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Albert Einstein College of Medicine, Bronx , NY

Principal Investigator: Michelle Dunn, Ph.D.

Understanding Cortical Auditory Processing Abnormalities in Children with Autism (funded through NAAR)

Sensitivities to sound, preference for music over speech, and slowed responding to verbal information are regularly observed in children with autism. Those with full scale IQs of at least 60 are not clinically distinct from children with typical development on peripheral audiometric measures and they demonstrate normal early auditory cortical responses associated with generators on the superior temporal plane. Dysfunction in children with autism is evident in abnormal slowing of early ERPs localizable to auditory association cortex of the lateral surface of the superior temporal gyrus. A prerequisite to establishing appropriate interventions for children with autism is precise definition of dysfunction, achieved through knowledge of information and processing demands that modulate neural responses. Auditory processing offers an important window into information processing in children with autism. The goals of this study are to elucidate through use of behavioral and neurophysiologic methods neural and cognitive/linguistic mechanisms associated with auditory processing in children with autism and to understand circumstances under which neural abnormalities are ameliorated or exacerbated.

Michelle Dunn

The Autism Research Foundation, Boston , MA

Principal Investigator: Margaret Bauman, M.D.

Neurobiological Investigations of the Autistic Brain

This project involves advancing neurobiological investigations of the autistic brain. Support from the Foundation is to go towards financing the modernization of The Autism Research Foundation's (TARF) tissue processing and slide preparation techniques, helping to upgrade TARF's original computerized cell counting system, and helping to provide essential personnel critical to the investigation of TARF's autistic brain material and integration of TARF's neuroanatomical projects into the collaborative research efforts of the Autism Research Consortium. Specifically, the Foundation provides support for a large magnitude cryostat microtome to prepare slide material for study. The cryostat utilizes frozen tissue which eliminates the prolonged fixation time needed in the outdated process for the processing of celloidin embedded tissue.

The Autism Research Foundation

Beth Israel Deaconess Medical Center , Boston , MA

Principal Investigator: Matthew Anderson, MD, Ph.D.

Innate Immunity and Thalamic Dysfunction in Autism

Sensory processing defects are a prominent feature of autism with descriptions of an over-reaction to noise, light, and touch and increased pain thresholds. The thalamus is the gateway of these sensory signals and recent reports indicate a marked suppression of thalamic metabolic activity in autistic children. Other studies reported excessive brain growth during the early life. The cause of these functional and structural brain abnormalities and resulting behavioral impairments remain unknown. A clue may be the recent finding of inflammation-activated glia in most autism brains. The inflammation was composed of glial cell growth and peptide secretion. Neurons perform the signal transmission and computations unique to the brain, while glial cells support these neuron functions. Resting glia provide structural and metabolic support to neurons improving their signaling properties. The effect of inflammation-activated glia on neurons is largely unknown. This project seeks answers to this question to understand what influence the inflammation-activated glia found in autism might have on the brain of individuals suffering from autism.

Beth Israel Deaconess Medical Center

Beth Israel Deaconess Medical Center, Boston, MA

Principal Investigator: Richard L. Sidman, M.D.

