Targeted Behavioral Therapy Can Effectively Control Tics in Adults with Tourette Syndrome

A comprehensive behavioral intervention is more effective than supportive therapy and education in helping adults control the tics associated with Tourette syndrome, according to an NIMH-funded study published in the August 2012 issue of the Archives of General Psychiatry. The study follows a previous study involving children with the disorder, which showed similar results. Background Tourette syndrome (TS) is a chronic neurological disorder associated with motor or vocal tics that can be disruptive and difficult to control. Tics begin in childhood, typically peak in early adolescence and often decrease by adulthood. For some adults, the tics persist and can be difficult to control. Many individuals with TS describe an unwanted urge or sensation prior to the tic that is relieved by performing the tic. TS is commonly treated with an antipsychotic medication such as pimozide or risperidone. But these medications rarely eliminate tics entirely and can cause troubling side effects such as weight gain and sedation. Because of these adverse side effects, many patients decline or discontinue use of these medications. Until now, few large-scale studies have examined the effectiveness of behavioral interventions for TS. A team of investigators from Massachusetts General Hospital/Harvard Medical School; Yale University; University of Texas Health Science Center at San Antonio; University of California, Los Angeles; the University of Wisconsin-Milwaukee; Johns Hopkins Medical Institutions; and the Tourette Syndrome Association tested the effectiveness of a Comprehensive Behavioral Intervention for Tics (CBIT), a therapy based on habit reversal training that includes two concepts: Tic-awareness training, which teaches how to recognize early signs that a tic is about to occur, and Competing-response training, which teaches how to engage in a voluntary behavior that is physically incompatible with the impending tic. For example, a person feeling an urge to jerk his or her shoulder may be taught to tense arm muscles while pushing the elbow against the torso (a competing response). This combination of awareness training and competing response training is intended to disrupt the cycle of premonitory urge and performance of the tic. The researchers randomized 122 adults at three research centers to either CBIT or a control treatment that included supportive therapy and education about TS. Each group received eight sessions over a 10-week period. Those who responded to therapy were assessed three months and six months after the end of the study period to determine if the therapy’s benefits persisted. Results of the Study Overall, 38 percent of patients receiving CBIT showed significant symptom improvement compared to 6 percent receiving the control treatment. The results complement the earlier CBIT study in children, which found that 52 percent of the children who received CBIT showed significant symptom improvement compared to 18.5 percent receiving the control treatment.

About 62.5 percent of those who responded to CBIT in the trial returned for follow-up assessments at three and six months. About 80 percent of the returning participants continued to show a positive response to CBIT, indicating the treatment has enduring benefits for a significant group. In comparison, about 50 percent of those who responded to the control treatment returned for post-treatment assessment, and only about 25 percent of those continued to show benefits after six months. Significance Given the limited medication options for treating TS and the adverse effects associated with the antipsychotic medications, CBIT provides an alternative treatment to manage tics in children and adults. However, the positive response among adults was lower than among the children. The researchers suggest that people with tics that persist into adulthood may have a more chronic form of the disorder that is more difficult to treat. What’s Next Future research focused on CBIT may uncover the role of behavioral learning in reducing the involuntary movements and tics associated with TS. In the meantime, the researchers are working with the Tourette Syndrome Association and the Centers for Disease Control and Prevention to disseminate this intervention by offering training workshops to clinicians around the country social worker ceus Reference Wilhelm S, Peterson AL, Piacentini J, Woods DW, Deckersbach T, Sukhodolsky DG, Chang S, Liu H, Dziura J, Walkup JT, Scahill L. Randomized trial of behavior therapy for adults with Tourette syndrome. Archives of General Psychiatry. 2012 August.

NIH researchers use brain imaging to understand genetic link between Parkinson's and a rare disease

Role of Gaucher disease-gene alterations is clarified by six-year study By Steven Benowitz Special to NHGRI A Composite PET scan showing how the areas with decreased dopamine synthesis (yellow) in patients with Gaucher disease and Parkinson's disease (left) and in typical Parkinson's disease (right) are very similar. A rare metabolic disorder is helping researchers at the National Human Genome Research Institute (NHGRI) and the National Institute of Mental Health (NIMH) uncover new clues about the biology underlying Parkinson's disease. The results of their six-year study, published online in the July 30, 2012, issue of the journal Brain, may explain how people with alterations in the gene involved in Gaucher disease are more likely to develop Parkinson's — and provide a window to potential inner workings of Parkinson's itself professional counselor continuing education "It's important to understand why having a mutation in this gene predisposes someone to Parkinson's," said Ellen Sidransky, M.D., co-senior author and senior investigator in NHGRI's Medical Genetics Branch. "Clinically, we've seen that people with Gaucher mutations are at increased risk of developing Parkinson's and have noted that these patients can have earlier and more progressive symptoms, but these new findings provide biological evidence to support those differences." Gaucher disease is an inherited disease caused by mutations in the GBA gene, which codes for the enzyme glucocerebrosidase, which breaks down fatty molecules in the cell for disposal. When this housekeeping enzyme doesn't work properly, the fatty molecules pile up and ultimately can damage the spleen, liver, bones and other organs. The most severe form results in severebrain damage and early death. People affected by Gaucher disease inherit two defective gene copies; those who carry only one gene mutation do not have the disease. Parkinson's disease is a neurodegenerative disorder that affects about 1.5 million Americans, causing tremors and motor impairment. It results from a combination of age, environmental factors and genetic susceptibility. Both patients with Gaucher disease and those who carry one mutation in this gene are at increased risk for developing Parkinson's. In 2009, Dr. Sidransky and her team coordinated a large, international study of the association between the two disorders. The results, published in The New England Journal of Medicine, showed that those with Gaucher-related gene mutations had a five-times greater risk of developing Parkinson's. "We didn't expect this metabolic disorder to be linked to an unrelated neurodegenerative disorder, and we've been working to understand the mechanisms involved and their implications," Dr. Sidransky said. Previous research showed that people with GBA mutations and Parkinson's tend to develop the disease earlier and have more cognitive difficulties than generally seen in Parkinson's. In the current study, the researchers set out to determine if the brain biology of GBA-associated Parkinson's is different from that observed in others with Parkinson's disease. Investigators looked at 107 study participants divided into four groups: people with both diseases; those with Parkinson's and no Gaucher mutations; people with Gaucher disease and a family history of Parkinson's; and healthy GBA-mutation carriers with a family history of Parkinson's. Each test group was matched with a comparison group of healthy people who were examined the same way. The researchers used two types of an imaging technique called positron emission tomography (PET) to study the brains of participants. One type measured the amount and distribution of dopamine, an important message-carrying brain chemical lacking in people with Parkinson's. The second technique gauged blood flow in the brain, which reflects brain function. The researchers found that people with Parkinson's disease — both those with and those without Gaucher disease — had a similar reduction in dopamine levels, indicating damage to certain nerve cells in the brain in both groups. "We're fairly early along in understanding how mutations in the GBA gene predispose people to Parkinson's," said Karen Berman, M.D., co-senior author and chief of NIMH's Clinical Brain Disorders Branch. "We now need to investigate the mechanisms by which mutations in this gene may affect dopamine function and the health of dopamine neurons in the brain." They also found striking differences in blood flow, which was significantly reduced in the people with GBA mutations. They saw this blood flow reduction in specific brain regions where people with different forms of dementia, including Alzheimer's disease, are affected. "This different blood flow distribution has been seen in other disorders that involve cognitive impairment," Dr. Sidransky said. "This provides biologic confirmation of our clinical impression of problems with cognition in some patients with GBA-associated Parkinson's disease. This observation may help us to better understand the causes of dementia that can develop in Parkinson's disease and related disorders and could ultimately lead to strategies to target these problems." The investigators also examined dopamine distribution and brain blood flow/brain activity in the two groups thought be at high-risk for developing Parkinson's — people with a family history of Parkinson's who either have Gaucher disease or are healthy yet carry a GBA mutation. They looked at the PET scans to identify any significant, early brain changes compared to people in the study control groups. Among seven mutation carriers and 14 patients with Gaucher without Parkinson's, only two had reduced dopamine levels. Dr. Sidransky said that while long-term follow-up is needed to see if any of these people develop Parkinson's, the observation that most of the patients with GBA mutations didn't have early signs of Parkinson's may be reassuring to those considered at risk. "Not everyone with GBA alterations will develop Parkinson's," Dr. Sidransky said. "Identifying an early marker associated with disease may show us who might go on to develop Parkinson's, and help identify a population that could benefit from pre-symptomatic management. In addition, discovering why other at-risk individuals do not develop Parkinson's disease may also help us to understand factors that protect people from developing this disease." The researchers plan to continue to follow people in their study with GBA mutations and a family history of Parkinson's to monitor their dopamine levels and cerebral blood flow to see whether they develop Gaucher disease. The researchers also will assess whether these clinical data might predict which patients will eventually develop Parkinson's disease.

Rate of Bipolar Symptoms Among Teens Approaches That of Adults

The rate of bipolar symptoms among U.S. teens is nearly as high as the rate found among adults, according to NIMH-funded research published online ahead of print on May 7, 2012, in the Archives of General Psychiatry. Background Nationally representative data indicate that about 3.9 percent of adults meet criteria for bipolar disorder in their lifetime, and 2.6 percent meet criteria in a given year.1 However, limited data exist on the rates of bipolar disorder among adolescents, despite strong evidence indicating that bipolar disorder tends to emerge in adolescence or early adulthood. Kathleen Merikangas, Ph.D., of NIMH, and colleagues analyzed data from the NIMH-funded National Comorbidity Survey-Adolescent Supplement (NCS-A), a nationally representative, face-to-face survey of more than 10,000 teens ages 13 to 18. Using criteria established by the American Psychiatric Association’s Diagnostic and Statistical Manual (DSM-IV), the researchers assessed teens for the hallmark symptoms of bipolar disorder—mania and depression. They also examined the rates of teens who showed evidence of mania alone. Results of the Study The researchers found that 2.5 percent of youth met criteria for bipolar disorder in their lifetime, and 2.2 percent met criteria within a given year. About 1.7 percent reported having mania alone within their lifetime, and 1.3 percent reporting having mania alone within a given year. Rates increased with age—about 2 percent of younger teens reported bipolar disorder symptoms, whereas 3.1 percent of older teens did. Significance The findings reveal that the prevalence of bipolar disorder in adolescents approaches that of adults, underscoring the widely held belief that the disorder first appears in youth. In addition, the presence of mania alone suggests that mania without depression should receive greater attention when evaluating mood disorders in teens, especially since it may precede or be associated with behavioral problems such as substance use disorders and attention deficit hyperactivity disorder, according to the researchers. What’s Next The researchers highlighted the need to follow up with these youth, to see if they continue to manifest bipolar symptoms as they age. More research is needed on the overlap of mania with other emotional and behavioral disorders, as well as the core features and risk factors for the development of mania in adolescents social worker continuing education Citation 1 Merikangas K, Cui L, Kattan G, Carlson G, Youngstrom E, Angst J. Mania with and without depression in a community sample of U.S. adolescents. Archives of General Psychiatry. Online ahead of print May 7, 2012.

Phase III trial of dapivirine ring begins in Africa: New HIV prevention approach for women

WASHINGTON, D.C., July 24, 2012 – A large clinical trial testing the long-term safety and effectiveness of a new approach for preventing HIV in women – a vaginal ring used once a month – is now underway in Africa, researchers announced today at the XIX International AIDS Conference (AIDS 2012)Alcoholism and Drug Abuse Counselors Continuing Education ASPIRE – A Study to Prevent Infection with a Ring for Extended Use – is a Phase III trial evaluating a vaginal ring that contains dapivirine, a potent antiretroviral (ARV) drug originally developed to treat HIV. The ring slowly releases dapivirine to cells inside the vagina throughout the one-month period that it's worn, potentially giving women discreet, long-acting protection against HIV transmitted through sex. Nearly 3,500 women in Africa will take part in ASPIRE, which is being led by the Microbicide Trials Network (MTN) and funded by the National Institute of Allergy and Infectious Diseases and the National Institute of Mental Health, which are part of the U.S. National Institutes of Health. The Makerere University-Johns Hopkins University Research HIV Clinical Trial Unit in Kampala, Uganda this week began screening women interested in joining the study. A second site, the Emavundleni Research Center at the Desmond Tutu HIV Foundation, University of Cape Town, South Africa, should be ready to screen potential participants next week. The MTN hopes to conduct ASPIRE at a total of 17 sites in Malawi, Uganda, South Africa, Zambia and Zimbabwe. A second trial, The Ring Study, is being conducted in parallel with ASPIRE. The Ring Study is being led by the International Partnership for Microbicides (IPM), which developed the dapivirine ring, and will involve about 1,650 women. IPM has already enrolled more nearly 400 participants at trial sites in South Africa since the study launched in April. The Ring Study will also be conducted in Rwanda and is expected to start there in August. The two sister studies are the first effectiveness trials of a vaginal ring for HIV prevention. Vaginal rings, which are flexible products that fit comfortably high up inside the vagina and are seldom felt by either partner during sex, are already used in many countries as a way to deliver hormonal contraception. ASPIRE and The Ring Study are also the first large-scale prevention trials involving an ARV other than tenofovir or a tenofovir combination. For this reason, and because it is used for a month at a time, the dapivirine ring is seen as an alternative to tenofovir gel used daily or at the time of sex, and oral pre-exposure prophylaxis (PrEP), which involves the use of a daily ARV tablet – tenofovir or Truvada (tenofovir plus emtricitabine). "As a field, we must continue to develop new strategies for HIV prevention. No single approach will be right for every person. In the same way there is a range of effective choices when it comes to birth control, women must have multiple effective options for HIV prevention," explained Jared Baeten, M.D., Ph.D., of the University of Washington in Seattle, who is leading ASPIRE with Thesla Palanee, Ph.D., of the Wits Reproductive Health and HIV Institute (WRHI) in Johannesburg, South Africa. "The most effective HIV prevention product can only work if it's used consistently. The recent PrEP and microbicide studies have taught us that using a product every day can be challenging for many people. A sustained delivery product like a vaginal ring can release an antiretroviral drug in the vagina over an entire month following a single insertion. We think this will be an attractive option for many women, and we hope that women in ASPIRE will like the ring and use it consistently," added Sharon Hillier, Ph.D., principal investigator of the MTN, which is based at the University of Pittsburgh School of Medicine and Magee-Womens Research Institute. ASPIRE is designed to enroll approximately 3,476 HIV-negative women between the ages of 18 and 45 who will be randomly assigned to use either the dapivirine ring or a placebo ring that looks the same but contains no active drug. Participants will be instructed how to insert and remove the ring, which they will replace every four weeks over the course of the one to two years they are in the study. All participants will receive ongoing HIV risk reduction counseling, condoms and diagnosis and treatment of sexually transmitted infections (STIs). The results of ASPIRE, which are expected late 2014 or early 2015, together with results of The Ring Study, as well as smaller, supporting studies, will form the basis of an application that IPM plans to submit to regulatory authorities seeking approval of the dapivirine ring for widespread use. "Through IPM's partnership with MTN and NIH, we are able to conduct two pivotal studies in parallel and get the answers we need quickly," said Zeda Rosenberg, Sc.D., chief executive officer of IPM, a nonprofit product development partnership based in Silver Spring, Md. "Regulators usually require results of two large-scale Phase III trials, along with data from other supporting studies, to approve a product for use. This unique collaboration aims to help us make dapivirine ring available as quickly as possible to women in developing countries if it is proven effective and safe for long-term use." Of the more than 34 million people living with HIV, half are women; and women account for 59 percent of adults with HIV in sub-Saharan Africa, where unprotected heterosexual intercourse is the primary driver of the epidemic. Young women are especially vulnerable; women ages 15 to 24 are up to five times more likely to become infected with HIV than young men. Efforts to promote abstinence, monogamy and the use of male condoms have not been enough to stop the HIV epidemic nor are these practical methods in many settings. IPM is developing dapivirine for use as a microbicide through a royalty-free licensing agreement with Janssen R&D Ireland (previously Tibotec Pharmaceuticals), one of the Janssen pharmaceutical companies of Johnson & Johnson. Dapivirine, also known as TMC-120, belongs to a class of ARVs called non-nucleoside reverse transcriptase inhibitors (NNRTIs) that bind to and disable HIV's reverse transcriptase enzyme, a protein that HIV needs to make copies of itself. In addition to the Uganda and Cape Town, South Africa sites, ASPIRE will be conducted at the following MTN-affiliated trial sites, pending all necessary approvals: In Malawi – the University of North Carolina Clinical Research Site in Lilongwe and the College of Medicine-Johns Hopkins University Research Project at Queen Elizabeth Central Hospital in Blantyre; in South Africa – the Medical Research Council of South Africa in KwaZulu-Natal (seven sites), the eThekwini site for the Centre for the AIDS Programme in Research in South Africa (CAPRISA) in Durban; WRHI in Johannesburg; in Zambia – the Centre for Infectious Diseases Research in Zambia in Lusaka; and, in Zimbabwe – the University of Zimbabwe-University of California, San Francisco HIV Prevention Trials Unit in Harare (three sites). ### More information about ASPIRE is available at http://www.mtnstopshiv.org/news/studies/mtn020 and about The Ring Study at http://www.ipmglobal.org/the-ring-study. About the Microbicide Trials Network The Microbicide Trials Network (MTN) is an HIV/AIDS clinical trials network established in 2006 by the National Institute of Allergy and Infectious Diseases with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health. Based at Magee-Womens Research Institute and the University of Pittsburgh, the MTN brings together international investigators and community and industry partners who are devoted to preventing or reducing the sexual transmission of HIV through the development and evaluation of products applied topically to mucosal surfaces or administered orally.

Wayne State develops better understanding of memory retrieval between children and adults

DETROIT — Neuroscientists from Wayne State University and the Massachusetts Institute of Technology (MIT) are taking a deeper look into how the brain mechanisms for memory retrieval differ between adults and children. While the memory systems are the same in many ways, the researchers have learned that crucial functions with relevance to learning and education differ. The team's findings were published on July 17, 2012, in the Journal of Neuroscience. According to lead author Noa Ofen, Ph.D., assistant professor in WSU's Institute of Gerontology and Department of Pediatrics, cognitive ability, including the ability to learn and remember new information, dramatically changes between childhood and adulthood. This ability parallels with dramatic changes that occur in the structure and function of the brain during these periods. In the study, "The Development of Brain Systems Associated with Successful Memory Retrieval of Scenes," Ofen and her collaborative team tested the development of neural underpinnings of memory from childhood to young adulthood. The team of researchers exposed participants to pictures of scenes and then showed them the same scenes mixed with new ones and asked them to judge whether each picture was presented earlier. Participants made retrieval judgments while researchers collected images of their brains with magnetic resonance imaging (MRI). Using this method, the researchers were able to see how the brain remembers. "Our results suggest that cortical regions related to attentional or strategic control show the greatest developmental changes for memory retrieval," said Ofen. The researchers said that older participants used the cortical regions more than younger participants when correctly retrieving past experiences. "We were interested to see whether there are changes in the connectivity of regions in the brain that support memory retrieval," Ofen added. "We found changes in connectivity of memory-related regions. In particular, the developmental change in connectivity between regions was profound even without a developmental change in the recruitment of those regions, suggesting that functional brain connectivity is an important aspect of developmental changes in the brain." This study marks the first time that the development of connectivity within memory systems in the brain has been tested, and the results suggest that the brain continues to rearrange connections to achieve adult-like performance during development. Ofen and her research team plan to continue research in this area, focused on modeling brain network connectivity, and applying these methods to study abnormal brain development continuing education for mfts ### This research was funded by the National Institute of Mental Health of the National Institutes of Health; grant number R01-MH-080344. Wayne State University is one of the nation's pre-eminent public research institutions in an urban setting. Through its multidisciplinary approach to research and education, and its ongoing collaboration with government, industry and other institutions, the university seeks to enhance economic growth and improve the quality of life in the city of Detroit, state of Michigan and throughout the world. For more information about research at Wayne State University, visit http://www.research.wayne.edu.

Many Youths with Autism Not Employed or In College 2 Years After High School

Young adults with autism spectrum disorder (ASD) are less likely to have a job or be enrolled in any type of postsecondary education when compared to peers with a speech/learning impairment or learning disability, according to a study partially funded by NIMH. Published in the June issue of Pediatrics, the findings emphasize the need to improve transition planning for students with ASD before they leave high school. Background Past studies on post-high school activities of youths with ASD were limited by having relatively few participants, lacking adequate diversity in the study population, or studying a narrow set of outcomes. As a result, it was unclear if those studies gave accurate descriptions of the ASD youth population as a whole, and if so, how broadly any findings could be applied. Using nationally representative data from the National Longitudinal Transition Study-2, Paul Shattuck, Ph.D., of Washington University, and colleagues assessed the activities of about 1,900 youths identified as having autism, speech/language impairment, learning disability, or mental retardation between the years 2007-2008. Data were provided by the youths’ parents or guardians or from the youths themselves if they were able to understand and answer the survey questions. All participants had previously received special education services and were no longer in high school. Results of the Study Compared to youths in other disability categories, those with ASD were less likely to have a job after high school. Youths with ASD were also less likely to be enrolled in any type of schooling than youths with speech/learning impairment or learning disability, but more likely than youths with mental retardation. In the first 2 years after leaving high school, youths with ASD were at significant risk of being completely disengaged, meaning to not be employed or in any postsecondary education. The participation rates, with rounded percentages, are summarized in the table below: *Additional data on youths’ participation in vocational or technical education showed a similar distribution social worker continuing education Youths from low-income families were much more likely to become disengaged, regardless of the severity of their disability. More impaired youths were also at greater risk of disengagement. Significance The results indicate that young adults with ASD experience unique challenges in finding work or enrolling in appropriate educational opportunities after leaving high school. In a related paper, also partially supported by NIMH funding, Dr. Shattuck noted that “the evidence base on services for adults with ASD is inadequate for informing policy and program decisions to meet the needs of this growing population.” In this context, the researchers emphasized the need to improve transition planning for youths with ASD or other special education needs as they prepare to leave high school. What’s Next According to the researchers, as more and more children are diagnosed with ASD, the demand for specialized adult services, jobs, and education will also continue to grow. Supporting targeted initiatives such as JobTIPS and further research on how to reduce or prevent disengagement will help inform efforts to better serve this population. References Shattuck PT, Narendorf SC, Cooper B, Sterzing PR, Wagner M, Taylor JL. Postsecondary Education and Employment Among Youth With an Autism Spectrum Disorder. Pediatrics. 2012 Jun;129(6):1042-9. Epub 2012 May 14. PubMed PMID: 22585766; PubMed Central PMCID: PMC3362908. Shattuck PT, Roux AM, Hudson LE, Taylor JL, Maenner MJ, Trani JF. Services for adults with an autism spectrum disorder. Can J Psychiatry. 2012 May;57(5):284-91. PubMed PMID: 22546060. Related funding: R01-MH086489

Social Brain Circuits Disrupted in Autism

In a study of high-functioning adolescents with an autism spectrum disorder, scientists using functional brain imaging have found reduced connectivity selectively affecting parts of the brain that form circuits supporting social behavior. The findings sharpen the focus of previous reports suggesting disruptions in connectivity across the brain in autism, and offer a target for future studies to search for the genes that shape the development of these circuits and how they become disrupted in the disorder. Background Difficulties with communication and social interactions are central features of autism spectrum disorders (ASD), and are universally present in those with an ASD. In an effort to determine how brain function is disrupted in autism, scientists have used noninvasive functional brain imaging to explore connectivity in the brain—the extent to which patterns of activity in functionally related parts of the brain correlate with each other. Scientists increasingly see the brain and its disorders in terms of circuits, with a given behavior engaging multiple centers across the brain, functioning in tandem. Functional imaging of people with an ASD has suggested that there are disruptions in connectivity across the brain. Narrowing the search to determine if losses in connectivity affect only specific circuits has been difficult, however. Mapping which centers of the brain are tightly connected in most people but disrupted in illness potentially involves comparisons in activity between thousands of points in different brain regions. Accordingly, previous studies have focused on a predetermined, small handful of regions to evaluate connectivity differences in ASD. This Study Stephen Gotts, Alex Martin and colleagues at the National Institute of Mental Health developed an approach to identify regions throughout the entire brain for which connectivity was reduced in ASD, and measure the magnitude of the reductions. The scans were done on 31 adolescents with ASD and 29 without the disorder, while they were at rest, not engaged in any task. Scan results revealed decreases in connectivity among those with ASD compared to individuals without ASD, concentrated in areas of the brain involved in social functions. In particular, the greatest decreases occurred between a cluster of brain regions involved in the emotional aspects of social behavior (the limbic brain) and two other clusters: one involved in language and communication and the other in the interplay between visual perception and movement. Moreover, participants in the study who had the greatest difficulties with social interactions were those in whom the decreases in connectivity were the most marked. Significance These data offer evidence in terms of brain activity to confirm what scientists have suspected but have been unable to examine systematically, that disruptions in connectivity in autism are concentrated in social centers of the brain. According to Dr. Gotts, what they found was not that this circuit was inactive, but that, among participants with ASD, patterns of activity in the three clusters of brain centers did not correlate with each other. “So a circuit that is normally in sync with the rest of the social brain has become decoupled. The limbic brain is composed of areas and structures that mediate emotional and affective components of our social interactions, so you can understand the social rules about how other people are behaving and acting. These brain regions are active in autism spectrum disorders and are coordinated amongst themselves, but they are not interacting appropriately with the rest of the social brain.” The clusters of brain centers identified in the study as functionally connected are also anatomically connected circuits. One of the most exciting aspects of the research, says Gotts, is that in humans, this brain circuit shows a different developmental growth trajectory relative to the rest of the brain's cortex during typical development. Since genes are responsible for guiding growth during development, these findings provide a target for searching for genes that drive abnormal growth and limbic circuit functioning in ASD. The differences in connectivity also offer the possibility of a “systems-level” marker—an indicator reflecting function across the brain—to use in developing and testing possible treatment. Local abnormalities in cell signaling or, alternatively, loss of longer range neuronal connections could explain the differences reported. If the differences can be traced to more local dynamics, it may be possible to identify new medications or behavioral therapies; variations in circuit activity as shown by functional brain imaging could be used as markers of whether therapy was effective.

Brain regions showing decreases in connectivity in high functioning adolescents with an autism spectrum disorder (ASD) are shown to the left: Limbic-related regions involved in emotional/affective aspects of social behavior (shown in red), regions involved in social communication and comprehension (shown in blue), and regions involved in visual, somatosensory and motor aspects of social behavior (shown in green). In typically developing adolescents, these circuits are interactive and coordinated, exhibiting correlated patterns of brain activity over time (traces of neural activity would appear as illustrated in upper right plot). In adolescents with an ASD, the activity in the limbic circuit has become decoupled from the other social brain regions (see red activity trace in lower right plot). Activity within the limbic circuit itself remains coordinated but no longer interacts appropriately with the other two circuits nursing ceus Reference Gotts, S.J., Simmons, W.K., Milbury, L.A., Wallace, G.L., Cox, R.W., and Martin, A. Fractionation of Social Brain Circuits in Autism Spectrum Disorders. Brain 2012 doi:10.1093/brain/aws160.