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Boston University , Boston , MA


Principal Investigators: Helen Tager-Flusberg, Ph.D., Dae-Shik Kim, Ph.D.

Functional and Connectivity Neuroimaging of Autism.

The goal of this project is to develop over a three year period new methods that will allow exploration of brain regions that are critical for processing sounds and language. This project will utilize novel brain imaging technologies, including magnetic resonance imaging (MRI), to map out areas of the brain in control subjects that process sounds and language. This will allow us to locate brain areas in which certain processes take place and to determine how these areas are connected to one another. The project will use these technologies and knowledge on adolescents with autism to shed light on regions of the brain which may not be processing sounds or language efficiently and where connections between critical brain regions may break down in autism.

Helen Tager-Flusberg

Boston University School of Medicine, Boston , MA

Principal Investigator: Robert Joseph, Ph.D.

Neurobiological Markers of Language and Functioning in Autism (funded through NAAR)

This project will investigate the relationship of language acquisition to developments in connectivity between language regions of the brain, as measured by diffusion tensor magnetic resonance imaging in children with autism. Many children with autism fail to develop language or are impaired in their language functioning. Research has shown that language impairment appears to represent the influence of genes that increase susceptibility to autism. An understanding of neurobiological bases of the language deficits in autism will contribute to an understanding of autism's genetic underpinnings and neurodevelopmental etiology. Evidence of white matter brain abnormalities, particularly of cerebral white matter overgrowth, has emerged from magnetic resonance imaging (MRI) studies of children with autism. These findings have been limited to macrostructural estimates of differences in white matter volume in autism. Dr. Joseph will use diffusion tensor imaging (DTI) technology to (a) examine the microstructural integrity and coherence of white matter tracts connecting language-related regions of the cerebral cortex and (b) to evaluate relationship of white matter connectivity to actual language functioning. Dr. Joseph will collect anatomical and diffusion tensor brain images from children with autism at age 3 and one year later, and examine the relationship between white matter connectivity in language regions of the brain to measures of children's language development taken at each time. Dr. Joseph will assess whether microstructural changes in language-related white matter predict acquisition and development of language skills in children with autism.

Boston University School of Medicine

Robert Joseph

The Children's Hospital of Philadelphia, Philadelphia, PA

Principal Investigator: Timothy Roberts, Ph.D.

Neonatal Biomagnetometer (Co-Funded with the Lurie Family Foundation)

In partnership with the Lurie Family Foundation, the NLM Family Foundation has provided funding to the Children's Hospital of Philadelphia for the purchase of a Neonatal Biomagnetometer, a magnetoencephalography (MEG) system that provides non-invasive, 4-dimensional imaging of human brain function necessary to detect developmental disorders. When installed, this system will serve as the world's first dedicated infant-MEG system serving children 18 months to two years, thereby providing better opportunities for successful, appropriate interventions to occur at an earlier age. This technology conducts passive recordings of "brain waves" during rest or stimulation through finger-tapping, sounds, and pictures. A typical scan of the brain may take less than one hour. MEG measures small electrical currents inside the neurons of the brain and generates an accurate representation of the magnetic fields produced by the neurons. Developmental disorders, including autism spectrum disorders, attention deficit hyperactivity disorders and learning disabilities, exploit the ability of MEG to track deficits in rapid temporal processing. This helps identify when and where in the brain and at what stage of linguistic complexity deviations from typical development occur, providing physicians with better opportunities to treat children with the most appropriate form of care. In addition to providing physicians with the best insight into the exact location of abnormalities that cause epilepsy and seizure disorders, the MEG also provides state-of-the-art, pre-surgical mapping for brain tumors and vascular malformations so that surgery can be planned in an effort to minimize postoperative weakness or loss of brain function.

Click here to read the NLMFF Interview with Dr. Roberts

Children's Hospital of Philadelphia

The Children's Hospital of Philadelphia, Philadelphia, PA

Principal Investigator: Timothy Roberts, Ph.D.

MEG of Language Impairment in Autism (Co-funded with the Lurie Family Foundation)

Language impairment is a devastating feature of Autism Spectrum Disorders (ASD); however, presence and severity of language impairment varies across the spectrum. The purpose of this project is to use advanced brain imaging (magnetoencephalography) to identify the temporal stage of language processing, and the neural substrates thereof, that depart from typical development in children with autism. Using a battery of auditory processing and linguistic stimuli, the investigator seeks to identify neural signatures or endophenotypes, with which to more specifically characterize language impairment in autism. Additionally, the use of characteristic brain-level endophenotypes will be explored as a mechanism for tightening the connection between experimental and clinical laboratories. Experimental models of autism might now be evaluated in terms of such electrophysiological (as well as behavioral) traits associated with ASD and thus provide a more specific approach for understanding the underlying neurobiology. Furthermore, such specific brain-level phenotyping may offer more specific measures for ongoing genomic efforts at the Children's Hospital of Philadelphia and elsewhere.

