No one has pinpointed genes or pathways that cause the condition and, partly because it can be triggered by ordinary stressors, it’s difficult to diagnose. Its biology now becomes even more baffling with the release of two new mouse models of compulsive behaviors, each implicating a different type of brain cell.

Three years ago, Guoping Feng‘s team created mice that compulsively groom themselves by deleting the SAPAP3 gene. SAPAP3 makes a protein expressed exclusively at neuron connections in the striatum, a deep region that’s important for planning movements.

Circuits in the striatum are also highlighted in one of the new studies, which appeared in May in Nature Medicine. By knocking out part of SLITRK5, which encodes a synaptic protein found in the striatum, researchers created mice whose intense self-grooming leads to severe facial lesions.

The second new report looked at mice carrying mutations in the HOXB8 gene. Scientists first noticed in 2002 that these animals feverishly groom themselves and their littermates, but didn’t know why. In the 28 May issue of Cell, they reported that HOXB8 is expressed only in microglia, immune cells that originate in the bone marrow and then migrate to many regions across the brain.

Although the two studies finger very different systems, they might begin to explain how and why OCD overlaps with other psychiatric illnesses, such as autism. For instance, some people with autism have movement problems, or abnormally big striata.

There are also many genetic and neurobiological links between the immune system and autism. Most relevant, a study presented at a meeting last year found that postmortem brain samples from individuals with autism have large numbers of microglia.

Over the past few years, Pawan Sinha has worked out a provocative theory that might help explain these anecdotes: people with autism have trouble with ‘temporal integration’, or drawing upon information learned in the past to anticipate the future.

The basic idea is that meaningful social interactions — which are difficult for people with autism — hinge on precisely synchronized events. For example, to understand spoken language, you must quickly and seamlessly integrate sounds to form meaningful words: myoo plus zik becomes music, not muse, use or sick. Similarly, imagine how difficult it would be to have a party conversation if you couldn’t monitor, in real time, your companion’s facial expressions or gestures in response to your words.

In between setting world records, carrying out vision experiments on his infant son, and launching a campaign to build a large eye hospital in New Delhi, Sinha has led an effort to test about 40 children with autism on a variety of visual and auditory experiments. Preliminary data from his team at the Massachusetts Institute of Technology (MIT) show that these children do have deficits in temporal integration.

“We know that motion plays a crucial boot-strapping role in vision, and motion processing has been shown to be deficient in autism,” Sinha says. “Our working hypothesis is that autism might, at least in part, be the manifestation of difficulties in processing dynamic information.”

If this timing problem occurs in early development, he says, it could cascade into the myriad of difficulties seen in the disorder, including difficulty in recognizing faces, hypersensitivity to sounds and lights and the insistence on a daily routine.

Sinha’s theory is provocative because scientists have already identified the brain circuits that are responsible for integrating information over time, says Tony Movshon, director of the Center for Neural Science at New York University.

“Autism needs a mediating hypothesis that takes the behavioral descriptions in one hand, and the molecular-circuitry descriptions in the other, and brings them together,” he says. “Pawan’s ideas are efforts to bridge that gap.”

These ideas have stirred up much intellectual debate in the autism field because they assert that the disorder’s fundamental deficit is perceptual, rather than social. But Sinha didn’t set out to study autism. Like many of his projects, this one took a circuitous route — beginning with a blind man in India.

In July of 2004, Sinha was sitting with a young man in a sticky, nondescript hotel room in New Delhi.

The man was poor, and born without lenses in his eyes, making him all but blind for 29 years. Two weeks earlier, he had received a pair of glasses, which allowed him to discriminate light levels and motion for the first time.

By carrying out some simple experiments, Sinha hoped that the man, known as S.K., would help answer the question that’s motivated most of his scientific career: how does the brain learn to see?

S.K. watched black outlines of a square, triangle and circle pop up in different combinations on a computer monitor. “How many things are these?” Sinha asked. When a circle and a square were separated, S.K. could easily count them. But when they overlapped, he saw three objects, and pointed to the three regions contained by the intersecting lines. He had no sense of which segments made up the circle, and which ones the square — until the shapes began to move.

“The world seems to be broken up into too many pieces and he can’t quite put it together. But motion brings about a very significant change,” Sinha says as he watches, for the umpteenth time, a grainy video of the scene.

The soft-spoken scientist proudly plays this clip whenever he gives talks about this work, called Project Prakash, named for the Sanskrit word for light. Like Sinha himself, the project’s goals are equal parts humanitarian and scientific: to restore sight in Indian children with curable blindness, and to then observe how they learn to navigate the visual world.

