Neuroscience

The very first medical descriptions of autism, published in the 1940s, noted that children with autism don’t respond normally to human voices. Picking up on the nuances of spoken communication is especially difficult for those with autism: Even if they can speak and read, they often struggle to hold a back-and-forth conversation or understand emotional cues in others’ voices.

Now, new brain research from Stanford may explain why. Functional MRI scans showed that in kids with autism, brain regions specialized to respond to speech are poorly connected to the brain centers that process rewards and interpret emotions. The new study, which appears today in Proceedings of the National Academy of Sciences, also found that, for individual children, greater impairment in these brain connections translated into more severe communication deficits, as measured by the verbal portion of a standard test of autism severity.

From our press release about the new findings:

“Weak brain connectivity may impede children with autism from experiencing speech as pleasurable,” said Vinod Menon, PhD, senior author of the study.

…

“The human voice is a very important sound; it not only conveys meaning but also provides critical emotional information to a child,” said Daniel Abrams, PhD, a postdoctoral scholar in psychiatry and behavioral sciences who was the study’s lead author. Insensitivity to the human voice is a hallmark of autism, Abrams said, adding, “We are the first to show that this insensitivity may originate from impaired reward circuitry in the brain.”

The findings could help scientists improve existing autism therapies or design new ones. Now that they know that these particular circuits are weak, they can use brain scans taken before and after a child receives an autism therapy to check whether the treatment strengthens the child’s brain.

Previously: A mother’s story on what she learned from her autistic son, New imaging analysis reveals distinct features of the autistic brain and New public brain-scan database opens autism research frontiers
Photo by Kevin Shorter

Embryonic stem cells (or ESCs) and their younger cousins the induced pluripotent stem cells (iPSCs) are prized because they can, alternatively, replicate themselves indefinitely in a dish or differentiate into every cell type in the body. This makes them potentially valuable tools for regenerative medicine.

And because iPSCs can be made from a person’s skin cells, manipulating their differentiated progeny lets investigators study disease processes at the cellular level, in a dish and in a personalized way. By custom-producing, for example, a given individual’s nerve cells,  researchers can study the specific defects of those cells in a dish, without having to first perform the ethically unthinkable – and, therefore, purely hypothetical – act of slicing chunks of tissue out of that person’s brain in order to do so. The researchers can, further, toss thousands of different compounds into thousands of tiny “wells” containing these nerve cells to see which ones might restore those cells’ proper function. (Different drugs are likely to work better with different individuals’ defective cells, depending on the nature of the cell’s defining defect.)

Scientists have successfully coaxed both ESCs and iPSCs down the developmental pathway to become nerve cells. They’ve even generated nerve cells directly from skin cells. But up to now, the procedures they’ve used have been plagued by two problems. First, quality assurance: The extent to which nerve cells generated by these methods actually look and act like nerve cells are supposed to look and act varies a lot, depending on which particular ESC line, or which iPSC line, was used to generate them. Second, the process is slow and the yield is low (it typically takes months to get from the beginning to the end, and many of the “starter” ESCs or iPSCs don’t successfully convert to decently functioning nerve cells).

But in a recently published paper in Neuron,  a team under the direction of Stanford cell physiologist and neuroscientist Tom Sudhof, PhD, has showed that just boosting the level, in human ESCs or iPSCs, of one single substance (a type known as a transcription factor) results in an abundant and quite pure population of nerve cells within as little as two weeks. And unlike previous methods, this one seems to generate nerve cells of equally high functional quality regardless of which “starter” cell line was used to get the process underway.

Clearly, if you’re doing regenerative medicine for a stroke or brain-trauma victim etc., you’re going to need a lot of nerve cells, and time is of the essence. So the new method represents a major forward step toward the realization of the dream of personalized regenerative medicine.

