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Imaging, Pediatrics, Research, Stanford News

Neural networks show impairment from fragile X syndrome

Neural networks show impairment from fragile X syndrome

Fragile X syndrome – caused by a gene mutation on the X chromosome – doesn’t get a lot of press, but it’s the most common form of inherited intellectual disability.

Approximately 1 in 4,000 males and 1 in 8,000 females have it. According to my quick back-of-the-envelope calculation, based on 2010 data from the U.S. Census Bureau, that works out to roughly 56,000 afflicted people in the U.S.

The findings could aid in developing different kinds of treatment for fragile X

Researchers have known that certain regions of the brain are structurally altered in people with the condition, but now some researchers at Stanford and Lucile Packard Children’s Hospital have identified several large-scale neural networks that appear to be impaired by the condition. The findings could help in devising treatments for the disorder.

The researchers conducted a magnetic resonance imaging study of some children and young adults with fragile X syndrome, which, combined with some recently developed methods of quantifying brain activity, revealed the impairments. The neural network that showed the greatest impairment was the salience network, which is thought to be involved in evaluating emotional stimuli and generating appropriate responses.

According to researcher Scott Hall, PhD, an assistant professor of psychiatry and behavioral sciences here and a member of the Child Health Research Institute at Packard Children’s who worked on the study:

The findings could aid in developing different kinds of treatment for fragile X, both by helping researchers understand where the processing problems or deficits lie in the brain and also in potentially giving them a way to assess the effectiveness of a particular treatment, either by comparing brain scans from before and after a behavioral therapy session or observing scans during a course of medication.

The outward symptoms of fragile X syndrome are similar to those of people with autism – pronounced social awkwardness, language impairment and repetitive actions. Although autism is diagnosed solely on behavioral criteria, the researchers are hopeful the technique they employed might also be useful in diagnosing subgroups of children with autism, which could aid in developing new therapies.

You can read a more detailed account of the study, which was published online today in JAMA Psychiatry, and its possible ramifications in our press release.

Previously: How better understanding Williams syndrome could advance autism research and Two robust fragile X syndrome findings intersect

Cancer, Imaging, Research, Stanford News

Dynamic duo: Nanoparticle/prodrug combination finds and fights tumors, files reports

Dynamic duo: Nanoparticle/prodrug combination finds and fights tumors, files reports

Hazard_Journal of Small_COVER_v04Routine chemotherapy is a somewhat sloppy way of combating cancer, because the drugs employed work by killing rapidly dividing cells, not just cancerous ones. Hair cells, skin cells, the immune system, cells lining the intestine, and even a small but critical set of cells in the brain necessary for forging new memories – all these can be adversely affected.

But a Stanford team under the direction of radiologist/physician Heike Daldrup-Link, MD, and chemist Jianghong Rao, PhD, has produced a seek-and-destroy cancer therapy that could sharpen the attack while simultaneously making it easier to noninvasively visualize the therapy’s progress. In a study just published in the nanotechnology journal Small, the team describes the linking of an easily imaged, FDA-approved iron-rich nanoparticle, ferumoxytol, to a prodrug (a compound that, while lacking activity on its own, can get converted in the body into a potent drug).

The key to the success of this so-called theranostic is the pummeling it gets from matrix metalloproteinases, a family of enzymes that make their living by breaking down the molecular latticework that positions cells within  tissues. Most tumors are particularly rife with one of this family’s members, MMP-14, whose activities help tumors invade other, healthy tissues. Conveniently, MMP-14 is precisely the enzyme best equipped to carve up the prodrug,  releasing its active component. MMP-14 is found not only on tumor cells but, importantly, on the tiny blood vessels that pervade and feed them. When the theranostic particles, circulating in the bloodstream upon intravenous administration, reach those blood vessels, the drug is released, causing the vessels to cave in and starving the tumor mass that so depends on them.

The nanoparticles tend to stick around inside the collapsed microvasculature, allowing radiologists to see just where the drug has done its job (and, by extension, where cancerous lesions, including previously unknown ones, are in the body). Meanwhile healthy tissues are spared, tests in mice suggest.