In November, Sinha published the results of his experiments with S.K. and two other Prakash participants. For all of them, the key to visual integration — perceiving objects as coherent wholes, rather than a mish-mash of spaces and lines — is motion.

He suspects that motion is also a key concept for understanding autism.

Five years ago, Sinha didn’t know much about autism beyond the adage that people with the disorder have trouble ‘seeing the forest for the trees’. After delving into the scientific literature, he discovered that not only do people with autism show abnormalities in visual integration — as shown, for example, by their ability to quickly find hidden pictures in a complex scene — but that they have deficits in processing motion. “The connection [with Project Prakash] seemed to be an obvious one,” he says.

…read the rest at SFARI

In fact, Darwin performed what may be the world’s first study of how people interpret and understand the emotions of others, according to a paper published in the April issue of the Journal of the History of the Neurosciences.

The experiment originated from a disagreement between Darwin and French neurologist G.B.A Duchenne. Duchenne believed that every emotion expressed on a person’s face is created by a separate muscle. To support this, he went about the grim task of electrically stimulating participants’ facial muscles and photographing the resulting expression, ultimately producing a set of 65 different plates.

Darwin thought it was much more likely that there were just a core number of emotions expressed by a face, and that these were shared across many cultures and species.

To test this, Darwin and his wife, Emma, set up an experiment in their home: they showed 24 house guests a series of 11 Duchenne plates and simply asked them to describe what emotion they saw in each. Only a handful of the faces received similar descriptions from all participants. Darwin reasoned that these emotions — surprise, fear, disgust, anger, happiness and sadness — are universally understood, and described them in his 1872 book, Expression of the Emotions in Man and Animals. The rest of the plates, he argued, showed unnatural expressions.

What’s amazing to me is that today’s researchers use photographs showing the same six expressions to learn about the cognitive underpinnings of autism, and to evaluate possible treatments for the disorder.

Of course, these modern experiments have some technological upgrades, such as computerized faces, eye-tracking machines or brain scanners but, once again, Darwin it seems was ahead of the curve.

Now, it looks like another hyped application of fMRI — lie detection — may also have its first day in court, depending on what one judge decides. As ScienceInsider reports:

The defendant in the case is a psychiatrist named Lorne Semrau, who is accused of defrauding Medicare and Medicaid. As reported last week by Wired Science, Semrau claims he had no intention to do so and has retained the services of Cephos, a Massachusetts-based company that sells fMRI-based lie-detection services, to help establish that he is telling the truth. Court documents indicate that Semrau’s lawyer introduced a motion for Cephos CEO Steven Laken to testify as an expert witness on his behalf.

Today [May 13], Judge Tu Pham will hear testimony for and against the inclusion of the fMRI evidence in what’s known as a Daubert hearing, which takes its name from a 1995 Supreme Court case that established guidelines for the admissibility of expert testimony in federal cases. These include factors such as the error rates associated with a given technology, whether it is supported by published research, and whether it is accepted by the scientific community.

But my other readers — my family, friends, or random Googlers — may only have a vague understanding of what personal genomics is, let alone what its importance may be for their lives. So, for this group, I must highly recommend a post on the personal genomics landscape by Dan Vorhaus, a lawyer who specializes in genomic technology. It lays out in clear, layman’s English the various ways that genetic testing is being used, and how that might change in the future. Here’s a snippet:

Genomic researchers with novel questions will continue to require novel, and increasingly participatory, research models. Clinical practice will grow and is likely to become simultaneously more specialized (e.g., increasing availability of genetic diagnostic tests) and more generalized (e.g., incorporation of whole-genome sequences into medical records as a default). Consumer personal genomics will go wherever the entrepreneurial imagination can take it and regulatory bodies permit it, leading to splintering and further blurring between its boundaries with other categories.

[Scientology staffers] signed a contract for a billion years — in keeping with the church’s belief that Scientologists are immortal. They worked seven days a week, often on little sleep, for sporadic paychecks of $50 a week, at most.

…The defectors say [Scientology staff] were repeatedly beaten by the church’s chairman, David Miscavige, often during planning meetings; pressured to have abortions; forced to work without sleep on little pay; and held incommunicado if they wanted to leave.

Part of a great slideshow of Scientology photos by the New York Times: http://www.nytimes.com/slideshow/2010/03/05/us/0303SCIENTOLOGY_index.html

Read the whole thing for more unbelievable details — the church stole its staffers’ passports, forced them to do menial labor, separated husband and wife… The exposé is timed perfectly for Oscar night. I hope this stirs up lots of drama for Cruise, Travolta, and the rest of the Hollywood crazies who continuously defend this bullshit.

