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| ANATOMY & PHYSIOLOGY -
PAST GRANTS |
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Albert Einstein College of Medicine, Bronx , NY
2003
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.
The
Neurology Department - Albert Einstein College of Medicine
The Autism Research Foundation, Boston , MA
1998
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
Margaret
Bauman
Boston
University Medical School , Boston , MA
2000-2001
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.
Blatt
Laboratory for Autism Research
Oregon
Health & Science University , Portland , OR
2003
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.
Neurological
Services Institute - Oregon Health & Science University
Princeton University , Princeton
, NJ
2003-2006
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
2000-2001
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 Louisville , KY
2003
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
2000
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
2001-2003
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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