Previously: Iron-supplement-slurping stem cells can be transplanted, then tracked to make sure they’re making new knees and Nano-hitchhikers ride stem cells into heart, let researchers watch in real time and weeks later
Image provided by Kim Gray Hazard

Imaging, Neuroscience, Research, Stanford News

Humor as a mate selection strategy for women?

Humor as a mate selection strategy for women?

woman laughingMy colleagues and I recently had a paper, “Sex-differences during humor appreciation in child-sibling pairs,” published in the journal Social Neuroscience. The gist of our work was that girls’ and boys’ brains respond differentially to funny versus positive (enjoyable to watch but non-funny) movie clips. Shortly after its appearance, stories began to circulate on the Internet with titles such as: “Women prefer funny guys, it’s scientifically proven.” As our study was performed in children, we were initially surprised by these comments. But on further thought, we realized that while speculative, this interpretation deserves comment.

A good sense of humor is an important human-mate preference worldwide. But why is it that humor ranks so high amongst other desirable mate characteristics? And why should humor serve as a tool for choosing a mate, particularly for women?

Sexual selection theory in mammals suggests that females, as compared to males, invest more time and energy in childbearing and parenting. Therefore, females are more restricted than males in the number of offspring they can conceive. This restriction normally entails higher selectivity during mate selection in females, as they prioritize quality, rather than quantity, of offspring.

One consequence of this theory, when applied to humans, is that men compete for women’s attention. And here is where humor may come into play. Humor could serve as a mate selection tool because it provides women with information about men’s mating quality beyond what meets the eye. Humor does not equate to just “being funny;” it is associated with more complex characteristics such as creativity, intelligence, resilience and social skills. By selecting men with a good sense of humor, women may be more likely to choose mates who are witty, smart, adaptive and socially talented.

Finally, if humor is one tool for selecting a potential mate, women’s and men’s brains could have evolved differentially to make use of this mechanism. Specifically, women’s brains may have developed a predisposition for evaluating humor while men’s brains may have developed a different predisposition for producing humor. Combined with previous adult research from our lab, our new findings provide very preliminary neuroimaging evidence of sex-differences related to humor evaluation versus production. One possible neural mechanism may be related to reward expectation, a finding discussed in our paper.

As we pointed out in our paper, this study had relatively small group sizes and was in children, and as such, more research at many levels is needed to elaborate on the theoretical relations among humor, sex, and mate selection.

Pascal Vrticka, PhD, is a postdoctoral scholar in Stanford’s Center for Interdisciplinary Brain Sciences Research. Center director Allan Reiss, MD, was senior author of the paper discussed here.

Previously: Making kids laugh for science: Study shows how humor activates children’s brains and How sense of humor develops in the brain
Photo by wickenden

Imaging, Neuroscience, Pediatrics, Research

Study shows brain scans could help identify dyslexia in children before they start to read

Study shows brain scans could help identify dyslexia in children before they start to read

In adults, reading ability is linked Reading boy and girlto the size and structure of the left arcuate fasciculus – a bridge-like structure in the brain that connects two regions associated with written and spoken language. In people that have had difficulty reading their entire life, a condition called developmental dyslexia, this bridge is smaller and less structurally sound. Until recently, it was unknown if the architecture of this bridge determines how easily we can read, or if it’s a consequence of how often we practice reading.

Now research of children just beginning to read shows that kids with early signs of dyslexia have a smaller and less-organized left arcuate fasciculus. This study, led by researchers from Massachusetts Institute of Technology’s McGovern Institute for Brain Research, is notable because it suggests that the size and integrity of this region of the brain may influence reading ability. The applications of these findings are discussed in the MIT press release:

About 10 percent of the U.S. population suffers from dyslexia, a condition that makes learning to read difficult. Dyslexia is usually diagnosed around second grade, but the results of a new study from MIT could help identify those children before they even begin reading, so they can be given extra help earlier.