Stem Cell Injections Prevent Loss of Cerebellar Purkinje Neurons

The most consistent pathological abnormality found in autopsied cases of individuals with Autism Spectrum Disorder (ASD) is a decrease in number of cerebellar Purkinje neurons. Purkinje neurons are at risk in many neurological disorders, and undergo cell death in circumstances that may cause debilitating damage in other brain areas. The investigators’ belief that stem cells may help ASD patients comes from their experiments on mice with different neurogenetic disorders which cause selective destruction of Purkinje neurons. They injected neural stem cells (NSCs) into mouse cerebellum and found that mice injected with NSCs as babies, before Purkinje neurons were destined to die, grew up healthy, with cerebella that contained abundant Purkinje neurons. They established that stem cells had rescued the mouse’s Purkinje cells from dying! Before testing stem cell therapy in humans with brain disorders, the investigators must learn in mouse experiments what types of stem cells to use, how many cells to inject, how often, and by what routes, to maximize their distribution though affected brain regions with minimal discomfort. They have discovered that tissue plasminogen activator (tPA) is increased 10-fold in the cerebellum of one of their mouse mutants, and that tPA reverts to normal in mice they treated with NSCs. They plan to test the idea that tPA may act as a common “death mechanism” in many diseases affecting Purkinje neurons, and that therapy with stem cells should be directed at correcting the chemistry involved in this mechanism. The use of stem cells for rescue of Purkinje neurons would be of benefit regarding restoration of cerebellar function and may provide clues to chemical abnormalities that would lead to therapeutic recovery in brain regions that are more subtly affected in ASD, though with serious behavioral consequences.

Beth Israel Deaconess Medical Center

Boston University Medical School , Boston , MA

Principal Investigator: Gene J. Blatt, Ph.D.

Neuropathological and Neurochemical Analysis of Key Speech and Language Areas in Autism

Autism is characterized by children and adults with a variety of speech and language impairments. Brain imaging studies have found that there is a different pattern of activation of speech and language regions in the brains of those with autism compared to normal controls in a variety of tasks. Despite an abundance of structural and functional MRI findings, there is a lack of information regarding the neurobiological basis of these changes, i.e., characterizing the specific cellular and neurochemical changes that may contribute to alterations in cortical activation of speech and language areas in autism. The investigator has therefore designed a novel study investigating critical speech and language areas in autistic brains, Broca's area and Wernicke's area in the frontal and temporal lobes respectively compared to adult age-matched controls. This investigation is designed to detect specific alterations in the density and distribution of key neuronal and glial types and in the neurotransmitter receptor subtypes within the layered cortical areas. In this way, the investigator can identify some of the core neurobiological substrates that may in part underlie the changes in language and social communication in autism. This work may guide geneticists toward finding autism genes and may guide the development of novel drug treatments. The investigator will also determine via detection of activated glia cells whether autism is a static process or a dynamic process in the brain. This part of the study may lead the investigator to identify the most vulnerable regions within selected brain areas and may lead to a greater understanding of ongoing cellular changes and their etiology.

Gene J. Blatt, Ph.D.

Boston University Medical School , Boston , MA

Principal Investigator: Gene J. Blatt, Ph.D.

Cerebellar Circuitry in Autism (funded through NAAR)

Neuropathological studies in autistic brains have reported cellular alterations in the cerebellum, a structure believed to be important in motor skills, balance, and cognition. In the posterolateral cerebellar cortex, many Purkinje cells (PCs) are missing, which are targets for afferent projection fibers from the inferior olivary nucleus in the medulla of the brainstem. The missing PCs raise an interesting question: Were the missing PCs ever produced or were they produced only to die later in migration or at their normal location between the molecular and granular layers? If they died later, then GABAergic basket cells should have formed their elaborate axonal plexuses that surround the PC body forming a nest. If the PCs were never generated then basket cell nests would not be expected. The first aim of this study is to determine whether basket cell nests have formed in areas with a decreased number of PCs leaving "empty nests". The second aim of this study investigates whether the surviving PCs in posterolateral cerebellar cortex of individuals with autism represent a particular subpopulation of PC neurons or whether it is a more diffuse loss. The third aim investigates a major structure in the medulla of the brain stem that sends a direct projection to PCs, the inferior olivary nucleus. Findings from these studies may allow us to understand the developmental timing of autistic behavior and may lead to the development of new early interventions that target specific neurotransmitter systems.

Gene J. Blatt, Ph.D.

Massachusetts Institute of Technology Media Laboratory, Cambridge , MA

Principal Investigators: Rosalind Picard, Sc.D. and Matthew Goodwin, Ph.D.