(Hat tip: Steve Silberman, who also points to the St. Petersburg Times’ five-part series on Scientology)

Canines and humans get many of the same diseases, and often respond to the same drug treatments. Dogs also tend to mimic the symptoms and pathology of human disease much more closely than rodents do.

“Understanding the underlying genetics in dogs is almost certain to enlighten us about the human condition,” notes Elaine Ostrander, chief of the Cancer Genetics Branch at the National Human Genome Research Institute.

Because dogs are purposely inbred for specific traits and are extremely well characterized, scientists have long used their pedigrees to study cancer and other biological diseases. But researchers are just beginning to use dogs as models of psychiatric and behavioral conditions, including obsessive-compulsive disorder (OCD) and autism.

In a January report, for instance, scientists pinpointed a genetic hotspot for compulsive behavior by screening a conspicuous subgroup of Doberman Pinschers: those that repetitively suck their flanks. The findings were published in Biological Psychiatry.

The gene may also drive compulsive behaviors in other dog breeds and other species, the researchers say.

“We think this gene will also be the same one involved in human OCD,” notes investigator Nicholas Dodman, director of the animal behavior clinic at Tufts University in Massachusetts. “This is really just the beginning of using [dog] behaviors to study behaviors of humans.”

The gene encodes a protein, cadherin 2, that helps form connections between brain cells. Researchers have recently implicated this family of proteins in other mental disorders. For instance, a report in the same issue of the journal links cadherin 7 to bipolar disorder; a large study last year tied two other cadherins to autism, which often includes repetitive behaviors.

With such robust corroborating evidence, the dog study throws a bone to researchers studying people with OCD. The disorder runs in families but has largely mysterious genetic origins, making it difficult to understand its biological underpinnings.

“This particular study has leap-frogged ahead of the human studies,” says Paul Arnold, who was not involved in the new work.

In 2007, dozens of investigators around the world, including Arnold, launched a genome-wide association study of about 1,600 people with OCD and their families. The researchers are searching the data for common genetic variants that increase risk of OCD.

“We haven’t had any really clear-cut genetic animal models of OCD. The fact that they have used this model to identify a gene that makes sense, mechanistically — that’s pretty exciting,” says Arnold, a staff psychiatrist at the Anxiety Disorders Clinic at the Hospital for Sick Children in Toronto.

Studies of dog genetics have exploded since 2005, when scientists decoded the canine genome. Ostrander’s lab — one of the largest focused on this work — has discovered genes related to cancer, eye disease and morphology, such as short legs and curly hair.

Fewer efforts have looked at dog genes to study brain conditions, but those findings are also encouraging. For instance, by studying dogs with narcolepsy, Emmanuel Mignot‘s lab at Stanford University isolated genes for hormones, called orexins, that turned out to play a role in humans with sleep disorders.

In 2005, an international group of researchers identified a mutation in dogs with epilepsy, and showed that animals carrying the mutation are good models of Lafora disease, a form of epilepsy that is seen in teenagers. And Samuel Wang, associate professor of neuroscience at Princeton University, is using images of dog brains to investigate whether the size of various brain regions correlates with specific behavioral characteristics, such as intelligence or aggressiveness.

The new genetic study is the first to focus on more subtle behaviors reminiscent of those seen in psychiatric disorders.

“We’ve known for a long time that at least a small subset of the neuropsychiatric disorders that we see in humans we see in dogs as well. Now’s the time to tackle those,” says Ostrander. “I think this will be the first of many such papers that we’ll see.”

The new study began one day in the late 1980s, when Dodman attended a dog-training class at Tufts’ veterinary school. He was training a 1-year-old white, male Bull Terrier. The dog’s owner approached him after class and asked if he knew anything about tail-chasing behavior in the breed. Coincidentally, Dodman had recently stumbled upon a case report about tail-chasing.

Dodman took the man upstairs to his office to look at the paper more closely, and discovered that it described a 1-year-old white, male Bull Terrier.

“Here they were displaying absolutely identical behaviors. And I went, oh my god, this is genetic,” Dodman recalls.

He began collecting blood samples of Bull Terriers. In 2000, he met Edward Ginns, director of the Molecular Diagnostics Laboratory at University of Massachusetts.

Interested in the genetic underpinnings of depression, Ginns had for years studied isolated groups of people, such as the Amish, or ethnic groups with fairly homogeneous genetic roots, such as Ashkenazi Jews. Because these groups are genetically similar, differences between individuals with and without a specific disease are relatively easy to spot.