This study builds on previous studies, including the work of UCSF’s Fumiko Hoeft, MD, PhD, formerly an instructor at Stanford’s Center for Interdisciplinary Brain Sciences Research. The center’s director, reading development expert Brian Wandell, PhD, weighs in on the findings of this new study in the release:

“The work identifies a clear marker that predicts reading, and the marker is present at a very young age. Their results raise questions about the biological basis of the marker and provides scientists with excellent new targets for study,” says Wandell, who was not part of the research team.

As the study explains, people with dyslexia often use specialized educational tools to address their reading skills and needs. Since this requires the coordinated care of parents, medical professionals and teachers, brain scans could help people manage dyslexia sooner and more effectively.

Holly MacCormick is a writing intern in the medical school’s Office of Communication & Public Affairs. She is a graduate student in ecology and evolutionary biology at University of California-Santa Cruz.

Previously: Researchers use brain imaging to predict which dyslexics will learn to readImaging study shows little difference between poor readers with low IQ and poor readers with high IQImproving patients’ lives through video games and Stanford study furthers understanding of reading disorders
Photo by ThomasLife

Aging, Imaging, Immunology, Mental Health, Neuroscience, Research, Stanford News

Protein known for initiating immune response may set our brains up for neurodegenerative disorders

Protein known for initiating immune response may set our brains up for neurodegenerative disorders

brain signalsA healthy person’s brain has thousands (maybe millions) of times as many synapses - contact points that relay signals from one nerve cell to the next – as there are stars in the Milky Way.

In a sense, “you” are your synapses. They’re the defining features of the brain circuits that fire up or chill out to generate every thought that passes through your mind and every flicker of emotion or glimmer of recollection you experience. You wouldn’t want to leave home without them.

Some of us get no choice. Massive synapse loss accompanies neurodegenerative diseases from Alzheimer’s to Parkinson’s to multiple sclerosis.

All these disorders are age-related, says Stanford neuroscientist Ben Barres, MD, PhD. “Kids don’t get Alzheimer’s or Parkinson’s,” he told me last week. “And now we think we know why.”

In a study just published in The Journal of Neuroscience, Barres and his colleagues have shown that in perfectly healthy brains, deposits of a protein called C1q gradually build up over time, concentrating at synapses. Interestingly, the first noticeable synaptic C1q deposits appear in the brain centers typically affected early in Alzheimer’s and Parkinson’s.

With advancing age, these deposits spread throughout the brain. By themselves, they don’t seem to impair brain function much. But they may set us up for catastrophic synapse loss.

That’s because C1q is not just any old protein. It’s well known to immunologists as the first batter on a 20-member team of immune-response-triggering proteins collectively called the complement system, as I wrote in my press release announcing Barres’ new study:

C1q is capable of clinging to the surface of foreign bodies such as bacteria or to bits of our own dead or dying cells. This initiates a molecular chain reaction known as the complement cascade. One by one, the system’s other proteins glom on, coating the offending cell or piece of debris. This in turn draws the attention of omnivorous immune cells that gobble up the target … The brain has its own set of immune cells, called microglia, which can secrete C1q. Still other brain cells, called astrocytes, secrete all of C1q’s complement-system “teammates.” The two cell types work analogously to the two tubes of an Epoxy kit, in which one tube contains the resin, the other a catalyst.

Barres has previously shown that in developing brains, which invariably produce a surfeit of synapses, C1q and its complement partner proteins team up to “prune” unused synapses (by flagging them for microglia to gobble up), resulting in more efficient brain architecture. But he suspects the same thing may be happening – inappropriately – in aging brains, where steady C1q accumulation may set the stage for induction of the complement cascade by an astrocyte-inciting incident: say, a head injury, inflammatory infection or series of tiny strokes.

Since, unlike most other cells in the body, nerve cells have no natural defenses against a complement-cascade onslaught, the outcome could be a self-sustaining feeding frenzy of synaptic snacking.

That’s the bad news. The good news: The finding could lead to ways of slowing or  stopping the waves of synaptic destruction that characterize neurodegenerative disease.