Previously: Revealed: the likely role of Parkinson’s protein in the healthy brain, Nervous breakdown: Preventing demolition of faulty proteins counters neurodegeneration in lab mice and Human neurons from skin cells without pluripotency?
Photo by Crystalline Radical

Epilepsy affects about one in 100 people across the globe. The brain is, in essence, a complicated electrochemical calculating machine, containing a huge number of circuits that process information and share it with other, often-remote circuits. The resulting networks can be of sometimes staggering complexity. Epileptic seizures are, at root, electrical storms triggered when a short-circuit at one tiny spot within the brain, called the focus, causes waves of electrical activity to spread throughout a specific network. The focus’s exact location varies from patient to patient, and the network affected also varies. That is why seizures can be different in type.

Seizures can usually be controlled with medication. But when they can’t, patients are prone to repeated seizures that can seriously impair their ability to lead normal lives. Fortunately, says neurologist Josef Parvizi, MD, PhD, director of the Stanford Program for Drug-Resistant Epilepsies, a surgical procedure can be tremendously effective, as long as the surgery itself does not cause any loss of brain function.

In this procedure, a portion of the patient’s skull is temporarily removed, allowing access to the brain’s surface near the spot thought to be responsible for initiating the seizures. A thin plastic film containing numerous electrode leads is placed next to the brain, with each electrode separately monitoring electrical activity there. (The procedure doesn’t destroy tissue or disrupt brain function.) The patient remains off medication, bedridden but fully conscious and pain-free, for up to a week. The resulting onset of repeated seizure activity lets the neurological team identify the focus of the patient’s seizures. It also allows the team to map the function of the brain areas that are being considered for resection and ensure that the surgery will be safe. Surgeons may then be able to remove just enough brain tissue at that position to halt the cycle of self-propagating electrical activity, like pulling out a fuse to break a short circuit, without affecting any important brain functions.

For our latest installment of Ask Stanford Med, we’ve asked Parvizi to answer questions regarding drug-resistant epilepsy and this procedure. You can submit a question by either sending a tweet that includes the hashtag #AskSUMed or posting it in the comments section below. We’ll collect questions until Wednesday (June 19) at 5 PM Pacific Time.

When submitting questions, please abide by the following ground rules:

• Stay on topic
• Be respectful to the person answering your questions
• Be respectful to one another in submitting questions
• Do not monopolize the conversation or post the same question repeatedly
• Kindly ignore disrespectful or off topic comments
• Know that Twitter handles and/or names may be used in the responses

Parvizi will respond to a selection of the questions submitted, but not all of them, in a future entry on Scope.

Finally – and you may have already guessed this – an answer to any question submitted as part of this feature is meant to offer medical information, not medical advice. These answers are not a basis for any action or inaction, and they’re also not meant to replace the evaluation and determination of your doctor, who will address your specific medical needs and can make a diagnosis and give you the appropriate care.

Previously: Positive results in deep-brain stimulation trial for epilepsy and Brain implant designed for patients with difficult-to-treat epilepsy
Photo in featured entry box by Ars Electronica

BRAIN SCAPES, a new art installation at the Stanford Center for Cognitive and Neurobiological Imaging, features the work of Stanford alumna and artist Laura Jacobson.

The pieces on display were inspired by MRIs of the human brain and reflect the work of the center to investigate connections between neuroscience and society. A recent Stanford Report article offers more details about the goal of the exhibit:

The center, in the basement of the Department of Psychology, uses the MRI to support research that advances understanding of the brain, including decision-making, cognition, perception, child development, education and emotion.

“It’s not a weird, scary place filled with chemicals,” said psychology professor Brian, Wandell, who directs the center. “But it’s an MRI and there is a scary quality to it.”

Wandell said one of the goals of the art installation is to break down some of that fear.

“It’s a place where we bring families to study brain function, why we do things, behavior. We thought having art that reflects what we see and do and our mission might make all of it more inviting,” he said.

