Archive for category Neuroplasticity

[VIDEO] Neuroplasticity – YouTube

The Sentis Brain Animation Series takes you on a tour of the brain through a series of short and sharp animations.

The fourth in the series explains how our most complex organ is capable of changing throughout our lives. This inspiring animation demonstrates how we all have the ability to learn and change by rewiring our brains.

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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

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.

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


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

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[WEB SITE] Newborn Neurons in the Adult Brain: Real Deal, or Glial Imposters? – Full Text Article

Deep in the hippocampus, are new neurons born throughout life? Just when scientists were about to reach some consensus that the answer was yes, two recent studies disagree. In the April 5 Cell Stem Cell, Maura Boldrini and colleagues at Columbia University, New York, report that adult neurogenesis not only exists, but remains steady into old age. The researchers counted newborn neurons in samples from people aged 14–79 years, and came up with similar numbers. In the March 7 Nature, researchers led by Arturo Alvarez-Buylla at the University of California, San Francisco, reported that while neural progenitors abounded in postmortem hippocampi from prenatal or early childhood brains, they fell off the map by age 7. What gives? In older people, some of the cells that expressed markers of budding neurons turned out to be glia, the authors claim.

  • Neural progenitor cells proliferate in human hippocampus throughout adulthood, says a new study.
  • It blames waning angiogenesis, not faulty neurogenesis, for lost neuroplasticity in old age.
  • In contrast, another paper claims brain neurogenesis fizzles during childhood.
  • It claims some cells bearing neural progenitor markers are actually glia.

Who is right? Researchers who spoke with Alzforum stood squarely behind Boldrini because she used stereology, a gold standard quantitation method, to estimate numbers of neural progenitors throughout the entire dentate gyrus of postmortem brain. Alvarez-Buylla’s team estimated cell numbers using only three to five slices from each postmortem sample. “It would be very difficult to rule out neurogenesis by this method,” said Orly Lazarov of the University of Illinois in Chicago, who pointed out that because the study relied on small numbers of individuals per age group, the data could be misleading.

Others, including Jonas Frisén of the Karolinska Institute in Stockholm, pointed to a long list of previous papers supporting the existence of neurogenesis in the adult human brain. “An analogy is that 10 people go into the woods to search for blueberries,” he wrote, “Nine come back with blueberries and one does not. Are there blueberries in that forest?”

Tracking Neurogenesis.
Scientists used a combination of cell-surface markers to count neural progenitors along the development spectrum in the dentate gyrus. While neurogenesis held steady, angiogenesis and neuroplasticity declined with age. [Courtesy of Boldrini et al., Cell Stem Cell, 2018.]

Still, others acknowledged that some of those “blueberries” might have been glia. “To me, it boils down to a single question: are these proliferating cells truly neural progenitors, or not?” asked Costantino Iadecola of Weill Cornell Medical College in New York.

Numerous studies in rodents support the idea that neural progenitors in the mammalian brain continue to trickle out fresh neurons into adulthood, though factors such as aging and disease dampen the flow (Altman and Das, 1965Sep 2001 newsFeb 2002 newsKempermann et al., 2003Mar 2010 news). Tracking neurogenesis in humans has been trickier, but a seminal study two decades ago set the stage: Five terminal cancer patients received an injection of bromodeoxyuridine (BrdU), a dye that incorporates into DNA during cell division. Postmortem analyses revealed evidence of dividing neurons in the dentate gyri of all of the patients (Eriksson et al., 1998). Since then, carbon-14 tracing and immunohistochemistry studies have supported the idea that new neurons arise in the adult human brain (Knoth et al., 2010Jun 2013 newsFeb 2014 news).

Boldrini and colleagues set out to determine if age affects adult neurogenesis. They acquired hippocampal samples from 11 women and 17 men, aged 14–79, who were cognitively normal, had suffered no brain trauma, had had no microvascular pathology in the brain, and had clean toxicology reports at the time of death. The researchers collected 50-micron thick sections every 2 mm along the entirety of the hippocampus, and used both immunofluorescence and immunocytochemistry to label various cell-surface markers associated with five different stages of neural development (see image below). Finally, they estimated cell numbers throughout the dentate gyrus using stereology, whereby a computer algorithm calculates total cell numbers in a region by combining data from multiple sections. They reported the number of neural progenitors in the anterior, mid-, and posterior dentate gyrus.

The earliest neural progenitors known, called quiescent radial-like type I neural progenitors (QNPs), express GFAP, a marker shared with astrocytes; nestin, an intermediate filament protein that marks neural stem cells; and the transcription factor Sox2, which is required for the maintenance of multipotent stem cells. The researchers found that numbers of these cells decreased with age in the anterior-mid dentate gyrus. This is in keeping with the prevailing view that people are born with a finite number of these QNPs, Boldrini said.

QNPs give rise to type II intermediate neural progenitors. INPs are proliferating cells that express Ki67, a marker of actively dividing cells. Neuroblasts, or type III INPs, also proliferate, but lose expression of GFAP and Sox2. Based on expression of Ki67, nestin, and Sox2, the researchers determined that numbers of type II and III INPs remained steady, on the order of thousands of cells, in all three regions of the dentate gyrus throughout life. These neural progenitors were found in the subgranular zone (SGZ), which is proposed to be the predominant neurogenic niche in the region, as well as the granule cell layer (GCL, see image below). The findings pointed to a stable supply of neural progenitors in the dentate gyrus throughout adult life.

The researchers next asked whether those progenitors would fulfill their destiny and give rise to immature neurons and, ultimately, bona fide granule neurons. On the way to becoming fully fledged neurons, type III INPs start to express doublecortin (DCX), a microtubule-associated protein involved in neural migration. They also produce polysialylated neural cell adhesion molecule (PSA-NCAM), a glycoprotein they need for plasticity. Together, DCX and PSA-NCAM mark young neurons, which continue to express both proteins until they differentiate into mature neurons, whereupon they suppress DCX. The researchers found that the tissue donors had similar numbers of cells co-expressing DCX and PSA-NCAM, regardless of their age, suggesting neurogenesis continued unabated throughout life. Numbers of NeuN+ mature neurons also held steady, indicating that neuronal loss in the dentate gyrus is not a characteristic of healthy aging, either.