“But one disadvantage of pedigrees is they’re very hard to find. And even if you find them, it’s difficult to exquisitely characterize the symptoms,” Ginns says. “So it was of high interest to me that Nick had this dog population.”

The duo formed a collaboration focused on finding an animal model for repetitive behaviors, and cast a wide net. Dodman passed out flyers at dog shows and gave lectures about the research to breed clubs. Eventually, he collected hundreds of samples from Bull Terriers and Dobermans — which often suck on their hindquarters or on blankets — as well as purebred horses and Siamese cats, which can also show repetitive behaviors.

“Early on, of course, they were just stuck in the fridge, waiting for the technology to catch up,” Dodman says.

By 2007, researchers had created a gene chip that could identify common genetic variants in the canine genome, called single-nucleotide polymorphisms (SNPs), from blood samples.

The new study reports their SNP comparison of 94 Dobermans that sucked either on their flanks or on blankets, or on both, and 73 Dobermans that did not show any repetitive behaviors. They found that dogs with compulsive behaviors tend to carry SNPs on a particular spot on canine chromosome 7 that contains the cadherin 2 gene.

Cadherin 2 is abundant in the hippocampus and cerebellum. It is active early in brain development, when nerve cells are forming connections, called synapses, with each other.

“It was very thrilling to find that we hit a neurological gene that sits at the synapse and has to do with transmission of signals in the brain,” says Kerstin Lindblad-Toh, co-director of the Genome Sequencing and Analysis program at the Broad Institute in Massachusetts who led the canine genome project. “That makes it a very believable hit, and could be the start of unraveling a very important pathway for what happens in OCD.”

Ginns is also excited about the clinical applications of the finding. “When you start a genome-wide scan, the anticipation is, ‘Gee, if you’re lucky you’ll see something that might be almost significant’,” he says. “When you run into something like this, which is highly significant, it’s just too good to pass up.”

The researchers shared these results with colleagues at the National Institute of Mental Health, who are sequencing the gene in people with OCD.

Meanwhile, Dodman says his work on Bull Terriers will be useful for autism research. He’s found that males in this breed that chase their tails can also exhibit autism-like behaviors, including aggression, seizures and something he calls “trancing”.

“They fixate on something, and the stare cannot be broken. It’s like they’re off in some kind of dream world,” he says. “The parallels with autism are striking.” His group is performing a similar SNP analysis of this breed.

Despite dogs’ value as models for certain behaviors, not everyone is optimistic that they will prove useful for studying autism.

Psychiatric phenotypes in dogs are tricky to measure because it’s impossible to assess whether the animals have obsessive thoughts or frequent anxiety, notes Arnold, who is collaborating with Finnish researchers to study repetitive behaviors in Bull Terriers. “You can’t ask dogs what they’re thinking, so many symptoms of OCD are just inaccessible,” he says. “Autism would be even more challenging.”

(Originally published on SFARI)

Paintings of trees with spindly brown branches and plump green leaves cover the walls. Books, plastic cars and coloring books spill out across the carpeted floor and fill several plastic bins.

The children who come here are as young as 3 months on their first visit, and return every few months to participate in a battery of tests of their social behavior and perceptual processing — the brain’s response to non-social stimuli, such as looking at an ordinary object.

About one in four of these children is particularly interesting to the researchers: They are the younger siblings of children with autism, and are much more likely to develop the disorder than are those without a family history of it. Over the past few years, scientists have gathered heaps of behavioral data from these so-called ‘baby sibs’, but the Baby Lab is among the first to look for distinct signatures of brain activity.

The lab’s studies are ongoing, but two published reports have uncovered surprising differences between baby sibs and age-matched controls. Previous imaging work on face processing in people with autism had found abnormalities, suggesting to many researchers that their brains are slow to process social information. But the Baby Lab team is finding that during tests of sensory or perceptual processing, baby sibs show abnormally fast brain responses, rather than a delay.

Lead investigator Karen Dobkins says these data suggest an alternate interpretation of autism’s origins. Instead of resulting from a disruption of the brain’s social behavior circuits, she says, the disorder could arise from early upsets in perceptual processing, which eventually cause more noticeable social problems.

“We know that the hallmarks of autism are social in nature, but social systems develop later than sensory systems,” says Dobkins, professor of psychology at UCSD. “How on earth are you supposed to respond appropriately, behave appropriately, if you don’t perceive your world properly?”

