Beth Israel Deaconess Medical Center, Boston
Principal Investigator: Michael D. Fox, M.D., Ph.D.
Identifying Treatment Targets for the Symptoms of Autism Spectrum Disorder Based
on Brain Lesions
Different patients with autism spectrum disorder (ASD) have different symptoms. Some of these symptoms can be disabling and resistant to current treatments. New types of therapies, such as brain stimulation, might be used to improve these symptoms. However, this can’t be done until we know what brain region we need to target to treat specific ASD symptoms. Dr. Fox has recently developed a new method to identify brain regions causing specific symptoms. He can apply this method to identify regions causing symptoms of ASD, regions that can then serve as treatment targets. There have been many experiments using brain imaging to identify differences in the brains of patients with ASD. However, these differences have been poorly reproducible across studies and may not actually cause ASD symptoms.
Patients with brain lesions may represent a new approach for localizing ASD symptoms. Lesions provide a causal link between the lesion location and resulting symptoms. Although lesion patients are very different from those with ASD, lesions can occasionally cause specific symptoms that are similar to those seen in ASD patients. These lesion cases provide a useful starting point for identifying the brain regions causing ASD
These lesions provide a valuable starting point, but not the end point. A complicating factor is that symptoms can come from regions connected to the lesion location, not just from the lesion location itself. As such, identifying the brain region causing a specific symptom requires more than a set of brain lesions, it also requires a map of brain connectivity. Dr. Fox’s new method integrates brain connectivity into lesion analysis, allowing for better localization of symptoms. Using this method, he has identified brain regions causing many different neurological and psychiatric symptoms. In some cases, these symptoms have been very complex, similar to symptoms seen in ASD. In this study, Dr. Fox will apply this same method towards identifying
brain regions causing symptoms in ASD. Once he has identified the relevant brain regions and networks based on lesions, he will confirm the importance of these regions in patients with ASD.
The end result of this work will be a set of candidate brain regions causally involved in generating specific ASD symptoms. These brain regions can then be targeted with invasive or noninvasive brain stimulation. This approach should allow for individualized therapy targeted to specific regions based on patient-specific symptom profile.
Beth Israel Deaconess Medical Center
Beth Israel Deaconess Medical Center, Boston
Principal Investigator: Matthew Anderson, MD,
Innate Immunity and Thalamic
Dysfunction in Autism
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
Beth Israel Deaconess Medical Center
Bradley Hospital/Brown University, Providence
Principal Investigator: Lindsay Oberman, Ph.D., Brown
Career Development Award for Lindsay Oberman
This grant provides
support for Dr. Lindsay Oberman in a translational research project that will
extend and bridge two independent lines of research, both previously funded by
the NLMFF. Specifically, with funding from NLMFF as well as NIH and Harvard
Catalyst, Dr. Alvaro Pascual-Leone and Dr. Oberman have developed methods to
noninvasively measure experience-dependent cortical plasticity both in healthy
controls and patients with idiopathic ASD and Fragile X syndrome. Using
noninvasive repetitive transcranial magnetic stimulation (rTMS), Drs. Oberman
and Pascual-Leone have shown that patients with idiopathic ASD show an
exaggerated LTD-like suppression of cortical excitability following a short
train of rTMS while those with Fragile X (without ASD) syndrome show a complete
lack of LTD-like suppression in response to the same rTMS protocol.
Under a separate line of research, also previously funded by the NLMFF,
Dr. Matthew Anderson developed a mouse model of ASD based on triplication of the
UBE3a gene (the genetic mutation that causes idic15 in humans) that
reconstitutes correlates of the three core behavioral deficits that define ASD.
Furthermore, they have developed a model mechanism where they propose that
social deficits in individuals with idic15 may be a consequence of excessive
experience-dependent social homeostasis.
Independently, these two lines of research have both
contributed to our understanding of the underlying pathophysiology of the
behavioral deficits that characterize ASD. A complete understanding, however,
requires the direct translation of insights that we gain from basic science to
applications that have direct impact for patients with the disorder. With this
focus, this project aims to create a multi-disciplinary collaboration between
the Anderson and Pascual-Leone lab with Dr. Oberman as the catalyst of this
translational bridge. Thus, the aim is to develop novel assays, based on the
previous work in the Anderson and Pascual-Leone lab, to evaluate neurological
and behavioral phenotypes in human patients with a specific syndromic form of
Institute on Communication and Inclusion, Syracuse
University, Syracuse, NY
2013 – 2015
Principal Investigator: Christine Ashby, Ph.D.