The researchers calculated that each dentate gyrus had between 10,000 and 15,000 young neurons (i.e., type III INPs and immature neurons). While the functional significance of these cell numbers is unclear, Boldrini speculated that this ongoing level of neurogenesis influences neural circuitry and cognition. For this reason, boosting neurogenesis could be a therapeutic strategy for neurodegenerative disease, she said.

A New Neuron?
An immature neuron (red arrow) co-expressing PSA-NCAM and DCX lingers between the subgranular zone (SGZ) and the granule cell layer (GCL) in the dentate gyrus. Two other PSA-NCAM+ cells do not express DCX (yellow arrows).[Courtesy of Boldrini et al., Cell Stem Cell, 2018.]

However, while older adults appear to generate as many new neurons as younger people, those new cells may be less plastic, judging by a decline in PSA-NCAM+/DCX– cells in the anterior dentate gyrus. Curiously, using endothelial markers and stereology to measure the numbers, length, bifurcations, and total volume of capillaries, the scientists also found an age-dependent decline in angiogenesis in the same regions. The researchers proposed that a decline in angiogenesis may trigger loss of neuroplasticity without necessarily affecting neurogenesis, for example by starving new neurons of essential growth factors or nutrients.

Others were not convinced, noting that reliance on a single marker—PSA-NCAM—made the plasticity results no more than an interesting correlation. Still, Lazarov and Iadecola said the connection between age-related decline in angiogenesis and neuroplasticity was plausible. Iadecola was surprised that loss of angiogenesis did not appear to affect neurogenesis, but he noted that the donors had no obvious vascular pathology in their brains. Perhaps in people with more severe vascular problems, neurogenesis would be affected, he said.

In Grown-Up Brain, Nary a Newborn Neuron
In the Nature paper, first author Shawn Sorrells and colleagues used many of the same markers—Sox2, GFAP, DCX, and PSA-NCAM—to assess neurogenesis in postmortem samples across the lifespan. This included 11 samples from prenatal donors, the youngest of whom was only at 14 weeks gestation. They also analyzed seven samples from infants who died during their first year of life, one from a 7-year-old, one from a 13-year-old, and 17 samples from adults up to 77 years of age at the time of death. The samples came from multiple sources, and were not limited to healthy donors, or all postmortem. They included hippocampal tissue from surgical resection in 22 people with epilepsy, who ranged from three months to 64 years old.

For the postmortem samples, the researchers used three to five coronal sections to assess cell numbers. Rather than using stereology to estimate the total number of cells in the dentate gyrus, the researchers counted cells in individual sections. Three researchers independently counted each section while blinded to the age of the donor. They identified key structural landmarks, most notably the cell-dense GCL, to infer the relative locations of the cells.

In prenatal samples, the scientists found abundant proliferating Ki67+ cells that expressed the progenitor markers Sox1 and Sox2. Numbers of these cells plummeted during the first year of life, and were near zero in samples from people 7 or older. Notably, these proliferating cells never coalesced beneath the GCL to form a distinctive layer in the SGZ, a structural niche that supports neurogenesis in rodent models. The researchers confirmed the absence of this layer by electron microscopy on a subset of their samples, ranging in age from 22 gestational weeks to 48 years of age.

Neurogenesis Decline. Sections of dentate gyrus reveal a sharp decline in young neurons (yellow) from birth to 77 years of age. Granule cell layer traced in blue. [Courtesy of Sorrells et al., Nature, 2018.]


DCX+/PSA-NCAM+ cells, representing intermediate neural progenitors and immature neurons, clustered throughout the GCL at birth to a density of about 1,600 cells per mm2. In prenatal and infant samples, these cells had a smooth, elongated morphology characteristic of young neurons. By 13 years of age, sections only contained around two young neurons per mm2, or roughly one or two cells per section. Likewise, the investigators found no evidence of young neurons in samples from epilepsy patients older than 11. As for adults, none of the surgical or postmortem samples contained DCX+/PSA-NCAM+ cells, however the researchers did find cells that expressed PSA-NCAM without DCX. Unlike the elongated young neurons in infant samples, these cells had a more mature neuronal morphology with distinct axons and dendrites, and expressed NeuN, suggesting they were highly plastic neurons. The researchers also identified DCX+ cells in some older childhood and adult samples, but these cells co-expressed glial markers, and under the gaze of electron microscopy, had glial morphology.

The researchers also looked for evidence of neurogenesis in rhesus macaques. By staining with similar neuronal markers, they found that unlike in the human brain, proliferating neural progenitors did gather in the SGZ before birth. However, the number of these young neurons decreased eightfold between birth and 1.5 years of age, and were sparse in 7-year-old animals. Similarly, labeling dividing cells with BrdU revealed a steep drop-off in dividing neurons between 1.5 and 7 years of age.

Glial Impostor?
DCX+ (green) cells co-expressing the oligodendrocyte marker Olig2 (red). [Courtesy of Sorrells et al., Nature, 2018.]

The researchers concluded that neurogenesis is robust only in the earliest stages of development, and that DCX+ cells in late childhood and adult samples were actually glia. In an email to Alzforum, Sorrells and Alvarez-Buylla speculated that the cells identified as young neurons in the Boldrini study were also likely non-neuronal. “Identifying new neurons is technically challenging—in our own recent study we made similar observations to what Boldrini et al. report, but after extensive additional analysis of the shape and appearance of the cells in question, including electron microscopy and gene expression, we determined that these cells were not in fact young neurons or neural progenitors but different types of cells altogether,” they wrote.

However, Boldrini asserted that in her study, the cells stained for both DCX and PSA-NCAM did not co-localize with cells that appeared to be glia based on the pattern of Nissl staining, and were present in the thousands. Boldrini added that the immature neurons took on a pyramidal shape, characteristic of neurons, not glia.