Assessing and Communicating Movement Stereotypy and Arousal Telemetrically in Individuals with Autism Spectrum Disorder

Stereotypical motor movements or stereotypies are one of the most common and least understood behaviors occurring in individuals with Autism Spectrum Disorder (ASD). Stereotypies are complex and thought to serve a multiplicity of functions. While no one theory has obtained overwhelming support, there is evidence for biological, operant, and homeostatic interpretations. Of particular importance to the current project, a small number of studies support the notion that there is a functional relationship between movement stereotypy and arousal in individuals with ASD, such that changes in autonomic activity either precede or are a consequence of engaging in stereotypies. Thus, it appears to be the case for some individuals that stereotypic movements are adaptively employed to help regulate stress, which in turn may help regulate attention, emotion, and social behaviors. Unfortunately, it is difficult to generalize these findings since previous studies fail to report reliability statistics that demonstrate accurate identification of movement stereotypy start and end times, and use autonomic monitors that are obtrusive and thus only suitable for short-term measurement in laboratory settings. This project aims to explore the relationship between movement stereotypy and autonomic activity in persons with ASD by combining state-of-the-art ambulatory heart rate monitors to objectively assess arousal across settings and wireless, wearable motion sensors (accelerometers) and pattern recognition software that can automatically and reliably detect stereotypical motor movements in individuals with ASD in real-time. Obtaining detailed and accurate information on the occurrence, type of movement, frequency, duration, and setting events associated with movement stereotypy is critical to understanding this behavior. Moreover, assessing and communicating stereotypical movements and arousal telemetrically may facilitate more precise intervention efforts before they are entrenched in an individual's repertoire.

MIT Media Lab

Massachusetts Institute of Technology Media Laboratory, Cambridge , MA

Principal Investigators: Rosalind Picard, Sc.D. and Matthew Goodwin, Ph.D.

Wearable Wireless Toolkit for Measurement and Communication of Autonomic Nervous System Activity in Autism

While many scientists have recognized the importance of characterizing stress and other Autonomic Nervous System (ANS) responses associated with Autism Spectrum Disorders (ASD), traditional measurements have been limited to snapshots taken in a laboratory setting, and to group averages that ignore the highly dynamic patterns in an individual's ANS responsivity during daily activities. The key problem is that existing measurement devices have not been usable in a continuous, unobtrusive way outside the laboratory.  This research will utilize state-of-the-art knowledge in technology, especially in wearable sensors and wireless communication technology, to construct a comfortable, low-cost toolkit that makes it possible for people on the autism spectrum and their caregivers to continuously monitor and communicate autonomic arousal in daily life, including activity at home, school, and in community settings.  Participants can also, if they choose, share their ultra-dense data with scientists, providing an unprecedented opportunity for analysis of the everyday dynamics of ANS reactivity in persons diagnosed with ASD. The investigators will design, build, test, deploy, and evaluate the use of a toolkit consisting of a wrist-worn set of ANS sensors, together with a tiny low-power wireless radio, software analysis tools, communication controls, and visualization tools to enable persons on the autism spectrum and their caregivers to communicate ANS state information to trusted others, and to visualize and compare patterns in their data across time and different daily activities.  Examining these patterns, they will evaluate their potential for alerting people to states of interest that are helpful to predict, such as seizures, given that the condition of repeated seizures (epilepsy) is conservatively estimated to occur in 25% of ASD cases.  They will also evaluate the presence of other dynamic patterns that may be person-dependent, but useful for communicating states that are conducive to learning, attention, and successful social interaction.

MIT Media Lab

Oregon Health & Science University , Portland , OR

Principal Investigator: John Welsh, Ph.D.