On display are clay sculptures, etchings and acrylics, including the above piece titled Neuron No. 3. According to the BRAIN SCAPES brochure (.pdf):

[The painting] references three moments in neuroscience history: Jan Evangelista Purkinje (1787-1869) discovered and named these large cerebellar neurons in 1837; Italian physician Camillo Golgi (1843-1926) developed a process in 1873 that stains only a few neurons from the tangled masses; and Spanish physician Santiago Ramón y Cajal (1852–1934) used Golgi’s staining technique for his seminal drawings of the nervous system in the early 20th century. Neuron No. 3 alludes to this history and aims to express the complex beauty of the neuronal landscape.

Typically, we  spend more than two hours each night dreaming. But often we wake with only a scant recollection of our dreams, unable to piece together the seemingly random events.

In an effort to decode our internal imagery, and better understand the minds of stroke, coma or neurodegenerative disease patients, scientists are using functional magnetic resonance imaging and software to monitor brain activity while sleeping. This recent ASAP Science video explores the latest research on visualizing and recording dreams. It’s fascinating stuff.

Previously: Eye movement in REM sleep: Rapid, but perhaps not random and What we know about the meaning of dreams

Last month, Stanford’s Karl Deisseroth, MD, PhD, and colleagues in his lab sparked excitement among the scientific community and general public after announcing their development of CLARITY, a process that renders tissue, specifically a mouse brain, transparent. But this wasn’t the first time Deisseroth garnered attention for his work pioneering a blockbuster brain technique. He dedicated a significant portion of this century’s first decade to creating a revolutionary method for studying the brain called optogenetics.

A lengthy Nature feature published yesterday offers an in-depth look at Deisseroth’s rise from “persistent and persuasive” PhD student to “a major name in science,” and his development of two paradigm-shifting methods. In the piece, writer Kerri Smith explains how a residency in psychiatry set him on his current path:

“Everything changed when I did my psychiatry rotation,” says Deisseroth. “A person can be right in front of you who looks intact, not obviously injured, and yet their brain is constructing for them a completely different reality. At the same time I saw how deep the suffering was.”

Studying depression or anxiety in a dish of cells was inadequate, he reasoned, because only whole brains can give rise to the sophisticated functions — and disorders — that characterize human behaviour. And techniques for studying whole brains in humans and model organisms were often limited to simply watching them at work.

So Deisseroth began thinking about ways to examine and control intact systems. “I was having a lot of discussions with a lot of people,” he says. During his residency, Deisseroth met [Edward] Boyden, a PhD student with similarly ambitious aims. The two began talking about ways to manipulate individual neurons as a side project. “It was a very adventurous collaboration, full of exploration,” says Boyden.

One idea involved using light to control neuronal firing. Boyden and Deisseroth knew about light-sensitive channel proteins called opsins, which algae use for generating energy, among other functions. Several groups — including … [Roger Tsien, PhD,] at the University of California, San Diego — were trying to insert these proteins into neuron cell membranes. The project needed “the wherewithal to spend the money and find the graduate students”, says Deisseroth. In 2004, having secured his own lab, he could do just that.

The feature also includes two podcasts of Deisseroth discussing his work.

Previously: Peering deeply – and quite literally – into the intact brain: A video fly-through, Lightning strikes twice: Optogenetics pioneer Karl Deisseroth’s newest technique renders tissues transparent, yet structurally intact, Researchers induce social deficits associated with autism, schizophrenia in mice, Anti-anxiety circuit found in unlikely brain region and Nature Methods names optogenetics its “Method of the Year
Photo by Linda Cicero/Stanford News Service

Why does ingesting a certain substance change our perceptions, our thought patterns, or our moods?

The very fact that a drug has a mind-altering effect is a strong clue that sitting somewhere on the surfaces of brain-situated nerve cells of one type or another are proteins that seem on first glance to have been made for the purpose of driving the cells on which they sit into a frenzy or a stupor when molecules of one or another specific drug bind to them.