Sorrells and Alvarez-Buylla further drew attention to the lack of a defined layer of proliferating cells in the SGZ in their study, adding that Boldrini’s samples also appeared to lack a distinct layer of cells there. In rodents, neural progenitors gather and proliferate in the SGZ. On this issue, Boldrini thinks that perhaps in humans neurogenesis occurs in a more scattered fashion. She said that for this reason, taking stock of cells throughout the entire dentate gyrus is crucial to capture these sparse cells.—Jessica Shugart

via Newborn Neurons in the Adult Brain: Real Deal, or Glial Imposters? | ALZFORUM

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[ARTICLE] Neurogenesis: Study Sparks Controversy Over Whether Humans Continue to Make New Neurons Throughout Life



A new study offers new data challenging the prevailing view that neurogenesis occurs beyond childhood into adulthood.

For two decades, humans have been comforted by scientific discoveries showing that specific regions of the human brain, primarily the hippocampus, continue to grow neurons throughout life, a finding that suggests more is better (for learning and memory that are governed by the hippocampus) and that there may be backup plans in case our old neurons die.

But scientists at the University of California, San Francisco (UCSF) have looked at dozens of tissue samples from autopsied brains and epilepsy patients undergoing resection and found that the birth of new neurons is robust in fetal life and during the first year of life but then decreases rapidly in childhood. In adults, it was not possible (with current technology used) to identify populations of new neurons. The oldest samples with evidence of neurogenesis came from seven-year-old and a thirteen-year-old, the researchers reported in the March 15 issue of Nature.

Until the late 1990s, it had long been thought that primates, including humans, are born with the complete set of neurons for a lifetime. Through development and beyond, humans lose neuronal cells, but never gain new ones. First came rodent and bird studies, then monkeys, refuting these age-old beliefs, and then evidence from humans as well.

In an editorial in the same issue of Nature, neuroscientist Jason Snyder, a doctoral candidate and assistant professor in the psychology department at the University of British Columbia, wrote that the findings “are in stark contrast to the prevailing view” and “certain to stir up controversy.”

The study was led by Arturo Alvarez-Buylla, PhD, the Heather and Melanie Muss professor of neurological surgery at the University of California, San Francisco. Dr. Alvarez-Buylla was at Rockefeller University in the 1980s working with his mentor, Fernando Nottebohm, PhD, who first reported the birth of new neurons in the brains of adult canaries and its possible link to learning their annual mating songs. Dr. Alvarez-Buylla has spent his career studying the mechanism of adult neurogenesis and began looking at human samples more than a decade ago.

“We find that neurogenesis in the adult hippocampus in humans, if it occurs at all, is an extremely rare phenomenon, raising questions about its contribution to brain repair or normal brain function,” said the neuroscientist. “We have just looked at one region of the brain. There is a lot more work to do. Clearly the fascinating process of making a new neuron continues in young children. We should continue to study how neurons are made and whether it is possible to induce new neurons to grow in the adult brain to treat brain diseases.”


Dr. Alvarez-Buylla and his colleagues studied 59 samples of human hippocampal tissue from UCSF and collaborating centers around the world. Thirty-seven came from postmortem brain samples and the rest were from fresh tissue excised from patients undergoing treatment for epilepsy. The samples came from fetuses, newborns, children, adolescents and adults. The oldest sample came from a 77-year-old.

The investigators used several techniques to tag neural stem cells and young neurons (the markers include doublecortin and PSA NCAM) to search for evidence of newborn and mature brain cells. They also used high resolution electron microscopy to examine the cell’s shape and structure to make sure they were looking at neurons and not glial cells.

Dr. Alvarez-Buylla and his colleagues found evidence of new neurons in the dentate gyrus of the hippocampus in the fetal brain tissue and in the samples from newborns and infants. They counted an average of 1,618 young neurons per square millimeter of brain tissue at birth. The older the infant, the fewer the new neurons. The tissue from one-year olds have five-fold fewer new neurons; there was a 23-fold decline by age seven, and new neurons were hard to find by adolescence. The teen brain had about 2.4 new cells per square millimeter of dentate gyrus tissue.

The investigators did find an occasional young neuron in a few adult post-mortem brain samples in the walls of the brain ventricles, as previously reported, but when looking at the hippocampus of samples from people over 18 years old, the group could not find the young neurons or much evidence of proliferation next to the dentate gyrus, said Dr. Alvarez-Buylla.

The group also looked for neural progenitor stem cells that give rise to neurons. Again, it was not surprising that the fetal brain was filled with these progenitors, particularly in regions were the dentate is growing, but these cells were gone by early childhood, he explained.

Dr. Alvarez-Buylla said that the idea for this study was sparked by a visit to the laboratory Zhengang Yang, PhD, at Fudan University in China and co-author on the current paper.

Dr. Yang showed him some beautifully stained samples of hippocampal tissue from a 35-year-old. The tissue was collected within hours of his death. “We could find some new neurons close to the walls of the ventricle, but not in the hippocampus,” said Dr. Alvarez-Buylla. That was four years ago.

Dr. Alvarez Buylla returned to California and started looking at more hippocampal tissue in samples collected at UCSF. Then, he and his colleagues looked at more tissue samples from Jose Manuel Garcia-Verdugo, PhD, of University of Valencia in Spain and from Gary W. Mathern, MD, from the University of California, Los Angeles, also study collaborators.

“We are simply reporting what we observed, and to correct the record that there is no significant neurogenesis in the adult human hippocampus,” Dr. Alvarez-Buylla said.

“The process of making a new neuron in the adult brain remains a fundamental problem that we need to understand,” added Dr. Alvarez-Buylla, who is co-founder of Neurona Therapeutics, and serves on its scientific advisory board. “What’s next is to do more research.”

He thinks that the replacement of neurons in the complex human brain could potentially change brain circuits in detrimental ways. “Neurons have the potential to live for very long periods of time. There may be important reasons why we may need to keep the neurons we develop in fetal and early postnatal development.