Inferior Olive & Autism: Electrical Synapses, Neuronal Synchrony, & Cognition (funded through NAAR)

It is thought that social and communication cues pass by too fast for children with autism to process, making them appear socially or emotionally detached. One of the most common disturbances of brain anatomy in autism is the altered shape of the inferior olive, a structure in the lowest portion of the brainstem that communicates directly with the cerebellum. This study will explore the possibility that there is a direct link between disruption of the inferior olive and inability of children with autism to process rapid-fire sequences of stimulus events. The hypothesis is that the inferior olive acts as a "cognitive clock" that generates a continuous, metronomic rhythm that allows cognitive separation of sensory events that are closely spaced in time. Experiments will be conducted in rats trained to blink their eyelid to an auditory stimulus in the absence of fast electrical transmission within their inferior olive. It is expected that electrically disconnected neurons in the inferior olive, as may occur in autism, will prevent rapid stimulus processing. Demonstration of this could point to a specific family of neuronal proteins (connexins) in the behavioral manifestation of autism.

Brain Institute - Oregon Health & Science University

Princeton University , Princeton , NJ

Principal Investigator: Alex Plakantonakis

Fellowship Support for Research into New Approaches for Discovering Cognitive-Enhancing Medications for Autism

The human brain is made up of many cells, each carrying out its function while maintaining its role in the larger context of groups of cells, thereby working side by side to perform specialized tasks that we attribute to behavior.  The formation and consolidation of memories is a cognitive task that has received much attention in the last decade, as neuroscientists are starting to delineate the molecular events that make memories possible.  Central to these events is a molecule called Calcium-Calmodulin dependent Kinase II (CaMKII).  CaMKII is a molecule capable of affecting practically every facet of cellular metabolism and homeostasis upon activation, which depends on transiently elevated concentrations of calcium in the cell.  Given the abundance of CaMKII in the brain it has been proposed that CaMKII plays a key role in storage of information.  Plakantonakis is interested in characterizing the interaction of CaMKII with other proteins that may be important in brain function.  Understanding the three-dimensional structure of the CaMKII molecule may be useful for understanding the way in which its function is carried out and for designing other molecules that can have a desirable physiological effect upon binding.  For instance, many drugs sold today have been designed to interact with a therapeutic target (a protein of special medical significance) whose three-dimensional structure is known.  It is possible that his efforts will provide the details required for the rational design of drugs that will have an effect on our ability to better retain and process information.

Department of Chemistry - Princeton University

Universidad Miguel Hernandez, Spain

Principal Investigator: Jorge J. Prieto, M.D., Ph.D.

A Microscopical Study on the Neuroanatomical Abnormalities of Language-Related Cortical Areas in Autistic Patients (funded through NAAR)

This project will explore the anatomical and neurochemical substrates of language disabilities characteristic of autism. Research has demonstrated abnormalities in parts of the autistic brain, including the cerebral cortex. The language impairment may be due to alteration of auditory processing in primary and secondary cortices and/or disruption of the normal functioning of higher-order cortical fields. Because there are alterations in functional explorations of cortical hearing and language processing, it can be hypothesized that such alterations are due to a disorganization of normal cortical architecture. Dr. Prieto will investigate the brains of deceased patients with autism, following a sequential approach: (1) analyze the gross anatomical alterations of the auditory cortical fields, and areas of Wernicke and Broca, (2) study the microscopical organization of the cerebral cortex in those three areas, and (3) study changes in cortical circuitry involving neurochemically identified pyramidal cells and interneurons in the language areas of both hemispheres from patients with autism.

Universidad Miguel Hernandez

University of Cambridge Autism Research Centre, Cambridge , UK

Principal Investigator: Simon Baron-Cohen, Ph.D.

Do Children with Autism Have Elevated Fetal Testosterone?

