Autism Consortium, Boston, MA
Autism Consortium Family and Clinician Support
As the Autism Consortium embarks on a Boston-wide research endeavor to develop a greater understanding of the etiology and treatment of autism spectrum disorders (ASDs), this grant will enable the Consortium to provide care and support to the families and clinicians involved in their research. Through the Family Support component of this project, the Autism Consortium will provide several participating Boston-area institutions with Autism Family Resource Specialists who will provide support to families grappling with the diagnosis of autism. The Resource Specialists will be trained in how to support families dealing with the feelings that accompany a diagnosis of ASD, and how to educate others at their institutions. The Resource Specialists will provide educational materials to families including research program information. In addition, Resource Specialists will provide consultation/coaching, set up parent-to-parent support programs, and arrange topical seminars. The Resource Specialists will thus provide critical continuity with families from the time of diagnosis over the course of the research program. Through the Clinician Support component of this project, the Consortium will provide support for quarterly meetings of participating clinicians to share best practices, raise issues or concerns about the research program, learn about emerging research findings, and identify opportunities for research and improved care.
The Autism Consortium
Beth Israel Deaconess Medical Center, Boston , MA
Principal Investigator: Matthew Anderson, MD, Ph.D.
Anderson Laboratory Translational Autism Research Program
This grant will be used to support the autism research performed by the Anderson Laboratory, which is focused on understanding the cellular and molecular mechanisms of autism and developing therapies aimed at treating it. Recent studies have uncovered copy number variations (CNV) in a subset of individuals with idiopathic, non-syndromic autism. Using mouse genetic engineering techniques and an array of biochemical, electrophysiological, and behavioral measurements, Dr. Anderson’s laboratory seeks to gain a deeper understanding of this still perplexing behavioral disorder. Using these novel tools and approaches, they seek answers to the following questions: 1) Do the CNVs cause behavioral deficits characteristic of autism (impaired social interaction and communication and increased repetitive behavior)? 2) What are the specific genes within these large deleted or duplicated genomic regions that cause the autism behavioral traits? 3) What specific neuronal populations and brain regions do these genetic defects cause the autism behavioral deficits? 4) What are the specific molecular and cellular defects within neuronal circuits that underlie these autism behavioral traits? 5) Do common pathophysiologic mechanisms exist across different etiologic causes of autism? 6) What behavioral and/or medical treatments can be targeted at these molecular and circuit defects to treat the autism?
Beth Israel Deaconess Medical Center
Boston Jewish Film Festival
REELAbilities Film Festival
The NLM Family Foundation provided support for the REELAbilities Boston Film Festival that united partners from across the Greater Boston community in an effort to promote awareness and appreciation of lives,stories and artistic expressions of people with different abilities from a variety of communities, all through the easily accessible art form of film. The Festival presented award-winning films, accompanied by discussions and other engaging programs, which brought together the community to explore, discuss and celebrate the diversity of our shared human experience. “Snow Cake”, “My Spectacular Theater”, “War Eagle, Arkansas”, “Shooting Beauty”, “Warrior Champions: From Baghdad to Beijing”, and “Anita” were amongst the films featured.
Boston Jewish Film Festival
Brown University Institute for Brain Science, Providence, RI
Principal Investigator: Eric Morrow, MD, Ph.D.