There could be other reasons, he explained: “Making a new neuron in large brains, like ours, may be complicated by the changes in development. We have speculated that the early specification of stem cells (that is linked to location) could make it very difficult to seed stem cells within niches that continually expand to incredibly large sizes. It could also be associated to longevity; stem cells may not be able to self-renew infinitively and in species that live as long as we do, these key progenitors may get used up in early life. We, simply, do not know why some species retain significant neurogenesis in adulthood, while others, like us don’t.”

He also stressed that this study focused only in the hippocampus and in the search for the new neurons in the dentate. “There is a lot of human brain yet to be explored.”

“I think that we need to step back and ask what that means,” added UCSF neuroscientist Shawn F. Sorrells, PhD, the first author of the Nature paper. “If neurogenesis is so rare that we can’t detect it, can it really be playing a major role in plasticity or learning and memory in the hippocampus?”


No one refutes the science that rodents continue to grow neurons throughout adulthood and that these neurons migrate to specialized regions like the dentate gyrus and the olfactory bulb. Elizabeth Gould, PhD, a neuroscientist at Princeton University, described neurogenesis in the dentate gyrus of adult rats in 1992. Fred H. Gage, PhD, a neurobiologist in the laboratory of genetics at The Salk Institute for Biological Sciences, published a series of studies suggesting that enriched environments and exercise could enhance adult neurogenesis in rats. Others showed that stress could diminish it.

Dr. Gage and his colleagues reported the first evidence of adult human neurogenesis in tissue samples from five cancer patients in 1997. Cancer doctors had used an imaging stain called bomodeoxyuridine (BrdU) in their patients to track tumor growth, and the scientists received permission to obtain brain slices right after the patients died. BrdU gets into the DNA of dividing cells, and the Salk scientists found staining in the dentate, which suggested that these were new neurons.


The science of adult neurogenesis continued to be debated as researchers questioned how robust the cellular growth is, where it is, and, most importantly, what is the purpose of this proliferation.

This new study may fuel this controversy. “This paper is the most thorough and rigorous study to date addressing human hippocampal neurogenesis,” said David R. Kornack, PhD, associate professor in the department of neuroscience at the University of Rochester. “It is such an important issue whether we continue to make new neurons in our brains as adults that the evidence has to be incontrovertible.”

Dr. Kornack has been studying neurogenesis for decades and was working with Pasko Rakic, MD, PhD, at Yale University School of Medicine, in the late 1990s when they identified evidence of adult neurogenesis in macaque monkeys — in a confocal microscope, they saw what they believed to be a small population of new neurons in the dentate gyrus of the hippocampus.

They published the study in 1999 in the Proceedings of the National Academy of Sciences, and Dr. Rakic continued to raise his concerns about adult neurogenesis in humans.

“For me, this new study closes the chapter about the prevalence of hippocampal neurogenesis in human adults,” added Dr. Kornack. “We are learning the powers and limitations of the technology and defining what a new neuron is. The strength of the finding is that they did see new neurons in younger tissue and not in older tissue. It confirms that hippocampal neurogenesis declines with age, which was already shown in monkeys and rodents. We are a long-lived species that rely on stored memories and behavior for our survival and stability. It may be a disadvantage to replace old neurons.”

His mentor agrees. “I feel vindicated,” said Pasko Rakic, MD, PhD, the Dorys McConnell Duberg professor of neuroscience and professor of neurology at Yale University School of Medicine. “I wanted to discover adult human neurogenesis, but I just couldn’t find it.”

Dr. Rakic said that adult neurogenesis is a limited event in the human brain, where even fewer new neurons were found than in the macaques. Additionally, he said adult rats had 10 to 14 times more new neurons in the hippocampus than the macaques had. The decreases in the number of these cells from rats to primates suggests, he said, “it must be more important not to have new neurons.”

Dr. Rakic added: “In evolution, our advantage is to preserve learned behavior. For memory, it isn’t productive to have new neurons but to preserve our old ones. We need stability of our neurons. If we added new neurons, they would not hold the memories of our past experiences. I use the same neurons I did as a child when I think of my mother. We need to invest in understanding how to keep our old neurons healthy. People think this is a negative finding. I think it is positive. It shows the value of keeping old cells in our brain, cells that have accumulated a lifetime of knowledge.”

Dr. Gage, PhD, of the Salk Institute for Biological Sciences, said that this latest study doesn’t disprove adult neurogenesis. Their conclusion is based “on the absence of morphological features and the lack of expression of two marker proteins, DCX and PSA-NCAM,” he said. “Both markers are very sensitive to methodological factors inherent to human brain tissue. One is the postmortem delay, the time between the death of a person and the moment the brain is removed and fixed. DCX is rapidly broken down after death and its staining disappears within a few hours of postmortem delay.”

He continued: “In this paper, many subjects had very long postmortem delays of ‘less than 48 hrs.’ As there is no mention of matching between subjects, or other optimization done in terms of the markers used, this influence of postmortem delay and on DCX integrity, which will also differ strongly between subjects, would question their conclusion about neurogenesis, as no control for DCX degradation was included.”

He added that adult mouse and adult human neurogenesis may use different proteins and they did not quantify or measure adult neurogenesis but rather proteins expressed in mice and immature cells.


•. Sorrells SF, Paredes MR, Cebrian-Silla A, et al Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults 2018; 555(7696): 377–381.

•. Snyder JS. Questioning human neurogenesis 2018; 555(7696):315–316.

•. Kornack DR, Rakic P. Continuation of neurogenesis in the hippocampus of the adult macaque monkey Natl Acad Sci USA 1999; 96(10):5768–5773.

© 2018 American Academy of Neurology


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[Abstract] Systematic review of high-level mobility training in people with a neurological impairment.



The objective of this paper was to systematically review the efficacy of interventions targeting high-level mobility skills in people with a neurological impairment.