Click here to read the NLMFF Interview with Dr. Roberts

Children's Hospital of Philadelphia

Georgetown University, Center for the Study of Learning Washington , D.C.

Principal Investigator: Thomas Zeffiro, Ph.D.

Ongoing Development of a Multi-channel Diffuse Optical Tomography System for Evaluation of Language and Communication Disorders

Diffuse optical tomography is a technique that uses interactions between light in the near-infrared part of the spectrum and blood components to allow non-invasive measurements of brain activity. Studies using this technology have demonstrated excellent sensitivity to subtle changes in brain blood oxygenation related to the performance of behavioral tasks involving language, perception and movement. Specifically, it has been possible to detect reliable and well-localized changes in brain activity while adult subjects performed voluntary finger movement and speech processing tasks. These results suggest that this technology could be scaled to systems that would allow simultaneous monitoring of the entire cortical surface. The NLM Family Foundation is supporting the development of an integrated non-invasive system to assess cortical brain activity involved in language and communication and is exploring possibilities of applying this technology to investigate communication difficulties experienced by those with autism.

Center for the Study of Learning

Harvard Medical School, Beth Israel Deaconess Medical Center, Boston , MA

Principal Investigator: Hugo Theoret, Ph.D.

Motor Output & Mirror Cell Systems in Autism Studied by Transcranial Magnetic Stimulation (funded through NAAR)

Many individuals with autism demonstrate difficulty performing simple motor imitation. This project will use a method called transcranial magnetic stimulation (TMS) to study the motor cortex and mirror cell system in adults with Asperger's syndrome. Dr. Theoret will assess the integrity of the motor cortex and mirror neuron system to gain insight into the basic cortical dysfunction that may lead to autism spectrum disorders. Dr. Theoret will use this information to investigate how these abnormalities interact with emotional processing and self-awareness, two areas of human cognition believed to be impaired in autism. The insights derived from the proposed experiments have the potential to increase our understanding of the causes of autism and lead to new therapeutic interventions.

Harvard Medical School

Kennedy Krieger Institute/ Johns Hopkins School of Medicine, Baltimore , M.D.

Principal Investigator: Stewart Mostofsky, Ph.D.

Dependent Motor Learning in Autism Examination of Visual and Somatosensory (funded through NAAR)

Increased insight into the brain mechanisms underlying autism can be gained from consideration of motor abnormalities of individuals with autism. By using tests of motor function for which the neurologic basis is well mapped out, it is possible to gain an understanding of the neural circuits impaired in autism. Motor signs can serve as markers for deficits in parallel brain systems important for control of social and communication skill impairments observed in autism. Among the most consistently observed motor abnormalities in autism is difficulty with imitation and performance of skilled motor tasks and gestures. These deficits could be secondary to a fundamental problem with acquiring motor skills. Deficiencies in motor skill learning could also result in development of a limited repertoire of movements and might explain observations of motor stereotypies. The goals of this project are to determine common factors underlying motor deficits in autism and to investigate brain abnormalities associated with these deficits using functional magnetic resonance imaging. A long-term goal is to examine the association of impaired motor skill learning with socialization and communication deficits that characterize autism. This study will provide insight into the neurologic basis of motor deficits in autism and may provide a basis for understanding the neurologic underpinnings of impaired social/communicative development.

Kennedy Krieger Institute

Stewart Mostofsky

Massachusetts General Hospital , Boston , MA

Principal Investigator: Martha R. Herbert, M.D., Ph.D.

NIRS Imaging and its Utility and Importance in Infants

The investigators are engaged in a DoD-funded comprehensive multisystem study of development beginning in early infancy to allow them to understand the mechanisms by which autism's brain-behavior-body relationships emerge. They propose that Near-Infrared Spectroscopy (NIRS) can make a unique contribution to studying autism's emergence by providing an infant- and toddler-friendly technology for examining the metabolic and vascular underpinnings of brain changes in early autism. They propose that NIRS measures of cerebral perfusion and of the redox state of the mitochondrial marker cytochrome c oxidase may provide objective early indicators of risk for autism. Reduced cerebral perfusion has been abundantly documented in autism, and mitochondrial abnormalities are of emerging interest as well. The investigators hypothesize that these cerebral and metabolic changes may temporally precede behavioral abnormalities. They propose that their detection may eventually allow the early institution of medical measures that could improve perfusion and mitochondrial function and that this could prevent autism or reduce its severity. They also propose that the investigation of neurovascular coupling, which can be done by simultaneous NIRS-EEG, may illuminate changes which may arguably be at ground zero of autism. If abnormalities in cerebral perfusion and metabolism develop dynamically in infancy in at least some cases, they may be central to mechanisms of autistic regression. Early detection of these abnormalities could lead to avenues of early medical intervention or even prevention of autism.  The purpose of this equipment grant will be to purchase an OxiplexTS FD-NIRS system ISS Inc. device which would allow the investigators to perform the above measures. They will initially study those at-risk infants in the DoD funded study, "A Multisystem Evaluation of Infants At Risk for Autism" whose parents would consent to this additional evaluation, and will also seek funding for a larger cohort and for studying older children and adults.