Previously: Neuroinflammation, microglia, and brain health in the balance, Malfunctioning glia – brain cells that aren’t nerve cells  – may contribute big time to ALS and other neurological disorders and Unsung brain-cell population implicated in variety of autism
Photo by A Health Blog

Aging, Imaging, Orthopedics, Research, Stanford News, Stem Cells, Surgery

Iron-supplement-slurping stem cells can be transplanted, then tracked to make sure they’re making new knees

Iron-supplement-slurping stem cells can be transplanted, then tracked to make sure they're making new knees

kneesAs a population ages, so do its knees. Americans undergo 700,000 knee-replacement operations annually – a number expected to quintuple within two decades.

Prosthetic implants, for the most part a godsend for those with knee problems, come with problems of their own. They can induce fractures in nearby bone. They can gradually loosen over time. Even in the absence of complications, they can wear out – their average lifetime is around 10 years – and a second surgery is technically tougher going than the first was.

In a fortunate development for the creaky-kneed among us, a study just published in Radiology and led by Stanford pediatric radiologist Heike Daldrup-Link, MD, PhD, promises to expedite clinical trials of  a class of “adult” stem cells with great potential for knee repair.

These cells, known as mesenchymal stem cells (which I’ll call MSCs), ordinarily reside in bone marrow. Unlike embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs), MSCs can’t differentiate into all the 200-plus tissues in the physiological rainbow that is our body. That’s good: A major concern about using ESCs or iPSCs for regenerative medicine is their capacity to form tissues wildly inappropriate for the job at hand or even to spawn tumors.

MSCs pretty much generate only bone, cartilage, muscle or fat, in response to cues from their immediate environment. Plus, they can be easily extracted from bone marrow of patients who are going to undergo the knee-repair procedure.

The trouble is, just shooting MSCs into a knee-injury site doesn’t automatically mean they’ll generate the wanted tissues, in the wanted amounts, right where they’re wanted. They might migrate away. They might die, refuse to engraft or fail to replicate and differentiate. They might develop into, say, scar tissue instead of cartilage or bone.

But how would you know? One way to see how newly transplanted MSCs are behaving requires labeling them, by loading them up with iron in the laboratory, between their extraction and their injection into the knee.  This makes them visible via magnetic-resonance imaging (MRI), so they can be monitored afterwards.

But, as I wrote in my news release on the study:

Upon extraction, the delicate cells have to be given to lab personnel, incubated with contrast agents, spun in a centrifuge and washed and returned to the surgeons, who then transplant the cells into a patient.

Regulatory agencies and opinion leaders rightly look askance at the potential contamination that can be introduced when stem cells are manipulated in lab glassware. Besides, MSCs in a lab dish have scant appetite for iron particles.

Daldrup-Link’s team showed that – for whatever reason – the very MSCs that eschew iron in a dish munch it right up when they’re hanging out in the bone marrow. They gave rats an injected “snack” of  ferumoxytol, an FDA-approved supplement composed of iron-oxide nanoparticles. When they later harvested MSCs from those rats’ bone marrow and infused them into other rats’ injured knees, they could track the the iron-stuffed MSCs for weeks afterward because they gave off a powerful MRI signal.

Stanford orthopedic surgeon Jason Dragoo, MD, plans to conduct a clinical trial this fall using the new MSC-labeling method. MSCs extracted from feroxytol-supplemented knee-damaged patients’ bone marrow will be delivered to those same patients in a single procedure, eliminating the delay and greatly reducing the contamination risk associated with lab-based labeling.

Previously: Nano-hitchhikers ride stem cells into heart, let researchers watch in real time and weeks later, FDA audit of Texas stem cell clinic revealed by Houston Chronicle and From college football player to team physician: A look at the career of Stanford’s Jason Dragoo
Photo by Jesse.Millan

Imaging, Neuroscience, Pediatrics, Research, Science, Stanford News

Peering into the brain to predict kids’ responses to math tutoring

Peering into the brain to predict kids' responses to math tutoring

Third grade is a critical year for learning arithmetic facts, but while math comes easily to some children, others struggle to master the basics.