A comprehensive electronic database search was conducted. Study designs were graded using the American Academy of Cerebral Palsy and Developmental Medicine (AACPDM) system and methodological quality was described using the Physiotherapy Evidence Database (PEDro) scale.


Twelve exploratory studies (AACPDM levels IV/V), of limited methodological quality (PEDro scores of 2-3 out of 10), were included. Interventions included treadmill training, a three-phase programme, a high-level mobility group, plyometric training, running technique coaching and walk training with blood flow restriction. Diagnoses included acquired brain injury, cerebral palsy, incomplete spinal cord injury and neurofibromatosis type 1. There were difficulties generalizing results from exploratory designs with a broad range of participants, interventions and outcome measures. However, it seems that people with a neurological impairment have the capacity to improve high-level mobility skills, running speed and distance with intervention. There were no adverse events that limited participation.


There is preliminary evidence to support the efficacy of interventions to improve high-level mobility skills in people with neurological impairments. Well-controlled research with a larger sample is required to provide sufficient evidence to change clinical practice.


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[ARTICLE] Technological Approaches for Neurorehabilitation: From Robotic Devices to Brain Stimulation and Beyond – Full Text

Neurological diseases causing motor/cognitive impairments are among the most common causes of adult-onset disability. More than one billion of people are affected worldwide, and this number is expected to increase in upcoming years, because of the rapidly aging population. The frequent lack of complete recovery makes it desirable to develop novel neurorehabilitative treatments, suited to the patients, and better targeting the specific disability. To date, rehabilitation therapy can be aided by the technological support of robotic-based therapy, non-invasive brain stimulation, and neural interfaces. In this perspective, we will review the above methods by referring to the most recent advances in each field. Then, we propose and discuss current and future approaches based on the combination of the above. As pointed out in the recent literature, by combining traditional rehabilitation techniques with neuromodulation, biofeedback recordings and/or novel robotic and wearable assistive devices, several studies have proven it is possible to sensibly improve the amount of recovery with respect to traditional treatments. We will then discuss the possible applied research directions to maximize the outcome of a neurorehabilitation therapy, which should include the personalization of the therapy based on patient and clinician needs and preferences.


According to the World Health Organization (WHO), neurological disorders and injuries account for the 6.3% of the global burden of disease (GBD) (12). With more than 6% of DALY (disability-adjusted life years) in the world, neurological disorders represent one of the most widespread clinical condition. Among neurological disorders, more than half of the burden in DALYs is constituted by cerebral-vascular disease (55%), such as stroke. Stroke, together with spinal cord injury (SCI), accounts for 52% of the adult-onset disability and, over a billion people (i.e., about a 15% of the population worldwide) suffer from some form of disability (3). These numbers are likely to increase in the coming years due to the aging of the population (4), since disorders affecting people aged 60 years and older contribute to 23% of the total GBD (5).

Standard physical rehabilitation favors the functional recovery after stroke, as compared to no treatment (6). However, the functional recovery is not always satisfactory as only 20% of patients fully resume their social life and job activities (7). Hence, the need of more effective and patient-tailored rehabilitative approaches to maximize the functional outcome of neurological injuries as well as patients’ quality of life (8). Modern technological methodologies represent one of the most recent advances in neurorehabilitation, and an increasing body of evidence supports their role in the recovery from brain and/or medullary insults. This manuscript provides a perspective on how technologies and methodologies could be combined in order to maximize the outcome of neurorehabilitation.

Current Systems and Therapeutic Approaches for Neurorehabilitation

The great progress made in interdisciplinary fields, such as neural engineering (910), has allowed to investigate many neural mechanisms, by detecting and processing the neural signals at high spatio-temporal resolution, and by interfacing the nervous system with external devices, thus restoring neurological functions lost due to disease/injury. The progress continues in parallel to technological advancements. The last two decades there has seen a large proliferation of technological approaches for human rehabilitation, such as robots, wearable systems, brain stimulation, and virtual environments. In the next sections, we will focus on: robotic therapy, non-invasive brain stimulation (NIBS), and neural interfaces.

Robotic Devices

Robots for neurorehabilitation are designed to support the administration of physical exercises to the upper or lower extremities, with the purpose of promoting neuro-motor recovery. This technology has a relatively long history, dating back to the early 1990s (11). Robot devices for rehabilitation differ widely in terms of mechanical design, number of degrees of freedom, and control architectures. As regards the mechanical design, robots may have either a single point of interaction (i.e., end effector) with the user body (endpoint robots or manipulanda) or multiple points of interaction (exoskeletons and wearable robots) (12).

Endpoint robots for the upper extremity, include Inmotion2 (IMT, USA) (13), KINARM End-Point (BKIN, Canada), and Braccio di Ferro (14) (Figure 1A1, left). Only some of these devices have been tested in randomized clinical trials (15), confirming an improvement of upper limb motor function after stroke (16). However, convincing evidence in favor of significant changes in activities of daily living (ADL) indicators is lacking (17), possibly because performance in ADL is highly affected by hand functionality. A good example of lower limb endpoint robot is represented by gait trainer GT1 (Reha-Stim, Germany). Its efficacy was tested by Picelli et al. (18), who demonstrated an improvement in multiple clinical measures in subjects with Parkinson’s disease following robotic-assisted rehabilitation when compared to physical rehabilitation alone (18). Endpoint robots are also available for postural rehabilitation. For instance, Hunova (Movendo Technology, Italy, launched in 2017) is equipped with a seat and a platform that induce multidirectional movements to improve postural stability (Figure 1A1, right).