Neurologist, Norman Geschwind, suggested that fetal testosterone may shape sex differences in brain development. Males produce more of this because it is generated by the testes, but females also produce it. Geschwind thought that the action of fetal testosterone on the brain might explain why girls tend to talk earlier than boys and why boys are overrepresented in clinics for language disorders and conditions such as autism. Human fetal testosterone can be measured through a method called amniocentesis. In this study, amniotic fluid taken from 3,000 women during their pregnancies will be studied with respect to levels of fetal testosterone. Dr. Baron-Cohen will determine how many of their children, who are now 4 years or older, have been diagnosed with an autism spectrum condition, or score highly on an autism spectrum scale, and will test if these 'affected' children had abnormally high levels of fetal testosterone.  Earlier studies in the general population have linked this hormone to social and language development. It is important to investigate whether it plays a role in the development of autism.

Autism Research Centre

Simon Baron-Cohen

University of Louisville , KY

Principal Investigator: Manuel Casanova, M.D.

Macroscopic Correlates of MiniColumnar Abnormalities in Autism (funded through NAAR)

In the cortex, cells are arranged in parallel, layered bundles, termed collectively as the cell minicolumn. It is a self-contained system linking the central nervous system to incoming, outgoing, and interneuronal signals. Preliminary study indicates that the neocortical organization of brains of individuals with autism differs from that of controls. Previous study of 3 neocortical sites in 9 brains of individuals with autism and 9 controls has shown significant differences in spacing that separates minicolumns, and differences in their internal structure: less space in outside edges of minicolumn and increased mean cell spacing within minicolumn. This project will attempt to find morphological correlates to these columnar findings in postmortem MRIs of 26 patients with autism available through University of California at Davis and the Autism Tissue Program.

Manuel Casanova

University of Wisconsin , Madison , WI

Principal Investigators: Morton Ann Gernsbacher, Ph.D. & H. Hill Goldsmith, Ph.D.

Toward a Dyspraxic Subtype of Autism Spectrum Disorder (funded through NAAR)

These researchers suggest that results of genetic and brain imaging studies have been less definitive because of the heterogeneity of symptom profiles in persons with autism. They aim to identify and validate a subtype of autism, which they refer to as "developmental verbal dyspraxia." Developmental verbal dyspraxia (DVD) is a motor-speech programming disorder resulting in difficulty coordinating and sequencing oral-motor movements necessary to produce and combine speech sounds to form syllables, words, phrases, and sentences. The researchers hypothesize that some minimally or nonverbal persons with autism are characterized by developmental verbal dyspraxia. This project will identify and validate a DVD subtype of autism by screening all children with autism in a metropolitan area; identifying members of this group who are also characterized by DVD; selecting an autism control group of children not characterized by DVD and a typically developing control group; collecting extensive behavioral, medical, and developmental histories of all children in these groups; obtaining neuroanatomical data; and collecting and storing DNA for future candidate gene studies.

Gernsbacher Laboratory

Weizmann Institute of Science , Israel

Principal Investigator: Henry Markram, Ph.D.

Altered Inhibitory Microcircuits in Autism (funded through NAAR)

These researchers believe that most of the deleterious neurological symptoms of autism, which can include distortions in perception, attention, memory, cognition, language, communication and social behavior, could come from a malfunction in the microcircuits of the neocortex. When the neocortex is excited by sensory stimulation or during higher cognitive processing, the excitation engages inhibitory mechanisms that command the sequence, spread and form of the evolution of electrical activity patterns. The operations of inhibitory microcircuits are central to normal perception, attention and memory that form the foundation for higher cognitive functions. With impaired inhibitory mechanisms, information processing at multiple levels will be profoundly affected. The researchers believe that altered inhibitory microcircuits could be the common denominator in autism spectrum disorders. Alterations in perception, attention and memory processes to different degrees, in different forms and in different regions of the neocortex could give rise to many autistic-like syndromes. They explore principles of recruiting and applying inhibition in the neocortex, their alterations in animal models of autism and plasticity of these inhibitory microcircuits. This project could indicate new directions for retraining inhibitory microcircuits to reinstate normal cognitive functions.

Department of Neurobiology - Weizmann Institute of Science

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