Now, researchers at Stanford have new insight into what separates adept young math students from those who have difficulty. The difference, described in a paper published today in the Proceedings of the National Academy of Sciences, can’t be detected with traditional intelligence measures such as IQ tests. But it shows up clearly on brain scans, as the new study’s senior author explained in our press release:

“What was really surprising was that intrinsic brain measures can predict change — we can actually predict how much a child is going to learn during eight weeks of math tutoring based on measures of brain structure and connectivity,” said Vinod Menon, PhD, the study’s senior author and a professor of psychiatry and behavioral sciences.

Menon’s research team conducted structural and functional MRI brain scans before third-grade students received 8 weeks of individualized math tutoring. The tutoring followed a well-validated format, combining instruction on math concepts with practice of math problems emphasizing speed. All the children who received math tutoring improved their math performance, but the performance improvements varied a lot — from 8 percent to 198 percent.

A few specific brain characteristics were particularly good at predicting which kids would benefit most from tutoring. In particular, a larger and better-wired hippocampus predicted performance improvements. The brain structures highlighted in the study are implicated in forming memories, and differ from the portions of the brain that adults use when they are learning about math. The fact that these systems are involved helps to explain why the combination of conceptual explanations and sped-up practice that the study’s tutors used is effective, Menon explained:

“Memory resources provided by the hippocampal system create a scaffold for learning math in the developing brain,” Menon said. “Our findings suggest that, while conceptual knowledge about numbers is necessary for math learning, repeated, speeded practice and testing of simple number combinations is also needed to encode facts and encourage children’s reliance on retrieval — the most efficient strategy for answering simple arithmetic problems.” Once kids are able to pull up answers to basic arithmetic problems automatically from memory, their brains can tackle more complex problems.

Next, the researchers plan to examine how brain wiring changes over the course of tutoring. The new findings could also help educators understand the basis for math learning disabilities, and may even provide a foundation for figuring out what kind of instruction could help children overcome these problems.

Previously: New research tracks “math anxiety” in the brain and We’ve got your number: Exact spot in brain where numeral recognition takes place revealed
Photo by Canadian Pacific

Image of the Week, Imaging, Neuroscience, Research, Stanford News

Image of the Week: 3-D rendering of a clarified brain

Image of the Week: 3-D rendering of a clarified brain

Earlier this week, fellow Scope contributor Bruce Goldman reported on a paradigm-shifting process developed by Stanford psychiatrist and bioengineer Karl Deisseroth, MD, PhD, and colleagues. Using the process, called CLARITY, scientists were able to turn a mouse brain into an “optically transparent, histochemically permeable replica of itself.”

National Institutes of Health Director Francis Collins, MD, PhD, commented on the breakthrough in a recent blog post, saying:

CLARITY is powerful. It will enable researchers to study neurological diseases and disorders, focusing on diseased or damaged structures without losing a global perspective. That’s something we’ve never before been able to do in three dimensions.

This haunting image depicts a three-dimensional rendering of clarified brain imaged from the ventral half. To fully experience the new method’s awe-inspiring capabilities, watch this fly-through video.

Previously: Scientific community (and Twitter) buzzing over Stanford’s see-through brain, Lightning strikes twice: Optogenetics pioneer Karl Deisseroth’s newest technique renders tissues transparent, yet structurally intact and Peering deeply – and quite literally – into
Photo by Deisseroth lab

Behavioral Science, Imaging, Medicine and Society, Neuroscience, Research, Stanford News

Brains of different people listening to the same piece of music actually respond in the same way

Brains of different people listening to the same piece of music actually respond in the same way

Ever wonder – say, while sitting quietly in a concert hall or screaming your lungs out in a crowded ampitheater – whether the musical experience you’re having is anything like that of the person three seats up or three sheets to the wind on your right?