Figure 1. Neurorehabilitation therapies. (A1) Endpoint robots: on the left the “Braccio di Ferro” manipulandum, on the right the postural robot Hunova. Braccio di ferro (14) is a planar manipulandum with 2-DOF, developed at the University of Genoa (Italy). It is equipped with direct-drive brushless motors and is specially designed to minimize endpoint inertia. It uses the H3DAPI programming environment, which allows to share exercise protocol with other devices. Written informed consent was obtained from the subject depicted in the panel. Movendo Technology’s Hunova is a robotic device that permits full-body rehabilitation. It has two 2-DOF actuated and sensorized platforms located under the seat and on the floor level that allow it to rehabilitate several body districts, including lower limb (thanks to the floor-level platform), the core, and the back, using the platform located underneath the seat. Different patient categories (orthopedic, neurological, and geriatric) can be treated, and interact with the machine through a GUI based on serious games. (A2) Wearable device: the recent exoskeleton Twin. Twin is a fully modular device developed at IIT and co-funded by INAIL (the Italian National Institute for Insurance against Accidents at Work). The device can be easily assembled/disassembled by the patient/therapist. It provides total assistance to patients in the 5–95th percentile range with a weight up to 110 kg. Its modularity is implemented by eight quick release connectors, each located at both mechanical ends of each motor, that allow mechanical and electrical connection with the rest of the structure. It can implement three different walking patterns that can be fully customized according to the patient’s needs viaa GUI on mobile device, thus enabling personalization of the therapy. Steps can be triggered via an IMU-based machine state controller. (B1) Repetitive transcranial magnetic stimulation (rTMS) representation. rTMS refers to the application of magnetic pulses in a repetitive mode. Conventional rTMS applied at low frequency (0.2–1 Hz) results in plastic inhibition of cortical excitability, whereas when it is applied at high frequency (≥5Hz), it leads to excitation (19). rTMS can also be applied in a “patterned mode.” Theta burst stimulation involves applying bursts of high frequency magnetic stimulation (three pulses at 50 Hz) repeated at intervals of 200 ms (20). Intermittent TBS increases cortical excitability for a period of 20–30 min, whereas continuous TBS leads to a suppression of cortical activity for approximately the same amount of time (20). (B2) Transcranial current stimulation (tCS) representation. tCS uses ultra-low intensity current, to manipulate the membrane potential of neurons and modulate spontaneous firing rates, but is insufficient on its own to discharge resting neurons or axons (21). tCS is an umbrella term for a number of brain modulating paradigms, such as transcranial direct current stimulation (22), transcranial alternating current stimulation (23), and transcranial random noise stimulation (24). (C) A typical BCI system. Five stages are represented: brain-signal acquisition, preprocessing, feature extraction/selection, classification, and application interface. In the first stage, brain-signal acquisition, suitable signals are acquired using an appropriate modality. Since the acquired signals are normally weak and contain noise (physiological and instrumental) and artifacts, preprocessing is needed, which is the second stage. In the third stage, some useful data or so-called “features” are extracted. These features, in the fourth stage, are classified using a suitable classifier. Finally, in the fifth stage, the classified signals are transmitted to a computer or other external devices for generating the desired control commands to the devices. In neurofeedback applications, the application interface is a real-time display of brain activity, which enables self-regulation of brain functions (25).

Continue —> Frontiers | Technological Approaches for Neurorehabilitation: From Robotic Devices to Brain Stimulation and Beyond | Neurology

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[WEB SITE] New brain cells are added in elderly adult brains too

According to a new study from the Columbia University however, brain cells are continuously added to our brains even when we reach our 70s. This is a process called neurogenesis. Their work is published in a study that appeared in the latest issue of the journal Cell Stem Cell this week.

Neuron detailed anatomy illustrations. Neuron types, myelin sheath formation, organelles of the neuron body and synapse. Image Credit: Tefi / Shutterstock

Lead author Dr. Maura Boldrini, a research scientist at the department of psychiatry, Columbia University and her colleagues investigated the brains of 28 dead people aged between 14 and 79 years. They were studying the effects of aging on the brain’s neuron production. The team examined the brains that were donated by the families of the deceased at the time of death. The brains were frozen immediately at minus-112 degrees Fahrenheit before they could be examined. This preserved the tissues.

Neurogenesis has been shown to decline with age in lab mice and rats as well as in experimental primates. The team wanted to explore if same rates of decline are seen in human brains as well. So they checked the brains samples for developing neurons. These developmental stages included stem cells, intermediate progenitor cells, immature neuronal cells and finally new mature neurons. They focused on the hippocampus region of the brain that deals with memory and emotional control and behavior.

The results revealed that for all age groups, the hippocampus shows new developing neurons. The researchers concluded that even during old age, the hippocampus continues to make new neurons. The differences that they noted with age include reduction in the development of new blood vessels as people got older. The proteins that help the neurons to make new connections are reduced with age. This was a finding that differentiated ageing brains from younger ones, they explained. Boldrini said the new neurons are there in older brains but they make fewer connections than younger brains. This explains the memory losses and decrease in emotional resiliency in older adults she said.

An earlier study last month came from another set of researchers led by University of California San Francisco researcher Arturo Alvarez-Buylla. The study titled, “Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults,” was published first week of March this year in the journal Nature.

The team found that after adolescence there is little or no neurogenesis in the brain. They examined the brains of 17 deceased individuals and 12 patients with epilepsy part of whose brains had been surgically resected. The debate between the two teams continues. Boldrini explained that Buylla’s team had examined different types of samples that were not preserved as her samples had been.

Further the other team examined three to five sections of the hippocampus and not the whole of it she explained. More studies on this needed to make concrete conclusions regarding neurogenesis in the elderly say experts.


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[ARTICLE] Cerebral Reorganization in Subacute Stroke Survivors after Virtual Reality-Based Training: A Preliminary Study – Full Text



Functional magnetic resonance imaging (fMRI) is a promising method for quantifying brain recovery and investigating the intervention-induced changes in corticomotor excitability after stroke. This study aimed to evaluate cortical reorganization subsequent to virtual reality-enhanced treadmill (VRET) training in subacute stroke survivors.


Eight participants with ischemic stroke underwent VRET for 5 sections per week and for 3 weeks. fMRI was conducted to quantify the activity of selected brain regions when the subject performed ankle dorsiflexion. Gait speed and clinical scales were also measured before and after intervention.