Martha Herbert

Massachusetts General Hospital , Boston , MA

Principal Investigator: Martha R. Herbert, M.D., Ph.D.

Electrophysiological Studies of Gating, Timing and Connectivity in Autism

Although autism is defined by three types of behavioral impairments, recent findings in autism research are pointing toward widespread network signal coordination or connectivity problems as underlying what we see as autism - various parts of the brain do not synchronize normally. Reduced connectivity has been found using methods that are better at locating things in space than in time; for example, functional MRI can give us pictures of where the brain activates but is not useful for revealing the sequence of activation, because it cannot register changes that happen in intervals shorter than a second. Electroencephalography (EEG) on the other hand has a time resolution at the millisecond level-more than a thousand times more fine-grained time resolution than can be achieved with MRI. To get the most detailed measurements of short range and long range coordination (which the investigator expects will each have a different kind of abnormality in autism) it is necessary to use a high-density electrode array which covers as much of the entire scalp as possible with electrodes that are closely spaced. To do so, the NLM Family Foundation supported the purchase of a 128-lead EEG machine to upgrade the investigator's capacity from her 32 lead system which limits the measurements she can make. The investigator believes that electrophysiological measures are key to showing the ways that brain functional changes are related to sensorimotor, perceptual, learning and behavioral differences in autism.

Martha Herbert

Massachusetts General Hospital , Boston , MA

Principal Investigator: Martha R. Herbert, M.D., Ph.D.

Neuroimaging of Young Children at High Risk for Autism (funded through NAAR)

In this project, Dr. Herbert will obtain MRI scans of siblings of individuals with autism at about the time of their 14-month old evaluations. These MRI scans have the potential to provide unique and crucial data related to the earliest signs of abnormal development in children who may later receive a diagnosis of autism spectrum disorder. Although many of the brain abnormalities present in autism are believed to occur prior to birth, there appear to be some abnormalities that occur after birth. Research has shown that head and brain size in individuals with autism are normal at birth but grow faster than normal during the first years of life. It has been suggested that this early increase is due to an increased amount of white matter. Dr. Herbert will analyze the MRI scans to learn about the size of various brain structures and to obtain information about the tissue characteristics in different parts of the brain. This research may provide a greater understanding about such abnormal brain growth and may lead to treatments designed to normalize the process.

Martha Herbert

Massachusetts General Hospital, Boston, MA

Principal Investigator: Tal Kenet, Ph.D.

Sensory Perception Deficits and Cortical Coherence in Children with Autism: A Study of the 'Noisy Cortex' Hypothesis

Autism is a behaviorally diagnosed disorder with defining impairments in socialization, interests, and communication abilities. Autism is also characterized by deficits in processing of simple visual and auditory information such as loudness discrimination or perception of moving dots, as well as complex visual and auditory information such as faces and language. Additionally, there is evidence of abnormal tactile sensitivity in autism. These functional findings are complemented by anatomical ones, the most robust of which is that the brains are large. Other neuroanatomical findings include neuroinflammation, and disrupted inhibitory circuitry. To date, no robust models have been formulated for either the neurobiological origin of the observed abnormalities, or the relationship between the pervasive anatomic abnormalities and the neural systems dysfunctions which are characteristic of autism. Furthermore, while the observed anatomical pathologies are distributed rather than localized, the vast majority of functional studies focus on localized features. The main objective of this project is to test the model that the neural substrates underlying the functional deficits of autism at the cortical level stem from a noisy cortex which has a poor signal to noise ratio. To this end, Dr. Kenet will employ magnetoencephalograpy (MEG) to record functional activation in response to sensory stimuli in children with autism and age matched controls. The central hypotheses are: (1) that the cortex of individuals with autism is inherently and internally a "noisy" cortex, i.e. a cortex with a low signal to noise ratio; (2) that the "noisiness" of the cortex is widely distributed rather than localized, resulting in widespread functional abnormalities; and (3) that from this distributed "noisy" cortex emanates a network in which connectivity is disrupted, with ensuing functional abnormalities that include widespread perceptual deficits, and alterations in neural circuitry that may drive higher order cognitive and social impairments emanating at least in part from abnormal network properties.

