Albert Einstein College of Medicine, Bronx , NY
Investigator: Michelle Dunn, Ph.D.
Cortical Auditory Processing Abnormalities in Children with
Autism (funded through NAAR)
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.
The Autism Research Foundation, Boston , MA
Investigator: Margaret Bauman, M.D.
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outdated process for the processing of celloidin embedded
Autism Research Foundation
Beth Israel Deaconess Medical Center , Boston , MA
Principal Investigator: Matthew Anderson, MD, Ph.D.
Innate Immunity and Thalamic Dysfunction in Autism
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.
University Medical School , Boston , MA
Investigator: Gene J. Blatt, Ph.D.
Circuitry in Autism (funded through NAAR)
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
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
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
Health & Science University , Portland , OR
Investigator: John Welsh, Ph.D.
& 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
Investigator: Alex Plakantonakis
Support for Research into New Approaches for Discovering
Cognitive-Enhancing Medications for Autism
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.
of Chemistry - Princeton University
Universidad Miguel Hernandez, Spain
Investigator: Jorge J. Prieto, M.D., Ph.D.
Microscopical Study on the Neuroanatomical Abnormalities
of Language-Related Cortical Areas in Autistic Patients
(funded through NAAR)
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.
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
of Louisville , KY
Investigator: Manuel Casanova, M.D.
Correlates of MiniColumnar Abnormalities in Autism (funded
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
of Wisconsin , Madison , WI
Investigators: Morton Ann Gernsbacher, Ph.D. & H. Hill
a Dyspraxic Subtype of Autism Spectrum Disorder (funded
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
Institute of Science , Israel
Investigator: Henry Markram, Ph.D.
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.
of Neurobiology - Weizmann Institute of Science