Increased activation in the primary sensorimotor cortex of the lesioned hemisphere and supplementary motor areas of both sides for the paretic foot (p < 0.01) was observed postintervention. Statistically significant improvements were observed in gait velocity (p < 0.05). The change in voxel counts in the primary sensorimotor cortex of the lesioned hemisphere is significantly correlated with improvement of 10 m walk time after VRET (r = −0.719).


We observed improved walking and increased activation in cortical regions of stroke survivors after VRET training. Moreover, the cortical recruitment was associated with better walking function. Our study suggests that cortical networks could be a site of plasticity, and their recruitment may be one mechanism of training-induced recovery of gait function in stroke. This trial is registered with ChiCTR-IOC-15006064.

1. Introduction

Gait impairment is a common consequence of stroke, and the decreases in gait velocity, stride length, and cadence are hallmark features of gait pattern alterations in stroke survivors [12]. Previous studies found that early intervention with physical therapy and gait training to restore walking after stroke was recommended to improve motor function and decrease disability [34]. As gait impairments are a result of deficient neuromuscular control, a better understanding of the impact and mechanism of those interventions on gait pattern recovery after stroke is therefore essential.

Environmental factors act as critical determinants for the level of community ambulation of stroke patient [5]. The development of computers has resulted in virtual reality (VR) tools which can create life-like scenarios via visual, auditory, and tactile feedback and can provide subjects with a safe and stimulating learning environment [6]. VR has been increasingly used in poststroke rehabilitation; therapy interventions using VR may improve motor function for those patients [715]. VR system might represent the main neural substrate for relearning or resuming impaired motor functions following stroke. A key challenge in neurorehabilitation is to establish optimal training protocols for the given patient [10]. VR could provide a person with senses of encouragement and accomplishment [1619]. However, two main concerns need to be investigated. What kind of rehabilitation strategies can combine with VR, and what degree for those VR combined rehabilitation strategies can facilitate stroke patients? Recently, motor relearning strategies can be applied in VR-enhanced treadmill (VRET) training by numerous movement repetitions and a multisensory approach to stimulate brain plasticity and patients receive visual feedback which is close to real-life experience [12]. While the positive benefits of VRET exercise on gait speed, cadence, step length, community walking time, and balance have been demonstrated [7911121415], the associated changes of brain activity with this training have not been investigated yet.

Advances in imaging, such as blood oxygenation level-dependent functional magnetic resonance imaging (fMRI), have been allowed for the observation of changes in cerebral plasticity and the exploration of recovery mechanisms. The control of gait involves the planning and execution from multiple cortical areas, such as secondary and premotor cortex [11]. Ankle dorsiflexion is an important kinematic aspect of the gait cycle. Using ankle movement, Enzinger et al. [20] observed increased activation in the unlesioned hemisphere associated with increasing functional impairment of the paretic leg in patients with stroke. fMRI studies of patients after stroke have suggested that VR could increase neural activations in the primary motor areas and improve lateralization of primary sensorimotor cortex (SMC) activity [2123]. We hypothesized that recovery of lower limb function after VRET would be associated with changes in brain activation during ankle dorsiflexion.

Therefore, the primary aim of this preliminary study was to investigate if functional reorganization takes place after VRET in subacute stroke survivors with gait impairment, using fMRI and an ankle dorsiflexion paradigm. Correlation between clinical scale changes after VERT and brain activation alterations was also studied to see the relations of the induction of cortical plasticity and functional recovery in subacute stroke survivors. We hope that the results of the current study could help to understand the mechanism of VRET as an early intervention for gait recovery for stroke.

2. Methods

2.1. Participants

Eight stroke survivors were recruited in this study, aged 41–72 years (mean: 58.38 years) and included 6 males and 2 females (Table 1 and Figure 1). Inclusion criteria: (i) 18 to 80 years in ages; (ii) right-foot dominant; (iii) first incident of ischemic cortical or subcortical stroke which resulted in gait impairment; (iv) stroke was confirmed by MRI within the past 3 months of inclusion; (v) at least 10° of dorsiflexion is available at the ankle. Exclusion criteria: (i) contraindication to MRI scan (implanted medical devices incompatible with MRI testing or claustrophobia); (ii) history of stroke resulted in function impairment; (iii) history of mental disorder or the use of antipsychotic medication; (iv) cognitive impairment (Mini-Mental State Examination score of less than 24 points); (v) unable to speak or hear; (vi) history of recent deep vein thrombosis of the lower limbs; (vii) recent myocardial infarction; (viii) medically unstable; (ix) existing lower extremity pathology. This study was approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University (SYSU), and all subjects provided informed consent before the experiments.

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Figure 1
Axial structural T1-weighted MRI scans at the level of maximum infarct volume for each patient. And right hemisphere patients flipped on the sagittal axis for better comparison.


Continue —> Cerebral Reorganization in Subacute Stroke Survivors after Virtual Reality-Based Training: A Preliminary Study

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[ARTICLE] Quantification of Upper Limb Motor Recovery and EEG Power Changes after Robot-Assisted Bilateral Arm Training in Chronic Stroke Patients: A Prospective Pilot Study – Full Text PDF

Background. Bilateral arm training (BAT) has shown promise in expediting progress toward upper limb recovery in chronic stroke patients, but its neural correlates are poorly understood.

Objective. To evaluate changes in upper limb function and EEG power after
a robot-assisted BAT in chronic stroke patients.

Methods. In a within-subject design, seven right-handed chronic stroke patients with upper limb paresis received 21 sessions (3 days/week) of the robot-assisted BAT. The outcomes were changes in score on the upper limb section of the Fugl-Meyer assessment (FM), Motricity Index (MI), and Modified Ashworth Scale (MAS) evaluated at the baseline (T0), posttraining (T1), and 1-month follow-up (T2). Event-related desynchronization/synchronization were calculated in the upper alpha and the beta frequency ranges.