Massachusetts General Hospital, Martinos Center for Biomedical Imaging

Neurofeedback Group, Inc., Newton , MA

Principal Investigator: Barbara Scolnick, M.D.

EEG Biofeedback as an Operant Training Technique to Ameliorate Some Symptoms in Children with Autism Spectrum Disorders

The goal of this project is to test whether biofeedback of electro -encephalographic (EEG) measurements can improve the ability of children with autism, ages 8 to 16 years, to control their behavior. The experiment involves a subject group of 20 individuals who are exposed to their continuous EEG profiles while engaged in playing computer games. Each subject and aged matched controls will participate in 40 one-hour sessions over a 20 week period. The hope is to investigate whether EEG biofeedback can be a useful operant training technique to ameliorate some symptoms in children with autism spectrum disorders.

University of California at San Francisco , San Francisco , CA

Principal Investigator: Timothy P.L. Roberts, Ph.D.

Neural Correlates of Phonological Processing in Autism: A MEG Investigation. (funded through NAAR)

Individuals with autism may have abnormal development of expressive speech and impairments in auditory and speech perceptual processing. Little is known about cortical mechanisms underlying impaired language development in autism. This study uses magnetoencephalography (MEG) to non-invasively measure neural activity in auditory cortical sites in individuals with autism. This technique allows researchers to track neuronal activity with sub-millisecond temporal resolution. Previous work has provided evidence that early sensory processing of simple and complex sounds appears to be intact in individuals with autism. However, the pervasive nature of language deficits in autism indicates that linguistically relevant sound processing may nonetheless be impaired in this population. The researchers hypothesize that while early processing of acoustic signal appears normal in individuals with autism, later phonological processes that provide feature extraction, discrimination, and categorization necessary for decoding the speech signal may be disrupted. They will measure later stages of neural activity, including correlates of phonological processing with the aim of providing quantitative measures to assess the nature and cortical timing of language related sound processing abnormalities in autism.

Click here to read the NLMFF Interview with Dr. Roberts

Children's Hospital of Philadelphia

University of Pittsburgh, Pittsburgh, PA

Principal Investigators: Nancy Minshew, M.D., Thomas Conturo, M.D., Ph.D.

Diffusion Tensor Tracking of Connectivity Abnormalities in Autism

Recent functional imaging studies (fMRI) have revealed a reduction in functional connectivity across cortical brain regions involved in language, problem solving, and social cognition; simple tasks showed normal connectivity. Structural brain studies have shown an increase in brain volume attributable largely to an increase in the outer white matter zone. This white matter connects immediately adjacent areas of cortex and makes longer distant connections between cortical regions within the same hemisphere. The corpus callosum, the major white matter pathway connecting the two hemispheres, is smaller in autism. This study will investigate white matter connections using a new method called diffusion tensor fiber tracking to map white matter pathways related to each of the major symptom areas of autism. The size, shape and density of these pathways in high functioning teens and adults with autism will be compared to matched normal controls and behavioral indices. This study will advance the understanding of connectivity in autism, pave the way for comparisons with functional connectivity, guide developmental neurobiologic studies, and provide an index for future cognitive rehabilitation strategies designed to enhance connectivity.

Nancy Minshew

University of Toronto , Toronto , Ontario

Principal Investigator: Timothy Roberts, Ph.D.

MEG Correlates of Linguistic Processing at and Below the Word Level in Autism (funded through NAAR)

Magnetoencephalography (MEG) results from past studies have shown delays in automatic neural responses to vowel-sound contrasts in subjects with autism relative to controls. This study focuses on the development of a novel MEG experiment (which allows for non-invasive measurement of neural activity in auditory cortical sites) to extend investigation of auditory linguistic processing of speech sounds from isolated sounds to speech sound combinations. The combination of speech sounds is governed by phonotactic rules, language particular constraints on how sequences of segments pattern. This project will investigate sensitivity to violations of phonotactic rules of children with autism compared to controls. Literature shows that phonotactic violations cause processing delays for subjects' task completion in an auditory discrimination experiment. It is important to identify neural correlates of such delays in controls so that we may look for the presence of the same effect in children with autism in an MEG experiment. It is hypothesized that neural activity related to phonotactic violation detection will be significantly delayed in subjects with autism. The researchers will adapt existing MEG word recognition experiments to passive paradigms suitable for study with an autistic population to test whether individuals with autism store and access words similarly to healthy age-matched controls.

Click here to read the NLMFF Interview with Dr. Roberts

Children's Hospital of Philadelphia


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