A partial answer is in: Our brains process music in pretty much the same way, providing it’s got the requisite combination of components (rhythm, melody, harmony, etc.), according to Stanford neuroscientist Vinod Menon, PhD. In a just-published study, Menon’s group monitored several healthy peoples’ brains while these subjects listened to the same piece of music. As the music played on, activity in a broadly distributed network of neuroanatomically connected brain areas waxed and waned very similarly for each listener. This synchrony among individual responses was absent when participants listened to “pseudomusic” stripped of  either rhythmic or tonal characteristics.

The inter-subject synchronization extended to the brain’s movement-planning zone. Evolution, it seems, has designed us this way. As I wrote in my release about the study:

[O]ur brains respond naturally to musical stimulation by foreshadowing movements that typically accompany music listening: clapping, dancing, marching, singing or head-bobbing. The apparently similar activation patterns among normal individuals make it more likely our movements will be socially coordinated.

It’s easy to imagine the survival value of coordinated movement in response to auditory cues. Hunting, gathering, warmaking – all benefit from choreography. That would objectively explain how people who run, shout and pump their fists in synch might win the evolutionary race.

But about the subjective aspect of this synchronization, I’m not so sure.

Look. It’s important that our brains respond similarly to identical stimuli. But what about our minds? In the house of mirrors that is our consciousness, how can we know whether music sounds the same, or color looks the same, to different people?

This takes me back to long ago when, as a philosophy major at the University of Wisconsin, I flunked a course in epistemology. That’s the philosophy of what we know and how we know it, and what we think we know that, actually, we don’t. Turns out I didn’t know much.

One day, the professor – a tweedy, pipe-puffing Princeton man who paced the room in an elbow-patch-bedecked jacket - shouted to the motley assortment of assembled esistentialist ectomorphs: “I PROPOSE. THAT. WHEN I SAY: ‘BLUE!’ ALL OF YOU. SEE. EXACTLY. THE SAME. COLOR!!!”

He paused. “Refute. That. Hypothesis,” he snarled, taking a toke from his pugnacious pipe.

I didn’t raise my hand. It raised itself. He called on me. “I see the same color slightly differently with each eye,” I said, illustrating my claim with alternating winks of my left and right eye. Seemed like a slam-dunk to this Milwaukee boy. (It also happened to be true.)

He glared at me, cross-examined me fiendishly for five long minutes and, striding to the blackboard (I did tell you this was long ago), multiplied the number of minutes we had dueled by the dwindled number of my classmates and thundered: “You’ve wasted 45 student-minutes of class time!”

It was right about then that I started thinking maybe I should switch to science.

So, what is “music,” really? Well, we don’t really know. But whatever it is, it makes us wanna shout, kick our heels up and shout, throw our hands up and shout, throw our heads back and shout.

Previously: New research tracks “math anxiety” in the brain, Why memory and math don’t mix: They require opposing states of the same circuitry and Can playing familiar music boost cognitive response among patients with brain damage?
Photo by gilmorec

Bioengineering, Imaging, Neuroscience, Research, Stanford News

Scientific community (and Twitter) buzzing over Stanford’s see-through brain

Scientific community (and Twitter) buzzing over Stanford's see-through brain

Yesterday’s announcement about Stanford scientists developing a process that renders tissue, specifically a mouse brain, transparent spurred a significant amount of excitement among both the scientific community and general public. We’ve captured the reactions in tweets, blog posts, videos and quotes from new articles on our Storify page.

Among the video content is an interview with Karl Deisseroth, MD, PhD, explaining the work, a fly-through of a complete mouse brain using fluorescent imaging, and commentary from Michelle Freund, PhD, a project officer in the National Institute of Mental Health Division of Neuroscience and Basic Behavioral Science, discussing the significance of the work. Mixed in with the videos are remarks from experts about how the breakthrough will advance the field of neuroscience and other research applications and candid comments from Twitter users. We hope the collection provides a broader perspective on the research and its potential to revolutionize cell biology.

Previously: Lightning strikes twice: Optogenetics pioneer Karl Deisseroth’s newest technique renders tissues transparent, yet structurally intact and Peering deeply – and quite literally – into the intact brain: A video fly-through

Stanford Medicine Resources: