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Autism, Mental Health, Neuroscience, Research, Science, Stanford News, Stem Cells

Brain cell spheres in a lab dish mimic human cortex, Stanford study says

Brain cell spheres in a lab dish mimic human cortex, Stanford study says

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Mental disorders like autism and schizophrenia are notoriously difficult to study at the molecular level. Understandably, people are reluctant to donate pieces of living brain for study, and postmortem tissue lets researchers see the structure, but not the function, of the cells.

Now researchers in the laboratories of psychiatrist Sergiu Pasca, MD, and neurobiologist Ben Barres, MD, PhD, have found a way to make balls of cells that mimic the activity of the human cortex. They use a person’s skin cells, so the resulting “human cortical spheroid” has the same genetic composition as the donor. The research was published in Nature Methods yesterday.

According to our release:

Previous attempts to create patient-specific neural tissue for study have either generated two-dimensional colonies of immature neurons that do not create functional synapses, or required an external matrix on which to grow the cells in a series of laborious and technically difficult steps.

In contrast, the researchers found they were able to easily make hundreds of what they’ve termed “human cortical spheroids” using a single human skin sample. These spheroids grow to be as large as 5 millimeters in diameter and can be maintained in the laboratory for nine months or more. They exhibit complex neural network activity and can be studied with techniques well-honed in animal models.

The researchers, which include neonatology fellow Anca Pasca, MD, and graduate student Steven Sloan, hope to use the technique to help understand how the human brain develops, and what sometimes goes wrong. As described by Barres:

The power and promise of this new method is extraordinary. For instance, for developmental brain disorders, one could take skin cells from any patient and literally replay the development of their brain in a culture dish to figure out exactly what step of development went awry — and how it might be corrected.

The research is starting to garner attention, including this nice article from Wired yesterday. Pasca’s eager to note, however, that he’s not working to create entire brains, which would be ethically and technically challenging, to say the least. But simply generating even a few of the cell types in the cortex will give researchers a much larger canvas with which to study some devastating conditions. As Pasca notes in our release:

I am a physician by training. We are often very limited in the therapeutic options we can offer patients with mental disorders. The ability to investigate in a dish neuronal and glial function, as well as network activity, starting from patient’s own cells, has the potential to bring novel insights into psychiatric disorders and their treatment.

Previously: More than just glue, glial cells challenge neuron’s top slot and Star-shaped cells nab new starring role in sculpting brain circuits
Photo of spheroid cross-section by Anca Pasca

Autism, Ethics, Genetics, Medicine and Society, Patient Care

Genetic testing, autism, and “fixing” the pathological body

Genetic testing, autism, and "fixing" the pathological body

2678541254_029f25704b_zHow do we know what is pathological, versus what is normal? It seems obvious until you start thinking philosophically, which was the goal of a panel hosted last week by the Science and Justice Working Group at University of California, Santa Cruz. The event was titled “‘Fixing’ the Pathological Body,” a pun on how fixing can mean both repairing and immobilizing.

An anthropologist, a philosopher, and a geneticist discussed how simple, everyday practices like using particular words or certain tests define a line between pathology and normalcy. That line has a huge impact on our experience as humans.

Matthew Wolfmeyer, PhD, professor of anthropology at UCSC, used the term “multibiologism” to indicate that pathology can be seen as a form of human variation. There are three kinds of bodies, he says: those that need no intervention of social, legal, or medical support to enable a livable life, those that do need such intervention (such as a quadriplegic or someone with severe Alzheimer’s), and those that could have such intervention (anyone from hyperactive kids or insomniacs to those with PTSD or arthritis). American society currently divides this spectrum such that the “no intervention” category is becoming empty and the “could have intervention” category is growing by leaps and bounds. Despite what he calls our “cure ideology” from our Judeo-Christian heritage, the pathologies we recognize are increasingly incurable, whether it be gluten sensitivity or chronic cancer, and must be treated with ongoing therapies.

Kelly Ormond, MS, professor of genetics at Stanford, provides genetic counseling and helps people think about these issues every day. She helps expectant parents face the grueling task of deciding what it means to have a baby who might be labeled disabled, pathological, or normal — how would such a child fit into their life, and are they able and willing to accommodate that? Do they even want the information that genetic tests can offer? When counseling parents, Ormond tries to emphasize the lived experience of a condition instead of its medical aspects. Medical information tends to categorize and stir up preconceived notions, but in everyday life the significance of such designations is more fluid, she said.

Janette Dinishak, PhD, professor of philosophy at UCSC, studies autism. She wants to reframe society’s understanding of people with autism such that those without autism are the ones who are limited.

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Autism, Genetics, Research, Stanford News

Unlocking autism’s secrets: Stanford researchers point fingers at a brain cell dark horse

Unlocking autism’s secrets: Stanford researchers point fingers at a brain cell dark horse

Snyder smilingGeneticist Michael Snyder, PhD, has a thing for ‘omes.’ He’s studied genomes, transcriptomes, proteomes and microbiomes. Each term represents looking at something (DNA, RNA, proteins or microorganisms on a grand scale, throughout an entire organism). Most recently he’s been known for combining omics information to generate a dynamic picture of his own changing health over time (he termed the analysis a “integrative personal omics profile, or iPOP, but really, the siren call of “the Snyder-ome” is almost too great to resist).

Now he and postdoctoral scholar Jingjing Li, PhD, have turned their attention to the human “interactome,” a database that includes information about more than 69,000 protein interactions. They’ve used sophisticated algorithms to identify who in the brain is playing nicely with whom, and identified a particular group that seems to play an important role in the development of autism in a part of the brain called the corpus callosum. Importantly, the analysis points a finger at a new cell type in the brain — the oligodendrocytes. These serve as kind of a pit crew for the neurons, coating them in an insulating material to keep electrical signals between cells running smoothly. They’ve published their work today in Molecular Systems Biology.

As Snyder explained in our release:

This is our first glimpse of autism’s underlying biological framework, and it implicates a cell type and region of the brain that have not been extensively studied in this disease. Until now, we’ve suspected that autism could be the result of defects in the neurons themselves. Now it appears that the oligodendrocytes can contribute to the problem by inhibiting neuronal signaling through poor cellular differentiation and myelination.

Snyder, who also directs Stanford’s Center for Genomics and Personalized Medicine, and Li hope that the finding will allow researchers to broaden their net to the corpus callosum, which helps the two halves of the brain communicate with one another. As psychiatrist and study co-author, Joachim Hallmayer, MD, commented:

Autism is an extremely heterogeneous disease. Many genes have been implicated, but environment also plays a role. This study suggests a possible way to subdivide patients into smaller, more homogenous populations based on which genes are mutated. Some of these may be very easy to treat, based on their mechanism, while others may be much more difficult. For those in this category, it’s possible we could one day find a way to train or improve the connection between the brain’s hemispheres.

It will be fascinating to see where this research goes next. In the meantime, here’s hoping the New Year-ome treats you and yours well!

Previously: New imaging analysis reveals distinct features of the autistic brain, Omics’ profiling coming soon to a doctor’s office near you? and A conversation with autism activist and animal behavior expert Temple Grandin
Photo of Snyder by Steve Fisch

Autism, Behavioral Science, Events, Stanford News

Thinking in pictures: Stanford hosts Temple Grandin

Thinking in pictures: Stanford hosts Temple Grandin

Grandin Temple - smallEarlier this week, I got to hear a presentation by Colorado State University animal behavior expert Temple Grandin, PhD, who is widely known not just for her extensive work to enhance animal welfare, but also because she is one of the world’s most prominent individuals with autism. Like many others, I first became familiar with Grandin’s work through Oliver Sacks’ 1995 book, An Anthropologist on Mars. (The title came from Grandin’s description of how she feels when trying to decode the subtleties of social interactions.) Since I first read Sacks’ book, I’ve written frequently about autism research and treatment, and I’ve gotten some sense of how phenomenally important Grandin is to the autism community. So it was quite a thrill to be sitting just a few feet from her as she spoke to an overflow crowd at the School of Medicine.

Grandin’s talk focused on understanding animal behavior and reducing animals’ stress, but she interwove descriptions of her research with comments on how living with autism has influenced her work – and, indeed, how it influences the world around us. “A little bit of autism gives you Silicon Valley,” she quipped in the introduction to her talk. Although her subject was animals’ stress, at the heart, she was explaining different ways of thinking: in words or in pictures.

Animals think in pictures, especially when it comes to determining which elements of their environment are stressful or frightening, Grandin said: “Animals are all about sensory detail, little bits of detail we tend not to notice.” At one point in the talk, she showed a photo of a cow bending forward to investigate a spot of sunlight on the floor of the room where it was about to have a veterinary exam. To a human, this spot would likely seem insignificant, but to the cow, it is a foreign object that needs to be approached with caution.

“Novelty is a strong stressor for animals,” Grandin said, adding that if something visually new is forced in an animal’s face, it’s scary. The cow in the photo needs a few minutes to sniff the sun spot and figure out that it’s harmless; a human trying to force the situation will soon have a frightened, resistant animal to handle. Humans also have to keep in mind that our word-oriented brains may not categorize “novelty” in the same way that an animal does. For instance, an animal that has become accustomed to the sight of a blue-and-white umbrella may still be frightened by an orange tarp, Grandin said. To people, they’re both rain protection, but to a horse or cow, “It’s a different picture!”

Like many children with autism, Grandin began speaking later than most kids, and she still thinks in images more intuitively than words. “I see movies in my imagination, and this helped me understand animals,” she said. She likened her memory to Google Images, explaining that for her, a particular word will pull up many associated images, categorized by type. Her designs for meat-processing plants, now in use in half of the meat-processing facilities in North America, rely on her ability to mentally take a “cattle’s-eye view” of each step in the animal’s journey before slaughter, playing out a movie in her head that shows her where animals could be forced to encounter new things that might frighten them.

As well as describing her own work, Grandin advocated for broader acceptance of different kinds of thinkers, both with and without autism. People may think predominantly in pictures, or in patterns (that’s the math whizzes among us), or in words, she said, and we need educational and employment systems that can nurture and benefit from each of these ways of thinking. “There is too much emphasis on deficits [of children with autism], and not enough on building their strengths,” she said.

Grandin’s complete talk, which was hosted by the Department of Comparative Medicine, will soon be available on the department’s news website.

Previously: A conversation with autism activist and animal behavior expert Temple Grandin, Growing up with an autistic sibling: “My sister has a little cup” and Finding of reduced brain flexibility adds to Stanford research on how the autistic brain is organized
Photo by Rosalie Winard

Autism, Events, Stanford News

A conversation with autism activist and animal behavior expert Temple Grandin

A conversation with autism activist and animal behavior expert Temple Grandin

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In the inspiring film, “Temple Grandin,” we learn the remarkable story of a woman born with autism who, as a young child, communicates through screaming and humming, and is given to fist-pumping outbursts of frustration. But Grandin, played brilliantly in the film by Claire Danes, has a rare affinity with animals and a keen sense of their needs. She ultimately becomes a renowned expert in animal behavior, a university professor and a consultant to major U.S. companies.

Grandin, PhD, one of the world’s most famous people with autism, will visit Stanford’s medical school next Wednesday to deliver a talk entitled, “Animals Make us Human.” In anticipation of her presentation, we asked her to answer five questions about the link between autism and animals. Her answers – like this one – offer a window into the world of autism, while providing a sense of Grandin’s character and thought process:

Animal cognition has similarities to autism cognition. Animals are very aware of small, sensory details in the environment. People on the autism spectrum excel at work involving details. SAP, a large computer company, is hiring people on the mild end of the autism spectrum to debug and correct computer programs.

Concepts are formed from specific examples. To train a dog to always obey the “sit” command, it must be taught in many different locations. If all the dog’s training is done in the living room, the dog may only obey the commands in the living room. To teach a child with autism about road safety, he needs to be taught in many different locations. These similarities between animals and autism apply only to cognition. They do not apply to the emotions. Animals are highly social and emotional creatures.

Her presentation begins at noon in the Clark Center on the medical school campus and will be followed by a book signing at the bookstore at the Li Ka Shing Center for Learning and Knowledge. The talk, sponsored by Stanford’s Department of Comparative Medicine, is free and open to the public. If you’re local and able to attend, I would get there early, as I believe this is going to be one very popular event.

Photo by Rosalie Winard

Autism, Behavioral Science, Parenting, Pediatrics, Research, Stanford News

Study validates oxytocin levels in blood and suggests oxytocin may be a biomarker of anxiety

Study validates oxytocin levels in blood and suggests oxytocin may be a biomarker of anxiety

Karen Parker Oxytocin, sometimes dubbed “the love hormone,” can be tricky to study in humans. To conduct research on the connection between oxytocin and emotion, scientists want to assess the hormone’s levels in the brain. But sampling cerebrospinal fluid, the liquid bathing the brain, requires an invasive technique called a lumbar puncture. Measuring blood oxytocin is much easier, but some researchers have questioned whether blood oxytocin levels truly reflect what’s happening in the brain.

A new Stanford study simplifies the problem: It is the first research in children, and some of the first in any age group of humans, to indicate that blood and CSF oxytocin levels track together. The research also found a correlation between low-oxytocin and high-anxiety levels in children, adding to findings from animal studies and adult humans that have documented this oxytocin-anxiety link. The paper appears today in Molecular Psychiatry.

The findings raise the possibility that oxytocin could be considered as a therapeutic target across a variety of psychiatric disorders

The researchers recruited 27 volunteers from among a group of patients who needed lumbar puncture for medical reasons. The volunteers agreed to have oxytocin levels measured in their blood and CSF, and the parents of 10 children in the study answered questions about their children’s anxiety levels. From our press releaseabout the research:

“So many psychiatric disorders involve disruptions to social functioning,” said the study’s senior author, Karen Parker, PhD, assistant professor of psychiatry and behavioral sciences. “This study helps scientifically validate the use of measuring oxytocin in the blood, and suggests that oxytocin may be a biomarker of anxiety. It raises the possibility that oxytocin could be considered as a therapeutic target across a variety of psychiatric disorders.”

Parker’s team is now conducting studies of possible therapeutic uses of oxytocin in children with autism. They recently published a paper demonstrating that autism is not a disease of oxytocin deficiency per se; instead, oxytocin levels in kids with autism fall across a broad range. The findings hint at a future in which patients’ oxytocin levels could be used to guide treatment for autism or other psychiatric or developmental disorders. As Dean Carson, PhD, the lead author of the new study, explained:

“Our belief is that there are oxytocin responders and nonresponders,” Carson said, adding that the team is now testing this hypothesis.

…“Being able to have objective measures of psychiatric illness really will enhance early diagnosis and measures of treatment outcomes,” Carson said.

Previously: Stanford research clarifies biology of oxytocin in autism, “Love hormone” may mediate wider range of relationships than previously thought and Study shows oxytocin may boost happiness among women
Photo of Karen Parker by Norbert von der Groeben

Autism, Parenting, Pediatrics, Research, Stanford News

Parents can learn autism therapy in groups to improve kids' verbal skills, Stanford study shows

Parents can learn autism therapy in groups to improve kids' verbal skills, Stanford study shows

HoldingHandsAutism is more than twice as common than it was 15 years ago. But the number of clinicians who treat the developmental disorder is growing more slowly than the number of new cases, prompting caregivers to look for novel ways to share their expertise as widely as possible.

One possible approach: Teach groups of parents an autism therapy they can deliver at home. A new study from Stanford and Lucile Packard Children’s Hospital Stanford, published today in the Journal of Child Psychology and Psychiatry, found that small groups of parents could learn to deliver a scientifically validated autism treatment to their own children in a short series of classes.

The therapy, called pivotal response training, which has been validated in several prior studies, was targeted to kids’ language skills. The therapy gives parents a structured method for nurturing children’s verbal skills during everyday interactions.

The approach of having parents give treatment is meant to complement, not replace, one-on-one therapy with autism professionals. But it can still be valuable to children and their families, as our press release explains:

“There are two benefits: The child can make progress, and the parents leave the treatment program better equipped to facilitate the child’s development over the course of their daily routines,” said study co-author Grace Gengoux, PhD, clinical assistant professor of psychiatry and behavioral sciences and a psychologist specializing in autism treatment at the hospital. “The ways that parents instinctually interact with children to guide language development may not work for a child with autism, which can frustrate parents. Other studies have shown that learning this treatment reduces parents’ stress and improves their happiness. Parents benefit from knowing how to help their children learn.”

… To use the treatment for building language skills, parents identify something the child wants and systematically reward the child for trying to talk about it. For instance, if the child reaches for a ball, the parent says, “Do you want the ball? Say ‘ball.’”

“The child might say ‘ba,’ and you reward him by giving him the ball,” [lead author Antonio] Hardan, MD, said. “Parents can create opportunities for this treatment to work at the dinner table, in the park, in the car, while they’re out for a walk.”

The researchers are now following up with studies that will give them more information about which children and families are most likely to benefit from this therapeutic approach.

Previously: Using Google Glass to help individuals with autism better understand social cues, Using theater’s sensory experience to help children with autism and “No, I’m not ready yet”: A sister’s translation for her brother with autism
Photo by Wilson X

Autism, Parenting

Growing up with an autistic sibling: "My sister has a little cup"

Growing up with an autistic sibling: "My sister has a little cup"

It was the photo that first draw my attention: the big sister and little sister, with their bed-head hair and pink-and-purple pajamas, hugging each other happily. It was like a scene straight out of my house, and I’m a sucker for stories about sisters – so I began reading. The Huffington Post piece was, indeed about two close, loving little siblings – but, more specifically, about the writer-mom’s concerns over how her youngest daughter’s autism has affected her daughter Phaedra.

Neither of my girls has autism, but Janel Mills is such a gifted writer (and her older daughter, with her maternal, sensitive ways, reminded me so much of mine) that it wasn’t difficult to feel what it would be like in this mother’s shoes. And this portion of the story, with Mills’ beautiful, simple description of what was going on in her younger daughter’s mind, brought me to tears:

One day, as we were driving to my mom’s house, Bella started having a full-blast, take-it-to-eleven, screeching meltdown because she dropped a toy somewhere in the car and neither she nor I could reach it. Phaedra hates the car meltdowns most of all because she can’t go anywhere to escape them. Listening to Bella melt down hurts her physically (the screams are LOUD) and emotionally (she’s a sensitive soul). When we finally pulled into my mom’s driveway and I got Bella her toy, Phaedra asked me with a shaky voice why Bella reacted the way she did. I must have heard this or read this somewhere, because there’s no way I was this clever on the spot, but this is what I told her:

“Everyone has a cup in their head. We pour all of our feelings, like happy, sad, mad, scared, anything, into that cup. Most people have regular-size cups. When you pour out your feelings into your cup, you have more than enough room for them. Bella has a cup, too, but her cup is little. When she pours her feelings out, her little cup can’t hold all of them, and it overflows. Does that make sense, honey?”

Apparently it did, because she uses this story to explain to others how Bella is different. She shares it with teachers, friends, basically anyone who will stand still and listen to her talk about her family.

“My sister Bella has a little cup.”

Previously: “No, I’m not ready yet”: A sister’s translation for her brother with autism and A mother’s story on what she learned from her autistic son

Autism, Pediatrics, Research, Stanford News

Stanford research clarifies biology of oxytocin in autism

Stanford research clarifies biology of oxytocin in autism

For years, scientists have been trying to sort out the role oxytocin plays in autism. The developmental disorder affects one in 68 U.S. children, causing social and communication deficits, repetitive behaviors and sensory problems. Oxytocin, which functions in the blood as a hormone and in the brain as a neurotransmitter, has long been known to have roles in enhancing social ability. Based on research in animal models, some people have speculated that oxytocin deficiency might contribute to autism. But prior human studies of the purported connection have produced a confusing picture.

The previous hypotheses saying that low oxytocin was linked to autism were maybe a little bit simplistic. It’s much more complex…

Now, a new Stanford paper publishing online this week in Proceedings of the National Academy of Sciences adds interesting details to our understanding. The study is the largest ever to examine blood oxytocin levels in children with autism and two comparison groups without autism: kids who have autistic siblings and children who do not have siblings with autism.

The researchers found the same range of blood oxytocin levels across all three groups, with similar numbers of children with low, medium and high oxytocin levels in each category. Although, as expected, the kids with autism had social deficits, blood oxytocin level was clearly linked to social ability within each group. Children with autism who had low blood oxytocin had poorer social ability than autistic children with high blood oxytocin, for example, and typically developing kids with low blood oxytocin also had poor social ability compared to other typically developing children.

From our press release on the research:

“It didn’t matter if you were a typically developing child, a sibling or an individual with autism: Your social ability was related to a certain extent to your oxytocin levels, which is very different from what people have speculated,” said Antonio Hardan, MD, professor of psychiatry and behavioral sciences and the study’s senior author. Hardan is a child and adolescent psychiatrist who treats children with autism at [Lucile Packard Children’s Hospital Stanford].

“The previous hypotheses saying that low oxytocin was linked to autism were maybe a little bit simplistic,” he said. “It’s much more complex: Oxytocin is a vulnerability factor that has to be accounted for, but it’s not the only thing leading to the development of autism.”

The findings suggest that, although oxytocin deficiency may not explain all cases of autism, some kids with autism may still benefit from oxytocin-like medications. The researchers caution that their study needs to be repeated with measures of oxytocin in cerebrospinal fluid, since this liquid that bathes the brain may give better information about the nuances of oxytocin biology.

A Duke University scientist commented for a story on NPR’s health blog, Shots, about what the findings imply for the potential value of oxytocin therapy:

“It could be that if a kid has low oxytocin levels then they might benefit,” says Simon Gregory, a genomics researcher at Duke University who was not involved in the study. He is part of another group investigating the use of oxytocin to treat people with autism.

Gregory says it’s not surprising that children with autism have widely varying levels of oxytocin. “Autism isn’t a disease, it’s a spectrum” that can’t be linked to any one cause, he told Shots.

Stanford’s research team is also doing more work to clarify further details of the biology of oxytocin in autism.

Previously: Volunteers sought for autism drug study, Using Google Glass to help individuals with autism better understand social cues and “No, I’m not ready yet”: A sister’s translation for her brother with autis

Autism, Neuroscience, Pediatrics, Research, Stanford News

Finding of reduced brain flexibility adds to Stanford research on how the autistic brain is organized

Finding of reduced brain flexibility adds to Stanford research on how the autistic brain is organized

A Stanford brain-imaging study has just shown that the brains of children with autism are less able to switch from rest to taking on a new task than the brains of typically developing children.

According to the study, which appears this week in the scientific journal Cerebral Cortex, instead of changing to accommodate a job, connectivity in key brain networks of autistic children looks similar to connectivity in the resting brain. The degree of inflexibility was linked to the intensity of children’s autism symptoms: those with less flexibility had more severe restrictive and repetitive behaviors, one of the hallmarks of the developmental disorder.

From our press release on the research:

“We wanted to test the idea that a flexible brain is necessary for flexible behaviors,” said Lucina Uddin, PhD, a lead author of the study. “What we found was that across a set of brain connections known to be important for switching between different tasks, children with autism showed reduced ‘brain flexibility’ compared with typically developing peers.” Uddin, who is now an assistant professor of psychology at the University of Miami, was a postdoctoral scholar at Stanford when the research was conducted.

“The fact that we can tie this neurophysiological brain-state inflexibility to behavioral inflexibility is an important finding because it gives us clues about what kinds of processes go awry in autism,” said Vinod Menon, PhD, the Rachel L. and Walter F. Nichols, MD, professor of psychiatry and behavioral sciences at Stanford and the senior author of the study.

The study is the first to examine unusual patterns of connectivity in the brains of children with autism while they are performing tasks; Menon’s team has previously published research on connectivity between different regions of the autistic brain at rest. Some regions of the autistic brain are over-connected to each other, that work has shown, and the degree of over-connection is linked to children’s social deficits, perhaps in part because it interferes with their ability to derive pleasure from human voices. Menon’s lab has also explored how differences in the organization of the autistic brain may contribute to better math performance in some people with autism.

“We’re making progress in identifying a brain basis of autism, and we’re starting to get traction in pinpointing systems and signaling mechanisms that are not functioning properly,” Menon told me. “This is giving us a better handle both in thinking about treatment and in looking at change or plasticity in the brain.”

Previously: Greater hyperconnectivity in the autistic brain contributes to greater social deficits, Unusual brain organization found in autistic kids who best peers at math and Stanford study reveals why human voices are less rewarding for kids with autism

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