In fact, these drug-responsive surface proteins turn out to be receptors for substances produced within our own brains, invariably for very good reasons. A study just reported in the journal NEURON suggests the probable explanation for the action of so-called benzodiazepines – a drug class that includes such famous brand names as the anti-anxiety compound Valium and the sleeping pill Halcion.

Stanford neurologist John Huguenard, PhD, has conducted several pathbreaking experiments in the past few years highlighting the seizure-inducing capacity of the thalamus, a deep-brain structure that acts as a combined relay station and resonance chamber, both shaping sensory inputs for distribution to various higher-level centers in the cerebral cortex and generating rhythms associated with sleep. Too much of the wrong kind of stimulation – or not enough of the right kind of inhibition – can cause the thalamic rhythms to get too dramatic, triggering seizures.

Now, in its most recent set of findings, his lab has shown that very specific nerve-cell clusters in the rodent thalamus (and presumably in the human one, too) secrete a protein that lands on precisely the same thalamic nerve-cell receptors, and induces precisely the same activity on the part of those receptors, that Valium does – and that it counters the thalamus’s aberrant tendency to initiate seizures in susceptible animals or people.

In addition to its archetypical sedative role, Valium, or diazepam, was among the earliest drug treatments for epilepsy. Now we know why. (Valium has long been superseded by other more-effective and safer drugs for treating epilepsy.)

This is by no means the first time an internally produced substance has been fingered as being the bone fide designated activator or inhibitor of a certain kind of brain activity – tasks for which psychoactive drugs are mere mimics (and pretty sloppy, often addictive ones at that).  As I wrote in my press release on this study, the past several decades have seen a series of such discoveries:

In 1974, [internally produced] proteins called endorphins, with biochemical activity and painkilling properties similar to that of opiates, were isolated. A more recently identified set of substances, the endocannabinoids, mimic the memory-, appetite- and analgesia-regulating actions of the psychoactive components of cannabis, or marijuana.

Kind of makes me feel like writing a book about the brain as a pulsing, gurgling drug factory. I know what I’m going to call it: “Sulcus of the Dolls.”

Previously: Possible trigger for childhood seizures identified and Light-switch seizure control? In a bright new study, researchers show how
Photo by codepo8

Amyotrophic lateral sclerosis, or ALS, is a horrible neurodegenerative disease that gradually robs patients of the ability to move and even breathe. Scientists have been trying for years to identify genetic causes of the condition, which is also known as Lou Gehrig’s disease. Studies of families in which several members are affected – the traditional way to identify genes involved in disease processes – have pinpointed some suspicious mutations, but most cases of ALS occur sporadically in the population.

Now Stanford geneticist, Aaron Gitler, PhD, has hit upon a way to identify the de novo mutations (that is, mutations occurring in the egg or sperm of a patient’s parents) that may contribute to the disease. To do so, he and postdoctoral scholar Alessandra Chesi, PhD, compared portions of the genome of ALS patients with those of his or her parents. The research (subscription required), which was conducted in collaboration with Stanford pathologist and developmental biologist Gerald Crabtree, MD, was published Sunday in Nature Neuroscience. From our release:

The researchers compared the sequences of a portion of the genome called the exome, which directly contributes to the amino acid sequences of all the proteins in a cell. (Many genes contain intervening, non-protein-coding regions of DNA called introns that are removed prior to protein production.) Mutations found only in the patient’s exome, but not in that of his or her parents’, were viewed as potential disease-associated candidates – particularly if they affected the composition or structure of the resulting protein made from that gene.

…

Using the exome sequencing technique, the researchers identified 25 de novo mutations in the ALS patients. Of these, five are known to be in genes involved in the regulation of the tightly packed form of DNA called chromatin - a proportion that is much higher than would have been expected by chance, according to Chesi.

Furthermore, one of the five chromatin regulatory proteins, SS18L1, is a member of a neuron-specific complex called nBAF, which has long been studied in Crabtree’s laboratory. This complex is strongly expressed in the brain and spinal cord, and affects the ability of the neurons to form branching structures called dendrites that are essential to nerve signaling.

