilepsies (GGEs) may involve all brain regions but can usually be controlled by drugs and are less damaging to patients.

Future developments

From the vantage point of the coordinator for the FAPESP-funded center, the findings published in the article will benefit research in the area and will also have future implications for the diagnosis of the disease. In parallel with their anatomical analysis, the group is also evaluating genetic alterations that may explain certain hereditary patterns in brain atrophy. The results of this genetic analysis will be published soon.

“If we know there are more or less specific signatures of the different epileptic subtypes, instead of looking for alterations everywhere in the brain, we can focus on suspect regions, reducing cost, saving time and bolstering the statistical power of the analysis. Next, we’ll be able to correlate these alterations with cognitive and behavioral dysfunction,” Cendes said.

 

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[WEB SITE] Learning stress-reducing techniques may benefit people with epilepsy

Learning techniques to help manage stress may help people with epilepsy reduce how often they have seizures, according to a study published in the February 14, 2018, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“Despite all the advances we have made with new drugs for epilepsy, at least one-third of people continue to have seizures, so new options are greatly needed,” said study author Sheryl R. Haut, MD, of Montefiore Medical Center and the Albert Einstein College of Medicine in the Bronx, NY, and member of the American Academy of Neurology. “Since stress is the most common seizure trigger reported by patients, research into reducing stress could be valuable.”

The study involved people with seizures that did not respond well to medication. While all of the 66 participants were taking drugs for seizures, all continued to have at least four seizures during about two months before the study started.

During the three-month treatment period all of the participants met with a psychologist for training on a behavioral technique that they were then asked to practice twice a day, following an audio recording. If they had a day where they had signs that they were likely to have a seizure soon, they were asked to practice the technique another time that day. The participants filled out daily electronic diaries on any seizures, their stress level, and other factors such as sleep and mood.

Half of the participants learned the progressive muscle relaxation technique, a stress reduction method where each muscle set is tensed and relaxed, along with breathing techniques. The other participants were the control group-;they took part in a technique called focused attention. They did similar movements as the other group, but without the muscle relaxation, plus other tasks focusing on attention, such as writing down their activities from the day before. The study was conducted in a blinded fashion so that participants and evaluators were not aware of treatment group assignment.

Before the study, the researchers had hypothesized that the people doing the muscle relaxing exercises would show more benefits from the study than the people doing the focused attention exercises, but instead they found that both groups showed a benefit-;and the amount of benefit was the same.

The group doing the muscle relaxing exercises had 29 percent fewer seizures during the study than they did before it started, while the focused attention group had 25 percent fewer seizures, which is not a significant difference, Haut said. She added that study participants were highly motivated as was shown by the nearly 85 percent diary completion rate over a five-month period.

“It’s possible that the control group received some of the benefits of treatment in the same way as the ‘active’ group, since they both met with a psychologist and every day monitored their mood, stress levels and other factors, so they may have been better able to recognize symptoms and respond to stress,” said Haut. “Either way, the study showed that using stress-reducing techniques can be beneficial for people with difficult-to-treat epilepsy, which is good news.”

Haut said more research is needed with larger numbers of people and testing other stress reducing techniques like mindfulness based cognitive therapy to determine how these techniques could help improve quality of life for people with epilepsy.

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