Results. Significant improvement in all outcomes was measured over the course of the study. Changes in FM were significant at T2, and in MAS at T1 and T2. After training,
desynchronization on the ipsilesional sensorimotor areas increased during passive and active movement, as compared with T0.

Conclusions. A repetitive robotic-assisted BAT program may improve upper limb motor function and reduce spasticity in the chronically impaired paretic arm. Effects on spasticity were associated with EEG changes over the ipsilesional sensorimotor network.

1. Introduction

Poststroke upper limb impairment strongly influences
disability and patients’ quality of life [1, 2]. Considering that
up to two-thirds of stroke survivors suffer from upper limb
dysfunctions, one of the main goals of rehabilitation is to
improve recovery of upper limb functioning. Many
rehabilitation approaches have been put forward [3–5].
However, there is strong evidence that the conceptual evolution
of stroke rehabilitation promotes high-intensity, taskspecific,
and repetitive training [3, 5, 6]. To this end, the
application of robot-assisted therapy has steadily gained
acceptance since the 1990s [7, 8]. Robotic devices, in fact,
allow repetitive, interactive, high-intensity, and task-specific

upper limb training across all stages of recovery and neurological
severity as well [6].
A meta-analysis has shown significant, homogeneous
positive summary effect sizes (SESs) for upper limb motor
function improvements and muscle strength with the use of
elbow-wrist robots in a bilateral mode [5]. Although subgroup
analysis revealed no significant differences between
phases post stroke [5], bilateral arm training (BAT) has
shown great promise in expediting progress toward poststroke
recovery of upper limb functioning even in the chronic
phase [6, 9–11].
BAT is a form of training in which both upper limbs perform
the same movements simultaneously and independently
of each other [12]. It can be undertaken in different
modes (in-phase, antiphase) and training modalities (i.e.,
active, passive, and active-passive) [13]. The beneficial effects
of BAT are thought to arise from a coupling effect in which
both limbs adopt similar spatio-temporal movement parameters
leading to a sort of coordination [14]. Active-passive
BAT of the wrist has been investigated in behavioral and neurophysiological
studies [11, 15]. It consists of rhythmic, continuous
bimanual mirror symmetrical movements during
which the patient actively flexes and extends the “unaffected”
wrist, while the device assists the movement of the “affected”
wrist in a mirrored, symmetrical pattern via mechanical coupling
[15–19]; that is, movement of the affected upper limb is
facilitated by the unaffected one [12]. Previous studies have
reported that this pattern of coordinated movement leads
to improvements in upper limb function [11, 16, 19, 20] associated
with an increase in ipsilesional corticomotor excitability
[11]. In addition, passive BAT of the forearm and the wrist
has been shown to lead to a sustained reduction of muscle
tone in hemiparetic patients with upper limb spasticity [20].
Current evidence indicates that the neural correlates of
BAT are poorly understood [13]. The limitations of previous
studies are threefold. First, patient characteristics such as
type and site of stroke lesion were not consistently reported
[21], precluding full understanding of motor and neural
responses to BAT. Second, different BAT modalities (i.e.,
in-phase, antiphase, active, and active-passive) combined or
not with other interventions (i.e., functional tasks or free
movements with rhythmic auditory cues) have been
reported. As different training modalities are thought to
exploit different clinical effects and neural mechanisms
[22], the relationship between each of these specific modes
(delivered as a single intervention) and brain activity patterns
needs to be more precisely explored [13]. Finally, a wide
range and variation of neurophysiological and neuroimaging
measures have been used among studies.
Essentially, transcranial magnetic stimulation (TMS)
and functional magnetic resonance imaging (fMRI) studies
have been used to investigate the neural correlates of BAT.
Strength and weakness might be acknowledged for both
techniques when applied in a neurorehabilitation setting
[23]. TMS is an important tool that fits in the middle of
the functional biology continuum for assessment in stroke
recovery. However, it has the disadvantage of not being as
relevant as other biologic measures in gathering information
on brain activity during different states (or tasks) [23],
unless electroencephalography (EEG) is recorded simultaneously
Functional imaging and related techniques ((fMRI),
positron emission tomography (PET), EEG, magnetoencephalography
(MEG), and near-infrared spectroscopy (NIRS))
are important tools to determine the effects of brain injury
and how rehabilitation can change brain systems [23].
fMRI is the most widely used technique for studying brain
function. Several fMRI studies have described movementrelated
changes in motor cortical activation during partial
recovery of the affected limb in stroke patients [25], and
many studies have described the effects of various rehabilitative
treatments on motor activation.
fMRI shows difficulties when exploring brain functions
during robot-assisted sensorimotor tasks because only a few
devices are MRI compatible [26–28] and their use in the clinical
setting is limited by regulation (i.e., CE marking).
The EEG technique, conversely, has considerable
advantages over other methods in the rehabilitation setting
[17, 18, 29] being portable and readily operable with different
robotic devices. Finally, the higher temporal resolution of
EEG than fMRI signals allows monitoring brain activity during
movement execution [30–32]. EEG alpha and beta band
powers decrease during motor execution over the premotor
and primary sensorimotor cortex; at the end of the movement,
a rebound of beta activity is observed over the ipsilesional
side. These power changes are termed, respectively,
event-related desynchronization (ERD)—that is, power band
decrease—and event-related synchronization (ERS)—that is,
power band increase [33].
To the best of our knowledge, no study has addressed
changes in EEG power alongside changes in upper limb
motor function after passive robot-assisted BAT (RBAT).
Therefore, the aim of this pilot study was to evaluate
changes in both EEG power by investigating the
topographical distribution of event ERD/ERS, and upper
limb recovery of function after passive R-BAT in chronic
stroke patients. Conducting a small-scale pilot study
before the main study can enhance the likelihood of success
of the main study. Moreover, information gathered
in this pilot study would be used to refine or modify
the research methodology and to develop large-scale studies
[34]. The work hypothesis was that R-BAT would
improve recovery of upper limb function and that these
effects would be associated with an increase in activation of
the ipsilesional hemisphere.[…]

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