Neurons from mice with the mutant SS18L1 showed defects in their ability to extend and create new dendrites in response to stimuli, the researchers found. They now plan to sequence the SS18L1 gene in many other ALS patients. According to Chesi:

This is the first systematic analysis of ALS triads for the presence of de novo mutations. Now we have a list of candidate genes we can pursue. We haven’t proven that these mutations cause ALS, but we’ve shown, at least in the context of SS18L1, that the mutation carried by some patients is damaging to the protein and affects the ability of mouse motor neurons to form dendrites.

Previously: In Stanford/Gladstone study, yeast genetics further ALS research and “Housekeeping” protein complex mutated in about 1/5 of all human cancers, say Stanford researchers

Each year the National Science Foundation runs a video contest for young IGERT-funded scientists to communicate to the public about their research, and viewers are encouraged to vote for their favorite videos by liking them on Facebook.

One of the entries in this year’s contest comes from a group of Stanford graduate students who show how the brain plans movement and discuss their work on neural prostheses - biomedical devices for restoring movement to individuals with paralysis or lost limbs. The students, who are all part of the Stanford Center for Mind, Brain and Computation, conduct their work in the labs of electrical engineer Krishna Shenoy, PhD, whose research we’ve written about in the past, and Surya Ganguli, PhD, an assistant professor of applied physics.

The take-away message of the video, student Sergey Stavisky told me yesterday, is that “neural prosthetics are an exciting class of medical technology with the potential to improve the lives of individuals with paralysis,” but that to develop better ones, “we still need to learn a lot about the basic science of how the brain controls movement.”

The video, called “Neural Prosthetics: Understanding Reach Planning,” is worth checking out, as are many of the other entries, whose topics range from “virtual blood vessels” to the use of stem cells to revitalize skeletal muscle. Voting is open until 7 PM Pacific time Thursday.

Previously: Researchers find neurons fire rhythmically to create movement and Stanford researchers uncover the neural process behind reaction time
Via Erica Seigneur from NeuroTalk
Video still courtesy of Sergey Stavisky

When babies are born with serious health problems, physicians’ main goal is to keep them alive. Thanks to decades of advances, such as support for preemies’ underdeveloped lungs and surgical procedures to correct complex birth defects, doctors can now save many babies who would once have died.

But some of these tiny survivors of high-risk birth still suffer permanent developmental problems. It’s only recently that physicians have begun to understand how to protect fragile infants’ developing brains.

As I describe in today’s issue of Inside Stanford Medicine, Lucile Packard Children’s Hospital recently became one of the first hospitals in the country to devote a section of its neonatal intensive care unit to specialized neurologic care for newborns. The new “Neuro NICU” will treat babies at risk for neurologic injury, including preemies, full-term infants deprived of oxygen during birth, and babies with congenital heart defects, who may receive too little oxygen in utero.

But knowing how to treat newborns’ brains is tricky because they change so fast, the story explains:

“The challenge and exciting thing about treating these tiny babies is that the brain is developing on a literally day-by-day basis,” said Courtney Wusthoff, MD, Packard Children’s neonatal neurologist.

Fortunately, new research findings and brain-monitoring technologies are helping doctors better understand infants’ immature nervous systems. For instance, they now have the tools to detect seizures that would once have gone undetected:

“In the past, it’s been assumed that you could just tell by looking if a newborn was having a seizure,” Wusthoff said. But it turns out that 80 to 90 percent of seizures in this age group cause no outward changes. “Newborns’ brains are not developed enough to show on the outside what’s happening on the inside.”

Wusthoff and her colleagues anticipate that the next several years will give doctors even better ways to understand and care for babies’ brains.

Previously: Increasing breast milk feeding rates for preemies at California hospitals , A look at the world’s smallest preterm babies and Advancing heart surgery for the most fragile babies
Photo of Jackson Thomas and Packard Children’s NICU nurse Diana Powell courtesy of the Thomas family