Category: Autism

The brain works because 100 billion of its special nerve cells called neurons regulate trillions of connections that carry and process information. The behavior of each neuron is precisely determined by the proper function of many genes.

In 1999, Baylor College of Medicine researcher Dr. Huda Zoghbi and her colleagues identified mutations in one of these genes called MECP2 as the culprit in a devastating neurological disorder called Rett syndrome . In new research in mice published in the current issue of the journal Nature, Zoghbi and her colleagues demonstrate that the loss of the protein MeCP2 in a special group of inhibitory nerve cells in the brain reproduces nearly all Rett syndrome features.

Children, mostly girls, born with Rett syndrome, appear normal at first, but stop or slow intellectual and motor development between three months and three years of age, losing speech, developing learning and gait problems. Some of their symptoms resemble those of autism.

These inhibitory (gamma-amino-butyric-acid [GABA]-ergic) neurons make up only 15 to 20 percent of the total number of neurons in the brain. Loss of MeCP2 causes a 30 to 40 percent reduction in the amount of GABA, the specific signaling chemical made by these neurons. This loss impairs how these neurons communicate with other neurons in the brain. These inhibitory neurons keep the brakes on the communication system, enabling proper transfer of information.

"In effect, the lack of MeCP2 impairs the GABAergic neurons that are key regulators governing the transfer of information in the brain," said Dr. Hsiao-Tuan Chao, an M.D./Ph.D student in Zoghbi's laboratory and first author of the report.

Chao made the discovery by developing a powerful new tool or mouse model that allowed researchers to remove MeCP2 from only the GABAergic neurons.

"We did this study thinking that perhaps all we would see was a few symptoms of Rett syndrome," said Chao. "Strikingly, we saw that removing MeCP2 solely from GABAergic neurons reproduced almost all the features of Rett syndrome, including cognitive deficits, breathing difficulties, compulsive behavior, and repetitive stereotyped movements. The study tells us that MeCP2 is a key protein for the function of these neurons."

Once the authors determined that the key problem rested with the GABAergic neurons, they sought to find out how the lack of MeCP2 disturbed the function of these neurons. Chao discovered that losing MeCP2 caused the GABAergic neurons to release less of the neurotransmitter, GABA. This occurs because losing MeCP2 reduces the amount of the enzymes required for the production of GABA.

Intriguingly, prior studies showed that expression of these enzymes is also reduced in some patients with autism, schizophrenia and bipolar disorder, said Chao.

"This tells us a lot about what is going on in the brains of people with Rett syndrome, autism or even schizophrenia," said Chao. "A child is born healthy. She starts to grow and then begins to lose developmental milestones. Communication between neurons is impaired, in part due to reduced signals from GABAergic neurons."

"This study taught us that an alteration in the signal from GABAergic neurons is sufficient to produce features of autism and other neuropsychiatric disorders," said Zoghbi, a Howard Hughes Medical Institute investigator and director of the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital.

Others who took part in this work include Hongmei Chen, Rodney C. Samaco, Mingshan Xue, Maria Chahrour, Jong Yoo, Jeffrey L. Neul, Hui-Chen Lu, Jeffrey L. Noebels and Christian Rosenmund, all of BCM, John L.R. Rubenstein of University of Calfornia in San Francisco, Marc Ekker of University of Ottawa in Ontario, and Shiaoching Gong and Nathaniel Heintz of The Rockefeller University in New York.

Funding for this work came from the Howard Hughes Medical Institute, the National Institute of Neurological Disorders and Stroke, the Simons Foundation, the Rett Syndrome Research Trust, the Intellectual and Developmental Disability Research Centers, the International Rett Syndrome Foundation, Autism Speaks, the National Institute of Mental Health, Baylor Research Advocates for Student Scientists and McNair Fellowships.

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Journal Reference:

1. Hsiao-Tuan Chao, Hongmei Chen, Rodney C. Samaco, Mingshan Xue, Maria Chahrour, Jong Yoo, Jeffrey L. Neul, Shiaoching Gong, Hui-Chen Lu, Nathaniel Heintz, Marc Ekker, John L. R. Rubenstein, Jeffrey L. Noebels, Christian Rosenmund, Huda Y. Zoghbi. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature, 2010; 468 (7321): 263 DOI: 10.1038/nature09582

Many gene variants have been linked to autism, but how do these subtle changes alter the brain, and ultimately, behavior?

Using a blend of brain imaging and genetic detective work, scientists at UCLA's David Geffen School of Medicine and Semel Institute for Neuroscience and Human Behavior are the first to illustrate how genetic variants rewire the brain. Published in the Nov. 3 online edition of Science Translational Medicine, their discovery offers the crucial missing physical evidence that links altered genes to modified brain function and learning.

"This is a key piece of the puzzle we've been searching for," said co-principal investigator Dr. Daniel Geschwind, a professor of neurology and psychiatry who holds UCLA's Gordon and Virginia MacDonald Distinguished Chair in Human Genetics. "Now we can begin to unravel the mystery of how genes rearrange the brain's circuitry not only in autism, but in many related neurological disorders."

The UCLA team scrutinized the differences in brain connectivity and function that result from two forms of the CNTNAP2 gene, one of which boosts risk for autism.

Earlier studies by Geschwind and others demonstrated that the gene is most active during brain development in the frontal lobe. The region is highly involved in learning, which is often disrupted in autistic children.

Suspecting that CNTNAP2 might influence brain activity, the researchers used functional magnetic resonance imaging (fMRI) to scan the brains of 32 children as they performed learning-related tasks. Half of the children had autism, and half did not.

The team's goal was to measure the strength of various communication pathways in different regions of the brain as they connected with each other.

The fMRI images excited the scientists — and confirmed their suspicions.

Regardless of their diagnosis, the children carrying the risk variant showed a disjointed brain. The frontal lobe was over-connected to itself and poorly connected to the rest of the brain. Communication with the back of the brain was particularly diminished.

"In children who carry the risk gene, the front of the brain appears to talk mostly with itself," explained first author Ashley Scott-Van Zeeland, now a Dickinson Research Fellow at Scripps Translational Science Institute. "It doesn't communicate as much with other parts of the brain and lacks long-range connections to the back of the brain."

Depending on which CNTNAP2 version the child carried, the researchers also observed a difference in connectivity between the left and right sides of the brain. In most people, the left side processes functions tied to language, like speech and understanding.

In the children with the non-risk gene, communication pathways in the frontal lobe linked more strongly to the left side of the brain.

In children with the risk variant, communications pathways in the front lobe connected more broadly to both sides of the brain. The unusual symmetry suggests that the gene variant rewires connections in the brain, perhaps explaining why this version of CNTNAP2 is associated with delayed speech.

"We saw that if you had the risk variant, your brain showed disrupted activation patterns whether you were diagnosed on the autism spectrum or not," explained co-principal investigator Susan Bookheimer, a professor of psychiatry who holds the Joaquin Fuster Chair in Cognitive Neurosciences. "We suspect that CNTNAP2 plays an important role in wiring neurons at the front of the brain, and that the risk variant interferes with that process."

By enhancing understanding of the relationship between genes, the brain and behavior, the UCLA finding could lead to earlier detection for autism, and new interventions to strengthen connections between the frontal lobe and left side of the brain.

"If we determine that the CNTNAP2 variant is a consistent predictor of language difficulties," said Scott-Van Zeeland, "we could begin to design targeted therapies to help rebalance the brain and move it toward a path of more normal development."

Researchers could test whether specific therapies actually change brain function by measuring connectivity of patients before and after therapy, she added.

The authors emphasized that the patterns of connectivity found in the study still fall along the spectrum of normal gene variation. "One third of the population carries this variant in its DNA," noted Geschwind. "It's important to remember that the gene variant alone doesn't cause autism, it just increases risk."

Led by the UCLA Autism Center of Excellence, the research was supported by grants from the National Institute of Child Health and Human Development, National Alliance for Autism Research, National Center for Research Resources, Autism Speaks, Whitehall Foundation, Training Program in Neurobehavioral Genetics and a National Research Service Award.

Other UCLA coauthors included Ana Alvarez-Retuerto, Lisa Sonnenblick, Jeffrey Rudie, Dara Ghahremani, Jeanette Mumford, Russell Poldrack, Mirella Dapretto and Brett Abrahams, now at Albert Einstein College of Medicine.

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Journal Reference:

1. A. A. Scott-Van Zeeland, B. S. Abrahams, A. I. Alvarez-Retuerto, L. I. Sonnenblick, J. D. Rudie, D. Ghahremani, J. A. Mumford, R. A. Poldrack, M. Dapretto, D. H. Geschwind, S. Y. Bookheimer. Altered Functional Connectivity in Frontal Lobe Circuits Is Associated with Variation in the Autism Risk Gene CNTNAP2. Science Translational Medicine, 2010; 2 (56): 56ra80 DOI: 10.1126/scitranslmed.3001344

University of Utah (U of U) medical researchers have uncovered a wiring diagram that shows how the brain pays attention to visual, cognitive, sensory, and motor cues. The research provides a critical foundation for the study of abnormalities in attention that can be seen in many brain disorders such as autism, schizophrenia, and attention deficit disorder.

The study appears Nov. 1, 2010, online in the Proceedings of the National Academy of Sciences (PNAS).

"This study is the first of its kind to show how the brain switches attention from one feature to the next," says lead researcher Jeffery S. Anderson, M.D., Ph.D., U of U assistant professor of radiology. Anderson and his team used MRI to study a part of the brain known as the intraparietal sulcus. "The brain is organized into territories, sort of like a map of Europe. There are visual regions, regions that process sound and areas that process sensory and motor information. In between all these areas is the intraparietal sulcus, which is known to be a key area for processing attention," Anderson says. "We discovered that the intraparietal sulcus contains a miniature map of all of these territories. We also found an organized pattern for how control regions of the brain connect to this map in the intraparietal sulcus. These connections help our brain switch its attention from one thing to another."

In addition, scientists discovered that this miniature map of all the things one can pay attention to is reproduced in at least 13 other places in the brain. They found connections between these duplicate maps and the intraparietal sulcus. Each copy appears to do something different with the information. For instance, one map processes eye movements while another processes analytical information. This map of the world that allows us to pay attention may be a fundamental building block for how information is represented in the brain.

"The research uncovers how we can shift our attention to different things with precision," says Anderson. "It's a big step in understanding how we organize information. Furthermore, it has important implications for disease. There are several diseases or disorders where attention processing is off, such as autism, attention deficit disorder, and schizophrenia, among others. This research gives us the information to test theories and see what is abnormal. When we know what is wrong, we can talk about strategies for treatment or intervention."

Deborah Yurgelun-Todd, Ph.D., professor of psychiatry in the U of U Schoold of Medicine and an investigator with the U of U Brain Institute and the Utah Science Technology and Research Initiative (USTAR), was the principal investigator and senior author of the study. The research was funded by a National Institutes of Health grant from the National Institute on Drug Abuse.

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Journal Reference:

1. Jeffrey S. Anderson, Michael A. Ferguson, Melissa Lopez-Larson, Deborah Yurgelun-Todd. Topographic maps of multisensory attention. Proceedings of the National Academy of Sciences, 2010; DOI: 10.1073/pnas.1011616107

 Succimer, a drug used for treating lead poisoning, does not effectively remove mercury from the body, according to research supported by the National Institutes of Health. Some families have turned to succimer as an alternative therapy for treating autism.

"Succimer is effective for treating children with lead poisoning, but it does not work very well for mercury," said Walter Rogan, M.D., head of the Pediatric Epidemiology Group at the National Institute of Environmental Health Sciences (NIEHS), part of NIH, and an author on the paper that appears online in the Journal of Pediatrics.

"Although it is not approved by the Food and Drug Administration to reduce mercury, succimer is reportedly being used for conditions like autism, in the belief that these conditions are caused, in part, by mercury poisoning," Rogan stated. "Our new data offers little support for this practice."

Although researchers found that succimer lowered blood concentrations of mercury after one week, continued therapy for five months only slowed the rate at which the children accumulated mercury. The safety of higher doses and longer courses of treatment has not been studied.

Most mercury exposure in the United States is from methylmercury, found in foods such as certain fish. Thimerosal, a preservative that was once more commonly used in vaccines, contains another form of mercury, called ethylmercury.

To conduct the study, the researchers used samples and data from an earlier clinical trial, led by NIEHS, called the Treatment of Lead-exposed Children (TLC) trial. In the TLC study, succimer lowered blood lead in 2-year-old children with moderate to high blood lead concentrations.

Using blood samples from 767 children who participated in the TLC trial, the researchers measured mercury concentration in the toddlers' blood samples collected before treatment began, one week after beginning treatment with succimer or placebo, and then again after three month-long courses of treatment. Mercury concentrations were similar in all children before treatment. Concentrations eventually increased in both groups, but more slowly in the children given succimer. Succimer had produced a 42 percent difference in blood lead, but only an 18 percent difference in blood mercury.

"Although succimer may slow the increase in blood mercury concentrations, such small changes seem unlikely to produce any clinical benefit," Rogan said. He and his colleagues had reported in an earlier paper that succimer has few adverse side effects, mostly rashes, and an unexplained increase in injuries in children given succimer rather than placebo.

The subjects of the study did not have unusually high blood mercury concentrations for African-American children and the study did not investigate where the mercury in the children came from.

"This research fills a gap in the scientific literature that could not be addressed any other way. We were fortunate to have samples already collected from toddlers who had been treated with succimer for lead poisoning allowing us to help answer this important question," said Linda Birnbaum, Ph.D., director of NIEHS and the National Toxicology Program.

Birnbaum noted NIH's commitment to supporting research that provides critically needed information that will help drive more prevention and treatment options for children with autism and other neurodevelopmental disorders.

The study was supported by the NIEHS Intramural Research Program, the National Institute for Minority Health and Health Disparities at NIH, and the National Center for Environmental Health at the Centers for Disease Control and Prevention. The succimer, Chemet, and the placebo, were gifts from McNeil Laboratories, Fort Washington, Pa.

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Journal Reference:

1. Yang Cao, Aimin Chen, Robert L. Jones, Jerilynn Radcliffe, Kim N. Dietrich, Kathleen L. Caldwell, Shyamal Peddada, Walter J. Rogan. Efficacy of Succimer Chelation of Mercury at Background Exposures in Toddlers: A Randomized Trial. The Journal of Pediatrics, 2010; DOI: 10.1016/j.jpeds.2010.08.036

 Autism was described as early as 1940, but a marked increase in the prevalence for the broader class of autism spectrum disorders (ASDs) during the past decade highlights the demand for treatment of affected individuals. The Centers for Disease Control and Prevention (CDC) reported that the prevalence of ASD was one in 110 children in 2006 and increased at an average annual rate of 57% between 2002 and 2006. The rising prevalence has heightened concern about the financial impact of treating ASDs in the private and public health care systems.

The escalating health care expenditures associated with autism spectrum disorders (ASDs) in state Medicaid programs is the subject of a study by Penn State College of Medicine researchers in the November issue of the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP).

In the article titled "Health Care Expenditures for Children with Autism Spectrum Disorders in Medicaid," Drs. Li Wang and Douglas Leslie used Medicaid data from 42 states from 2000 to 2003, to evaluate costs for patients aged 17 years and under who were continuously enrolled in fee-for-service Medicaid. Total expenditures included Medicaid reimbursements from inpatient, outpatient, and long-term care, as well as prescription drugs, for each treated patient.

During the study period over two million children were diagnosed with some type of mental disorder. Of these children, nearly 70,000 had an ASD, with approximately 50,000 having autism. Researchers found that total health care expenditures per child with ASD were $22,079 in 2000 (in 2003 US dollars), and rose by 3.1% to $22,772 in 2003.

Strikingly, the increase in the treated prevalence of autism was higher than in any other mental disorder, rising by 32.2% from 40.6 to 53.6 per 10,000 covered lives. Total health care expenditures for ASDs per 10,000 covered lives grew by 32.8% from $1,270,435 in 2000 (in 2003 dollars) to a remarkable $1,686,938 in 2003.

ASDs are known to occur in all ethnic and socioeconomic groups and are characterized by impaired social interaction. Symptoms can improve with age, although many individuals continue to need support into adulthood.

This study is the first to use recent national Medicaid data to estimate ASD-related health care expenditures. Medicaid expenditures per ASD child are much higher than those reported for privately insured children. The rapid rise in the Medicaid expenditures for ASDs is largely due to the increase of treated prevalence rather than an increase in per patient expenditures.

In conclusion, Wang and Leslie state, "Efforts should be made to ensure that adequate resources are in place to reduce barriers to care for this particularly vulnerable population."

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Journal Reference:

1. Li Wang, Douglas L. Leslie. Health Care Expenditures for Children With Autism Spectrum Disorders in Medicaid. Journal of the American Academy of Child and Adolescent Psychiatry, 2010; 49 (11): 1165-1171 DOI: 10.1016/j.jaac.2010.08.003

Magicians rely on misdirection — drawing attention to one place while they're carrying out their tricky business somewhere else. It seems like people with autism should be less susceptible to such social manipulation. But a new study in the U.K. finds that people with autism spectrum disorder are actually more likely to be taken in by the vanishing ball trick, where a magician pretends to throw a ball in the air but actually hides it in his hand.

In the vanishing-ball illusion, a magician throws a ball in the air a few times. On the last throw, he merely pretends to throw it, making a tossing motion and looking upwards while the ball remains concealed in his hand. But observers claim to "see" the ball leaving the hand. This misdirection depends on social cues; the audience watches the magician's face. People with autism are known for having trouble interpreting social cues, so Gustav Kuhn of Brunel University and his coauthors Anastasia Kourkoulou and Susan R. Leekam of Cardiff University thought they could use magic tricks to understand how people with autism function.

For this experiment, 15 teenagers and young adults with autism spectrum disorder and 16 without autism watched a video of a magician performing the vanishing-ball illusion. Then they were asked to mark where they last saw the ball on a still image of the magician. The last place it appeared was in the magician's hand, but many people mark a position higher up and say that he threw the ball. "We strongly suspected that individuals with autism should be using the social cues less than typically developing individuals," says Kuhn — that people with autism would watch the ball rather than the magician's face, and thus have a better idea of what happened.

But the exact opposite happened. People with autism were much more likely to think the magician had thrown the ball. Kuhn speculates that this is because the people in the study were all students at a special college for autism, where they would have been taught to use social cues. When he examined where their eyes had looked, he found that, like normally-developing people, they looked first at the magician's face — but their eyes took longer to fix there. They also had more trouble fixing their eyes on the ball.

The results are published in Psychological Science, a journal of the Association for Psychological Science.

"What we suggest is that individuals with autism have particular problems in allocating attention to the right place at the right time," Kuhn says. This may cause trouble in social situations, when you have to be able to pay attention to the right thing at the right time. Kuhn would like to repeat the experiment in children with autism, who may not yet have been educated in social cues, to see if they are also taken in by the illusion.

Note:

*Gustav Kuhn describes his study, "How Magic Changes Our Expectations About Autism" in this SciVee PubCast: http://www.scivee.tv/node/25133 (click on "video + document")

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Journal Reference:

1. Gustav Kuhn, Anastasia Kourkoulou, Susan R. Leekam. How Magic Changes Our Expectations About Autism. Psychological Science, 2010; 21: 1487-1493 DOI: 10.1177/0956797610383435

The last two decades have seen tremendous progress in understanding the genetic basis of human brain disorders. Research developments in this area have revealed fundamental insights into the genes and molecular pathways that underlie neurological and psychiatric diseases. In a new series of review articles published by Cell Press in the October 21 issue of the journal Neuron, experts in the field discuss exciting recent advances in neurogenetics research and the potential implications for the treatment of these devastating disorders.

Genetic discoveries have transformed clinical practice in neurology and psychiatry and provided new hope for many patients and their families. Recent advances in sequencing technologies coupled with improved analytical and computational approaches have led an amazing pace of discovery of genes linked to human disease. The complexity of neuropsychiatric and neurological disorders is apparent in the fast-growing list of genetic defects linked to these diseases. These genetic findings have provided key insight into underlying causes of these disorders and inspired further research aimed at prevention and therapy.

Genetic research has great potential for revolutionizing the treatment of human disease. However, the translation of genetic findings into the development of new disease therapies can take time. In an overview of the series, researchers Huda Zoghbi from Baylor College of Medicine and Stephen Warren from Emory University School of Medicine discuss recent achievements in neurogenetics research and the promise that it holds for disease treatment. They point out that gene discovery is a critical first step in the path to development of new therapies and that follow up investigations are needed to reveal disease pathways that lend themselves to therapeutic intervention. These preclinical investigations are a key step in the translation of genetic discoveries to clinical applications. Recent data from mouse disease models indicate that some developmental and degenerative diseases are reversible. These findings provide hope that genetic discoveries could potentially lead to the reversal of serious neurological and psychiatric disorders through the development of therapeutics that suppress the pathways contributing to disease.

Zoghbi and Warren make a strong case for the need for scientific collaboration and the appropriate infrastructure to support partnerships among academic research, governments, private institutions and foundations, and pharmaceutical industries. The authors argue that combining resources and expertise will help accelerate the development of therapies based on genetic discoveries.

This series of review articles covers a wide spectrum of recent research in neurogenetics, including the genetics of Parkinson and Alzheimer disease, human developmental and neurogenetics, and the genetics of child psychiatric disorders. All articles are freely available on the Neuron website (www.neuron.org) for a limited time.

Reviews:

• Neurogenetics: Advancing the ''Next-Generation'' of Brain Research H.Y. Zoghbi and S.T. Warren
• Tangles of Neurogenetics, Neuroethics, and Culture E. Brief and J. Illes
• Healing Genes in the Nervous System X.O. Breakefield and M. Sena-Esteves
• The Psychiatric GWAS Consortium: Big Science Comes to Psychiatry P.F. Sullivan
• Changing the Landscape of Autism Research: The Autism Genetic Resource Exchange C.M. Lajonchere and the AGRE Consortium
• The Simons Simplex Collection: A Resource for Identification of Autism Genetic Risk Factors G.D. Fischbach and C. Lord
• Nature versus Nurture: Death of a Dogma, and the Road Ahead B.J. Traynor and A.B. Singleton
• Genetic Analysis of Pathways to Parkinson Disease J. Hardy
• From Single Genes to Gene Networks: High-Throughput-High-Content Screening for Neurological Disease S. Jain and P. Heutink
• Neurocognitive Phenotypes and Genetic Dissection of Disorders of Brain and Behavior E. Congdon, R.A. Poldrack, and N.B. Freimer
• Human Brain Evolution: Harnessing the Genomics (R)evolution to Link Genes, Cognition, and Behavior G. Konopka and D.H. Geschwind
• Allelic Diversity in Human Developmental Neurogenetics: Insights into Biology and Disease C.A. Walsh and E.C. Engle
• The Genetics of Child Psychiatric Disorders: Focus on Autism and Tourette Syndrome M.W. State
• The Genetics of Alzheimer Disease: Back to the Future L. Bertram, C.M. Lill, and R.E. Tanzi
• Episodic Neurological Channelopathies D.P. Ryan and L.J. Ptácek
• Hearing Impairment: A Panoply of Genes and Functions A.A. Dror and K.B. Avraham
• Genetic Advances in the Study of Speech and Language Disorders D.F. Newbury and A.P. Monaco

Dogs may not only be man's best friend, they may also have a special role in the lives of children with special needs. According to a new Université de Montreal study, specifically trained service dogs can help reduce the anxiety and enhance the socialization skills of children with Autism Syndrome Disorders (ASDs).

The findings, published in the journal Psychoneuroendocrinology, may be a relatively simple solution to help affected children and their families cope with these challenging disorders.

"Our findings showed that the dogs had a clear impact on the children's stress hormone levels," says Sonia Lupien, senior researcher and a professor at the Université de Montréal Department of Psychiatry and Director of the Centre for Studies on Human Stress at Louis-H. Lafontaine Hospital, "I have not seen such a dramatic effect before."

Cortisol the telltale indicator of stress

To detect stress-levels, Lupien and colleagues measured the amount of cortisol present in the saliva of autistic children. Cortisol is a hormone that is produced by the body in response to stress. It peaks half-hour after waking up, known as the cortisol awakening response (CAR) and decreases throughout the day. Moreover, it is detectable in the saliva, which makes sampling its levels easy.

The researchers measured the CAR of 42 children with ASD. "CAR is a very useful marker of stress," say Lupien. "We used it to determine the effect of service dogs on the children's stress levels by measuring it in three experimental conditions; prior to and during the introduction of a service dog to the family, and after the dog was removed."

Cortisol and behaviour linked

Throughout the experiment, parents were asked to complete a questionnaire addressing the behaviours of their children before, during and after the introduction of the dog. On average, parents counted 33 problematic behaviours prior to living with the dog, and only 25 while living with the animal.

"Introducing service dogs to children with ASD has received growing attention in recent decades," says Lupien. "Until now, no study has measured the physiological impact. Our results lend support to the potential behavioural benefits of service dogs for autistic children."

This study was funded by MIRA Foundation, Quebec, Canada.

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Journal Reference:

1. Robert Viau, Geneviève Arsenault-Lapierre, Stéphanie Fecteau, Noël Champagne, Claire-Dominique Walker, Sonia Lupien. Effect of service dogs on salivary cortisol secretion in autistic children. Psychoneuroendocrinology, 2010; 35 (8): 1187 DOI: 10.1016/j.psyneuen.2010.02.004

 Just as we visually map a room by spatially identifying the objects in it, we map our aural world based on the frequencies of sounds. The neurons within the brain's "hearing center" — the auditory cortex — are organized into modules that each respond to sounds within a specific frequency band. But how responses actually emanate from this complex network of neurons is still a mystery.

A team of scientists led by Anthony Zador, M.D., Ph.D., Professor and Chair of the Neuroscience program at Cold Spring Harbor Laboratory (CSHL) has come a step closer to unraveling this puzzle. The scientists probed how the functional connectivity among neurons within the auditory cortex gives rise to a "map" of acoustic space.

"What we learned from this approach has put us in a position to investigate and understand how sound responsiveness arises from the underlying circuitry of the auditory cortex," says Zador. His team's findings appear online, ahead of print, on October 17th in Nature Neuroscience.

Neuronal organization within the auditory cortex fundamentally differs from the organization within brain regions that process sensory inputs such as sight and sensation. For instance, the relative spatial arrangement of sight receptors in the retina (the eyes' light-sensitive inner surface) is directly represented as a two-dimensional "retinotopic" map in the brain's visual cortex.

In the auditory system, however, the organization of sound receptors in the cochlea — the snail-like structure in the ear — is one-dimensional. Cochlear receptors near the outer edge recognize low-frequency sounds whereas those whereas those near the inside of the cochlea are tuned to higher frequencies. This low-to-high distribution, called 'tonotopy,' is preserved along one dimension in the auditory cortex, with neurons tuned to high and low frequencies arranged in a head-to-tail gradient.

"Because sound is intrinsically a one-dimensional signal, unlike signals for other senses such as sight and sensation which are intrinsically two-dimensional, the map of sound in the auditory cortex is also intrinsically one-dimensional," explains Zador. "This means that there is a functional difference in the cortical map between the low-to-high direction and the direction perpendicular to it. However, no one has been able understand how that difference arises from the underlying neuronal circuitry."

To address this question, Zador and postdoctoral fellow Hysell Oviedo compared neuronal activity in mouse brain slices that were cut to preserve the connectivity along the tonotopic axis vs. activity in slices that were cut perpendicular to it.

To precisely stimulate a single neuron within a slice and record from it, Oviedo and Zador, working in collaboration with former CSHL scientists Karel Svoboda and Ingrid Bureau, used a powerful tool called laser-scanning photostimulation. This method allows the construction of a detailed, high-resolution picture that reveals the position, strength and the number of inputs converging on a single neuron within a slice.

"If you did this experiment in the visual cortex, you would see that the connectivity is the same regardless of which way you cut the slice," explains Oviedo. "But in our experiments in the auditory cortex slices, we found that there was a qualitative difference in the connectivity between slices cut along the tonotopic axis vs. those cut perpendicular to it."

There was an even more striking divergence from the visual cortex — and presumably the other cortical regions. As demonstrated by a Nobel Prize-winning discovery in 1962, in the visual cortex, the neurons that share the same input source (or respond to the same signal) are organized into columns. As Oviedo puts it, "all neurons within a column in the vertical cortex are tuned to the same position in space and are more likely to communicate with other neurons from within the same column."

Analogously, in the auditory cortex, neurons within a column are expected to be tuned to the same frequency. So the scientists were especially surprised to find that for a given neuron in this region, the dominant input signal didn't come from within its column but from outside it.

"It comes from neurons that we think are tuned to higher frequencies," elaborates Zador. "This is the first example of the neuronal organizing principle not following the columnar pattern, but rather an out-of-column pattern." Discovering this unexpected, out-of-column source of information for a neuron in the auditory complex adds a new twist to their research, which is focused on understanding auditory function in terms of the underlying circuitry and how this is altered in disorders such as autism.

"With this study, we've moved beyond having only a conceptual notion of the functional difference between the two axes by actually finding correlates for this difference at the level of the neuronal microcircuits in this region," he explains.

This work was supported by grants from the US National Institutes of Health, the Patterson Foundation, the Swartz Foundation and Autism Speaks.

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Journal Reference:

1. Hysell V Oviedo, Ingrid Bureau, Karel Svoboda, Anthony M Zador. The functional asymmetry of auditory cortex is reflected in the organization of local cortical circuits. Nature Neuroscience, 2010; DOI: 10.1038/nn.2659

University of Utah (U of U) medical researchers have made an important step in diagnosing autism through using MRI, an advance that eventually could help health care providers identify the problem much earlier in children and lead to improved treatment and outcomes for those with the disorder.

In a study published on October 15, 2010 in Cerebral Cortex online, researchers led by neuroradiologist Jeffery S. Anderson, M.D., Ph.D., U of U assistant professor of radiology, used MRI to identify areas where the left and right hemispheres of the brains of people with autism do not properly communicate with one another. Those areas are in "hot spots" associated with functions such as motor skills, attention, facial recognition, and social functioning — behaviors that are abnormal in autism. MRI's of people without the disorder did not show the same deficits.

"We know the two hemispheres must work together for many brain functions," says Anderson. "We used MRI to look at the strength of these connections from one side to the other in autism patients."

Other than increased brain size in young children with autism, there are no major structural differences between the brains of people with autism and those who do not have the disorder that can be used to diagnose autism on a routine brain MRI. It has been long believed that more profound differences could be discovered by studying how regions in the brain communicate with each other. The study, and other work U of U researchers are doing using diffusion tensor imaging (measures microstructure of white matter that connects brain regions), reveals important information about autism. The advances highlight MRI as a potential diagnostic tool, so patients could be screened objectively, quickly, and early on when interventions are most successful. The advances also show the power of MRI to help scientists better understand and potentially better treat autism at all ages.

"We still don't know precisely what's going on in the brain in autism," says Janet Lainhart, M.D., U of U associate professor of psychiatry and pediatrics and the study's principal investigator. "This work adds an important piece of information to the autism puzzle. It adds evidence of functional impairment in brain connectivity in autism and brings us a step closer to a better understanding of this disorder. When you understand it at a biological level, you can envision how the disorder develops, what are the factors that cause it, and how can we change it. "

An increasing number of studies have shown abnormalities in connectivity in autism, but this study is one of the first of its kind to characterize functional connectivity abnormalities in the entire brain using MRI rather than in a few specific pathways. The research involved about 80 autism patients between the ages of 10-35 and took about a year and a half to complete. The results will be added to an existing autism study following 100 patients over time. "The longitudinal imaging data and associated knowledge gathered forms a unique resource that doesn't exist anywhere else in the world," says Lainhart.

In addition to someday using MRI as a diagnostic tool for autism, researchers also hope to use the data to biologically describe different subtypes of autism. "This is a complex disorder that doesn't just fall into one category," says Lainhart. "We hope the information can lead us to characterizing different types of autism that may have different symptoms or prognoses that will allow us to identify the best treatment for each affected individual."

The collaborative autism imaging research group led by Lainhart is working together to develop methods to use brain imaging to better understand autism and improve the lives of affected individuals. It includes researchers in the departments of psychiatry, radiology, and pediatrics, the Neurosciences Program, the Scientific Computing and Imaging Institute, and The Brain Institute at the U of U, as well as collaborators at Brigham Young University, the University of Wisconsin, and Harvard University.

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Journal Reference:

1. Jeffrey S. Anderson, T. Jason Druzgal, Alyson Froehlich, Molly B. Dubray, Nicholas Lange, Andrew L. Alexander, Tracy Abildskov, Jared A. Nielsen, Annahir N. Cariello, Jason R. Cooperrider, Erin D. Bigler, and Janet E. Lainhart. Decreased Interhemispheric Functional Connectivity in Autism. Cerebral Cortex, October 15, 2010 DOI: 10.1093/cercor/bhq190