This hypothesis agrees with previous reports from other labs conducting baby sib research, which converge on the idea that there is no fundamental social problem in autism, but rather gradual deficits in several different perceptual and sensory systems, according to a review of these studies published in June.

Chicken or egg?
The Baby Lab tests children for different abilities as they grow up. At 3 and 6 months of age, for instance, the infants sit on their mothers’ laps and watch gray lines flash on a computer screen — allowing researchers to assess how well they detect visual contrast. At 10 and 18 months, the toddlers wear electrodes on their scalp, allowing researchers to record brain activity during perceptual tasks, such as looking at pictures of faces or objects, and social ones, such as playing with a new toy along with their mothers.

The lab’s newest study, to be published in the 15 November issue of Biological Psychiatry, found that 10-month-old baby sibs produce brain-wave responses to pictures of toys significantly faster than do controls.

The findings support a 2007 report from the researchers in which they found that, compared with healthy controls, 6-month-old baby sibs show twice as much sensitivity to black-and-white visual contrast. The researchers say this heightened ability stems from unusual robustness in an early visual brain pathway — one that feeds into brain areas responsible for processing emotions and facial expressions.

But others are skeptical, saying the heightened processing does not necessarily indicate that perceptual glitches are the root cause of the disorder.

“If that were true, then you wouldn’t have something so specific happening in the social domain. They would have visual problems, and more global forms of intellectual disability,” notes Ami Klin, director of the Autism Program at the Yale Child Study Center.

A fundamental social deficit also makes more sense from an evolutionary perspective, Klin adds. “The things in the world that are important to an infant’s survival are people, not objects. Why should they pay more attention to objects?”

In his own studies, Klin has found that, unlike healthy controls, toddlers with autism show no preference for human motion, and tend to look at other people’s mouths instead of their eyes.

The question of which deficits come first “is very much a ‘chicken or egg’ problem,” says Mayada Elsabbagh, scientific coordinator of the British Autism Study of Infant Siblings. “What’s going on is actually affecting multiple systems at the same time, in a way that we don’t see very clearly within the first year.”

…read the rest of my latest feature at SFARI

The volume measurements of some areas seem to depend on the depth of nearby grooves. This unexpected finding could help explain the mixed results of previous studies measuring structural brain differences in people with schizophrenia and other psychiatric diseases, according to unpublished data presented today at the Society for Neuroscience meeting in Chicago.

The cortico-striatal-thalamic loop — a large brain circuit involved in planning and executive control — has been implicated in schizophrenia, obsessive-compulsive disorder and autism.

But studies looking at structural differences in the loop’s regions have found contradictory results.

For example, since 2001, 7 out of 10 structural magnetic resonance imaging (MRI) studies  looking at the size of the anterior cingulate gyrus (ACG) — a ridge on the cortex that feeds into the cortico-striatal-thalamic loop — in people with schizophrenia found a smaller volume when compared with controls; the other 3 did not find a decrease in volume.

Psychiatrist James Levitt measured the volume, thickness and surface area of two structures in the cingulate cortex — which includes the ACG and the paracingulate sulcus (PCS), a deep cortical groove — in 28 adults with chronic schizophrenia and 28 healthy controls.

Gyri and sulci, with their curved mounds and troughs, are extremely difficult to measure using manual tracings of two-dimensional brain slices, which are traditionally used in MRI studies. Levitt instead used FreeSurfer, a brain image processing software that automatically reconstructs a three-dimensional image of brain surfaces.

“The beauty of FreeSurfer is it lets you really look at the sulci in very elegant way,” says Levitt, an associate professor of psychiatry at Harvard Medical School. “You can contour surfaces and follow the deepest points along the sulcus, and really measure the length of the sulcus.”

Using FreeSurfer, Levitt found that 32 percent of people with schizophrenia in his study have an extremely deep PCS compared with just 11 percent of controls. What’s more, those in the schizophrenia group who have a deep PCS have a smaller ACG by volume — which could explain the conflicting results from previous studies.

Levitt suggests that future studies — not only of schizophrenia, but also of autism and other neuropsychiatric diseases — would gain a more complete picture by calculating both sulcal structure and volume. “Just getting a smaller volume, if you don’t actually know the sulcal pattern, can be misleading,” he says.

That’s what I asked Tracy Bale, neuroscientist at the University of Pennsylvania, yesterday at a morning session at SfN. Bale studies how maternal stress during pregnancy might lead to neuropsychiatric diseases, such as schizophrenia or autism. Check out a video of her answer, or the other SfN conference reports on SFARI.org.