Endosomal NHE6 in Long-Range Connectivity and Autism (Co-funded with the Simons Foundation)
Human mutations in NHE6 represent a novel autism-related developmental brain disorder. Such syndromic forms of autism have provided critical traction for discerning disease mechanisms and identifying potential treatment targets. Dr. Morrow’s group is also investigating an interesting and novel cellular mechanism, namely modulation of endosomal signaling through regulation of intra-endosomal proton concentration. They will link this mechanism to points of convergence for gene mechanism in autism, namely development of long-range circuitry, axonal branching and relevant signaling pathways. In addition, they will test a link between NHE6 and fever. Many parental reports have strongly suggested improvements in autism symptoms with fever, and neuronal pH has been pinpointed as one mediator of the effects of systemic fever on neuronal excitability. Dr. Morrow’s group will seek to reverse the cellular defects observed via addition of exogenous signaling molecules. Finally, they will attempt to develop a model for autistic regression in response to stress. If successful with these studies, they will create new opportunities to test treatments for circuit defects and/or to prevent regression in a subset of patients with autism. The research on this project is primarily led in Dr. Morrow’s lab. Dr. Morrow will be working in the setting of the Institute for Brain Science at Brown University. He will be collaborating closely with Dr. Julie Kauer, an electrophysiologist with over 20 years of experience in synaptic physiology and plasticity, and Dr. Pietro DeCamilli, a renowned neuronal cell biologist in the area of endocytosis. This pilot project will have broad impact in the field of autism because it will identify novel cellular mechanisms that are tightly linked to potential therapeutic strategies.
Eric Morrow, Brown University
Center for Biomedical Informatics at Harvard Medical School, Boston, MA
Principal Investigator: Dennis P. Wall, Ph.D.
Mobilized Technology for Rapid Screening and Clinical Prioritization of ASD (Co-funded with the Simons Foundation)
Autism rates continue to rise with more and more children being referred for autism screening every day. The behavioral tests currently administered for diagnosis are several hours long and the diagnosis process as a whole is cumbersome for families. In addition, clinical professionals capable of administering the exams tend to be too few and well above capacity. The average time between initial evaluation and diagnosis for a child living in a large metropolitan area is greater than one year and approaches five years for families living in more remote areas. The delay in diagnosis is not only frustrating for families, but prevents many children from receiving medical attention until they have past developmental time periods when behavioral therapy would have had appreciable impact. To combat this significant public health challenge, Dr. Wall has developed algorithms that rapidly analyze a short set of parent/caregiver-directed questions and a 2-5 minute video of the subject to yield an accurate classification of on or off the autism spectrum. The algorithms are derived from two of the most reliable and widely used behavioral instruments, the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS) and can be administered in minutes as compared to the hours typically required for delivery of the current methods. The present study is designed to test the potential of these highly abbreviated approaches directly in a high-volume clinical facility at Children’s Hospital Boston. Through the use of a mobilized web and iPad-friendly framework, Dr. Wall’s group will enroll 200 or more children, a majority of which will meet standard clinical criteria for an autism diagnosis, and a smaller but sizable percentage of which will be children with other developmental delays. In so doing, it will be possible to measure both the sensitivity and specificity of these algorithms and to evaluate the efficacy of the mobilized approach for assisting the clinical diagnostic process overall. The hope is that the work will bring us closer to a comprehensive technology that can provide rapid assessments and enable patient prioritization at the nearest and most appropriate clinical care facilities, and a technology that increases the reach to a larger percentage of the risk population to ensure timely delivery of therapies.
The Wall Lab, The Center for Biomedical Informatics at Harvard Medical School
Children's Hospital, Boston, MA
Principal Investigator: Isaac Kohane, M.D, Ph.D. and Alal Eran
Synaptic A-to-I RNA Editing in Autism Spectrum Disorders
Autism spectrum disorder (ASD) is likely caused by a combination of genetic and environmental factors acting at a sensitive period of neuronal development. Recent studies show that in many cases ASD is a disorder of abnormal synaptic function. To better understand the interactions between genes and the environment that modulate synaptic function, this research will investigate the role of adenosine-to-inosine (A-to-I) RNA editing in ASD. A-to-I RNA editing is a regulatory mechanism that takes place mostly in the brain, in which the sequence of RNA molecules, especially those making synaptic proteins, changes in response to environmental stimuli. Because tweaking the levels of A-to-I editing in model organisms (such as mice and flies) alters their behavior, it is thought that A-to-I RNA editing is one of the molecular mechanisms connecting environmental stimuli and behavioral outputs. Several lines of evidence suggest that A-to-I editing could be important in ASD, including findings of differential editing of synaptic candidate genes between postmortem cerebella of individuals with ASD and neurotypical controls. Investigators will validate and expand these findings by examining many more genes in more brain regions and more individuals. Using targeted capture and ultradeep sequencing of RNA and DNA, they will compare the patterns of neurodevelopmentally-regulated editing between brain regions, individuals, and groups. This will provide a comprehensive view of the potential extent of A-to-I editing alterations in ASD, and their contribution to the synaptic abnormalities underlying the disorder. This research will shed more light on environment-dependent epigenetic mechanisms involved in ASD, and more generally, complex human behavior in health and disease.
Children's Hospital Boston, MA
Principal Investigators: Mustafa Sahin, Ph.D., Wade Regehr, Ph.D., and Sam Wang, Ph.D.
Systems Biology of Autism: The Case for the Cerebellum
One of the most important unanswered questions in autism research today is the identity of the neural circuit(s) responsible for autistic behavior. Accumulating evidence suggests that cerebellar structural and functional abnormalities may play an ongoing role in, or even act as a developmental cause of the deficits experienced by autistic persons. However, directly proving such roles for the cerebellum requires an animal model, where perturbations can be done in a controlled manner. This project involves a collaborative, multi-dimensional approach by three investigators to interrogate the role of cerebellum in autism using a mouse model. The Sahin laboratory has recreated common autism-like traits in mice by mutating a single gene (Tsc1) in a specific cell type of the cerebellum - Purkinje cells (PCs), the cerebellum's output neuron. Importantly, treatment of these mice with an mTOR inhibitor prevents the development of autistic-like behaviors. Together with the Regehr and Wang laboratories, the overall goal of this project is to determine why mice with Tsc1 selectively eliminated from cerebellar PCs exhibit behaviors consistent with ASDs. Bringing together three investigators with complementary expertise, the experiments in this project present an unprecedented opportunity to understand the neural circuitry of autism.
Children's Hospital Boston
Children’s Hospital, Boston, MA
Principal Investigator: Sarah Spence, MD, Ph.D.
Treatment of Children with ASD and Epileptiform EEG with Divalproex Sodium (Co-funded with the Simons Foundation)
Epilepsy or seizure disorders happen relatively frequently in individuals with autism spectrum disorders (ASD) and seizures are always treated with medication. However, abnormalities on the electroencephalogram (EEG) can also be present in ASD even when there are no seizures. The need for treatment of these EEG abnormalities is unclear. Dr. Spence’s research group believes that these EEG epileptiform discharges may represent an important biomarker in some individuals with ASD and wants to explore them as a target for treatment. Studies suggest that epileptiform discharges contribute to problems in attention, language and behavior. Dr. Spence will test whether there is a positive effect of treating children with ASD and epileptiform EEGs using an anti-seizure medication that is known to help normalize the EEG (Depakote). Thirty subjects ages 4-8 will be recruited from two large autism centers (Children’s Hospital Boston and Vanderbilt University). Subjects will be in the study for 26 weeks receiving active drug for 12 weeks and placebo (inactive substance) for 12 weeks. EEGs and behavioral assessments will be done at the beginning, middle, and the end. The hope is to show that administration of Depakote will reduce the number of epileptiform EEG discharges. Dr. Spence’s group also wants to show that Depakote improves a wide range of behavioral measures including: language, mood, irritability, attention, motor, sensory, adaptive function and core ASD behaviors. Because there is a known relationship between Depakote, EEG discharges and sleep, they will look at changes in sleep and how these measures relate as well. Finally they will test a special EEG to see if brain connectivity measures change and are related to behavioral improvements.
Children’s Hospital of Philadelphia, Philadelphia, PA
Principal Investigator: Robert T. Schultz, Ph.D.
Characterizing IQ Impairments in ASD and Testing Their Genetic Foundations (Co-funded with the Simons Foundation)
Half or more of all persons with an autism spectrum disorders (ASD) have an intellectual disability (ID). IQ is one of the best predictors of which individuals will respond well to current interventions. It also is a good predictor of adult outcomes. Thus, it is important to try to understand the biological mechanisms that cause ID in order to reveal new avenues for devising effective treatments. Dr. Schultz and colleagues recently published the first genetics paper using the Simons Simplex Collection (SSC) focused on the relationship between genes that confirm risk for ASD and ID (Sanders et al, 2011). Contrary to the field’s expectation, they did not find any relationship between large genetic defects in persons with ASD and ID. In fact, the degree of ID was a poor predictor of overall genetic risk for autism. In the current project, Dr. Schultz’s group will collect additional data to make a re-analysis of their initial findings more powerful. In particular, they will collect IQ data on other family members, including both parents and other siblings. Family IQ data will help give much more precise estimates of the degree of ID in the youth with ASD. Including these data in their statistical analyses should yield much more powerful statistical analyses aimed at understanding the origins of ID in ASD. Dr. Schultz’s group expects that a better understanding of the genetics of ID in those with ASD will reveal important clues as to biological mechanisms that can lead to innovative treatments. Moreover, all of the new IQ data collected in this study will become part of the SSC and will be available for future use to all investigators, greatly enhancing the value of the important resource.
Robert Schultz, Developmental Neuroimaging Laboratory at Children’s Hospital of Philadelphia Research Institute
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
Support of Postgraduate Courses at Cold Spring Harbor Laboratory related to Autism Spectrum Disorders as part of the CSHL Brain Health Initiative: Focus on Autism and Related Developmental Disorders
The NLM Family Foundation, in partnership with other autism-focused organizations, supports educational programs at Cold Spring Harbor Laboratory (CSHL) related to autism spectrum disorders. As part of the Brain Health Initiative being developed at CSHL, CSHL is offering postgraduate courses designed to promote greater understanding of the neurobiological and genetic mechanisms affecting brain health. To enhance and extend research efforts on autism and related developmental disorders, the Initiative's Focus on Autism and Related Developmental Disorders has developed three postgraduate lecture courses led by a distinguished faculty of top researchers from around the world. These courses are briefly described below:
1) Biology of Social Cognition: This course addresses how cognitive processes involving social behavior are developed and how they are altered or dysregulated in autism spectrum disorders and other developmental disorders.
2) Autism Spectrum Disorders: This workshop takes an integrative approach to present the clinical, genetic, neurobiological and cognitive elements of autism spectrum disorders.
3) Neurobiology of Speech & Communication: This workshop seeks to integrate a broad spectrum of current research into the neurobiology of speech and speech perception.
Cold Spring Harbor Laboratory
Maine Medical Center Research Institute, Scarborough, ME
Autism & Developmental Disorders Inpatient Research Collaborative
This grant supported the first national meeting of physicians who specialize in the hospital treatment of children with autism. In the Fall of 2011, the directors of the eleven specialized psychiatric hospital units in the US that exclusively treat children with autism collaborated on a publication and formed a research collaborative. These hospital units admit over 600 children with autism a year into controlled environments for an average stay of 42 days. The collaborative has met monthly by teleconference since October 2011, developed a website for the Autism & Developmental Disorders Inpatient Research Collaborative and begun forming study questions. Areas of potential inquiry include: developing better tools to diagnose co-occurring psychiatric disorders in children with ASD; performing early clinical trials on novel compounds; evaluating treatments for self-injurious behavior and measuring the effect of intensive multi-modal treatment. This grant supported the gathering of 15-20 investigators at the Maine Medical Center Research Institute to facilitate communication and idea development to develop research questions into full-fledged proposals for external funding.
Autism & Developmental Disorders Inpatient Research Collaborative
Massachusetts Advocates for Children, Boston, MA
2002, 2003, 2004, 2005, 2006, 2007, 2008, 2009, 2010, 2011, 2012, 2013
Establishment and Support of the Autism Special Education Legal Support
The goal of this project
is to provide training, technical assistance, and advocacy
services necessary to ensure that children with autism receive
equal educational opportunities. Goals include: Providing
parents with information about state-of-the-art services
and programs available to meet individual needs of students
with disabilities; Insuring that children with autism receive
special education services necessary to reach their potential
in areas impacted by their disability; Increasing public
awareness and understanding of the potential and competency
of individuals with autism, targeting policy makers, media,
educators, service providers, as well as the general public.
The Autism Special Education Legal Support Center will accomplish
these goals by: providing community-based workshops for
parents, educators, and medical professionals regarding
legal rights and range of service options available for
children with autism; providing a hotline to give legal
and technical assistance to families of children with autism;
training attorneys to increase representation of low-income
students with autism to ensure that children receive legally
mandated special education services; and providing information
to the media, the legislature, and other policy makers regarding
changes necessary to ensure children with autism receive
services that reflect their potential.
here to read the NLMFF Interview with Massachusetts Advocates
Advocates for Children
Massachusetts General Hospital, Boston, MA
Principal Investigator: James F. Gusella, Ph.D.
Molecular Signatures of Strong-effect ASD Genes and 16p11.2 Deletion (Co-funded with the Simons Foundation)
Understanding how the genetic defects that cause autism lead to abnormal neurodevelopment is critical both to understanding the disorder and to developing effective treatments. One particularly important question is whether different genetic defects produce autism in completely different ways, or alternatively, whether alterations in quite different genes might trigger a cascade of cellular changes that overlap with each other and ultimately produce autism by the same biochemical mechanism. Recently a number of autism genes have been discovered whose normal function is to help in the regulation of the timing and level of expression of genes throughout the human genome. Using new sequencing techniques to simultaneously measure the regulation of all genes in the genome, Dr. Gusella’s group will explore the consequences on gene expression of each of these new autism genes and determine whether these effects are distinct or shared. They will also compare these changes in gene expression with the effects of the common autism-associated chromosome 16p deletion. Importantly, these comparisons will be done in authentic human cells at the immature nerve cell precursor stage and throughout their development into mature nerve cells, a process of fundamental relevance to the neurodevelopment in autism. The results of their analysis will test whether the different autism genes produce the disorder by leading to the same kinds of changes in nerve cell development and whether that biochemical mechanism is also triggered by the 16p deletion mutation. Identification of a shared disease process despite different initial triggering genes would allow that shared process to be targeted for development of interventions that would apply broadly in autism.
James Gusella, Massachusetts General Hospital
Massachusetts General Hospital, Boston, MA
Principal Investigator: Tal Kenet, Ph.D.
Local Functional Connectivity in ASD (Co-funded with the Simons Foundation)
Functional connectivity in the brain refers to the synchronization of neuronal assemblies for the purpose of transferring information within and between these assemblies. Long-range cortical functional connectivity refers to connectivity between distant cortical areas, and is often reduced in autism spectrum disorders (ASD). The nature of local cortical functional connectivity (connectivity within a neuronal assembly) has remained elusive in studies of ASD, but it has been generally believed that local functional connectivity is increased in ASD. Dr. Kenet and colleagues used magnetoencephalography (MEG), a technique that reveals cortical activity with high spatial and temporal resolution, to measure functional connectivity both locally and between distant cortical regions while ASD and typical individuals viewed houses and faces. Contrary to the prevailing hypothesis, they showed that local functional connectivity was reduced, not increased, in ASD. Furthermore, the strength of local functional connectivity correlated with ASD severity, and statistical classification using local and long-range functional connectivity data identified ASD diagnosis with 90% accuracy. Finally, they found that the strengths of local and long-range functional connectivity were correlated in both ASD and typical individuals. These results suggest that failure to adequately synchronize neuronal assemblies both within and across cortical regions is characteristic of ASD. For this grant, Dr. Kenet’s group will study local functional connectivity in ASD in multiple cortical areas during performance of both visual and auditory paradigms by younger subjects. Second, they will examine the links between local and long-range functional connectivity, to determine how the two patterns interact. Lastly, they intend to identify a set of measures of local and/or long-range functional connectivity that correlate highly with diagnosis and severity of ASD, for future development into early biomarkers of ASD.
Massachusetts General Hospital, Martinos Center for Biomedical Imaging
Massachusetts General Hospital, Boston, MA
Principal Investigator: Michael Talkowski, Ph.D.
Cryptic Chromosomal Aberrations Contributing to Autism (Co-funded with the Simons Foundation)
Half a century ago, the introduction of karyotyping transformed human genetics and clinical diagnostics by opening access to gross changes in the chromosomes, revealing an entire class of previously undetectable genetic lesions. More recently, microarrays revealed that DNA gains and losses can cause genetic disease; however, the rate of return of significant findings from genomic microarray is quite low, with over 80% of clinical referrals yielding unremarkable or inconclusive genomic profiles. Similarly, even in extensively studied common complex diseases such as autism, the fraction of genetic contribution not explained by conventional association methods remains quite large. This project brings together leading experts in genomics, statistics, clinical diagnostics, and computational genetics to open access to another potentially critical class of genomic variation that remains unseen to all current methods of gene discovery in autism: chromosomal rearrangements that do not involve gains and losses of DNA. Previous research suggests this class of 'cryptic' alterations (or not visible at microscopic resolution) can have a profound impact in autism, ranging from small microinversions that directly inactivate the message of a single gene to highly complicated shattering and reorganization of chromosomes in autism cases that went completely unnoticed by current gold standards in clinical diagnostics. Dr. Talkowski’s group will perform an innovative form of whole-genome sequencing to identify all classes of structural variations at an order of magnitude lower cost than standard whole-genome sequencing, enabling access to a large number of cases at modest overall cost. This study will thus rapidly fill this glaring knowledge void in autism genetics and identify individually causal genes.
The Prince’s Foundation for Children & the Arts, London, UK
Relaxed Performances Project
As highlighted in a number of recent high-profile news stories in the UK, there is a real and urgent need for more awareness and understanding of autism as well as a concerted effort to welcome and accommodate young people with autism as audience members in theatres across the UK. A recent development in the UK is activity and interest in increasing arts engagement for young people with special needs including autism and other sensory, communication and learning disorders through the programming of ‘Relaxed Performances’. Relaxed Performances are designed to have a less formal, more supportive atmosphere to reduce anxiety levels. This can be achieved by adapting the performance in a number of ways including changing lighting and special effects to accommodate sensory sensitivities and training theatre staff in how to work with children with special needs. The Prince’s Foundation for Children & the Arts, in partnership with the Society of London Theatre and the Theatrical Management Association, plan to research and develop a best practice model to share with all theatres across the UK and beyond to create a sustainable route into theatre for this new audience. This grant will support the presentation of ‘Relaxed Performances’ in theatres across the UK and these performances will be presented under one umbrella scheme which will support the development, production, marketing, presentation, and evaluation of the performances over the course of one school calendar year. A comprehensive research program will measure the impact of the project both during and beyond the project period. Ultimately, the aim is to provide access to creative, safe and inspiring public theatres for children with special needs and their families.
The Prince’s Foundation for Children & the Arts
Click here to read the press release from the Theatrical Management Association
UMASS Medical School Eunice Kennedy Shriver Center
Principal Investigator: Amy Weinstock
Support for Core Operations of the Autism Insurance Resource Center
Located at the UMass Medical School Shriver Center, the Autism Insurance Resource Center provides information to the public about insurance coverage under a new law, An Act Relative to Insurance Coverage for Autism (ARICA), which took effect in Massachusetts on January 1, 2011. There are many questions related to the implementation of the law (e.g., to whom ARICA applies, what treatments are covered, how to access coverage, etc.). The Center, a program of New England INDEX, a long-standing information resource for people with disabilities, is designed to provide information and support for self-advocates, family members, providers, employers, and educators on issues related to medical insurance for autism treatment. This is a two-year leadership grant to fund core operations of the Center, allowing it to provide support to the autism community to access insurance coverage and maximize the impact of this recently enacted groundbreaking legislation.
The Autism Insurance Resource Center