Integration of iPads and Other AAC to Improve
Communication for Individuals with Autism
Dr. Ashby’s research team
aims to understand the potential of the iPad and other mobile technologies in
supporting communication and inclusion of individuals with autism. What
applications are most useful for individuals who do not speak or whose speech is
highly limited? How can the iPad help individuals with autism develop greater
independence, improve their motor planning, or develop verbal speech? Also,
while the iPad has nearly unlimited potential, Dr. Ashby’s research team also
wants to understand how it can be meaningfully integrated in school and
community settings along with other communication strategies to increase
meaningful access to academic, work, and social experiences. Technology alone is
not sufficient; training and ongoing support is necessary to ensure that use of
the technology enhances communicative interactions and educational access. Many
schools and agencies are purchasing iPads with no plan for meaningful
integration and no plan for how this new technology fits into a larger total
The goal of this project is to enhance our
understanding of the potential for iPads and other mobile AAC devices to support
communication. Through this grant, Dr. Ashby’s research team will explore,
evaluate, and organize applications that are most useful in helping non-speaking
individuals with autism develop skills related to typed communication and
achieving independent communication. The grant will also support the development
of a pilot app, a multifaceted assessment tool that will aid in determining
candidacy for facilitated communication training, current pointing skills and
literacy levels. Finally, this project will focus specifically on the use of the
iPad for helping individuals with autism develop greater physical independence
when typing to communicate.
on Communication and Inclusion
Massachusetts Institute of Technology, Cambridge, MA
Principal Investigator: Matthew Goodwin, Ph.D.
Career Development Award
Matthew Goodwin’s research plan to be covered by this Career Development Award includes:
(1) Developing, supervising, conducting, evaluating, and disseminating autism technology and related research;
(2) Building infrastructure and a coordinated program of research and educational activities under the auspices of MIT’s Autism and Communication Technology Initiative;
(3) Engaging in advanced psychophysiological and statistical training opportunities; and
(4) Developing a competitive academic portfolio to obtain an eventual tenure-track faculty or equivalent research scientist position.
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
MGH/HST Martinos Center for Biomedical Imaging, Charlestown, MA
Principal Investigator: Maria Mody, Ph.D.
Exploring Communication Pathways in Nonverbal Individuals with Autism Spectrum Disorder: Speech and Print
To date, research in Autism Spectrum Disorder (ASD) has focused on individuals who are high functioning. Additionally, most of the research has been with infants and young children. In contrast, little is known about adult individuals on the spectrum who do not speak and may or may not have intellectual disabilities. These individuals pose a challenge to study due to compliance issues and difficulties with producing a reliable response. Additionally, they frequently present with co-morbid inattention, anxiety, aggression and sensory problems. Insofar as the ability to communicate is considered a positive prognostic indicator for individuals with ASD, Dr. Mody and colleagues focus their efforts on the neurobiology of communication deficits in nonverbal adults with ASD for a clearer understanding of the underlying disruptions for potential application in improved intervention. They take advantage of recent advances in neuroimaging using EEG, MEG, fMRI and DTI with passive paradigms, in the context of a novel combination of experiments targeting speech and print to assess the integrity of spoken and written communication pathways in the brain in nonverbal ASD. Specifically, nonverbal adults with ASD and age- and gender-matched neurotypical controls will participate in three experiments in which investigators will examine (a) oromotor representations for speech vs. non-speech; (b) access to meaning via print; (c) structural and functional intactness of speech and reading networks. Taken together, these experiments have the potential to reveal articulatory and orthographic mappings as related to speech-language deficits in nonverbal ASD.
Rutgers University, Piscataway, NJ
Principal Investigator: Elizabeth Torres, PhD
Career Development Award for Elizabeth Torres
Natural behaviors flow continuously. They are dynamically composed of movements with different levels of intent, ranging from deliberately controlled motions to motions that spontaneously occur largely beneath our conscious awareness. The signatures of motor output variability from these movement classes carry an ever-changing blend of noise and signal that informs the central nervous system of critical changes at the periphery. They help discriminate sensory changes of relevance to the biological organism. The modulation and control of this efferent output flow depends on the returning afferent stream, which such motions themselves cause.
Although physical movements have been exclusively treated as efferent output in autism, they also constitute a form of sensory input that can be measured at the periphery in non-invasive ways. The returning afferent information can thus be precisely parameterized in a controlled manner and paired with other forms of sensory feedback to augment the sensory bubble of the autistic system. In this way, there is a higher probability of inducing perceptual stability along some sensory modality so as to create proper anchors or frames of reference to scaffold the type of sensory-motor integration processes that enable predicting ahead, in a causal manner, the sensory consequences of impending actions. In turn such feedback can be used to make the system cognizant of its own spontaneous actions and intentions, and of the spontaneous actions and the intentions of others in the social environment.
Recent work from Torres’ laboratory has taken the first steps towards this paradigm shifting approach to movement in autism. They have invented a new statistical platform for individualized behavioral analyses (SPIBA). This platform helps close the feedback loops in autism, to detect real-time changes in the internal somatosensation of the child as a function of external sensory guidance. SPIBA combined with physical body micro-movements that are hidden to the conscious human eye has helped shift the stochastic regimes of the autistic system from random and noisy to predictive and reliable, thus broadening the bandwidth of their peripheral motor-sensory signal. Even in 25 non-verbal children with ASD Dr. Torres’ team was able to systematically evoke volitional control of their actions and enhance intentionality in their spontaneous gestures, according to the shifts in the stochastic signatures of their motor output variability, the rate of which was unique to each child.
This project will combine SPIBA, the new conceptual framework for motor control and wearable sensing technology to open a window into the hidden communicative capacities of the autistic system. Torres’ lab will combine movement-based peripheral sensory feedback with precisely parameterized external sensory input to engage the autistic child in the intentional control of actions and decisions. The impact of the peripheral signal on centrally driven decisions will also be assessed.
Sensory-Motor Integration Research Laboratory of Elizabeth Torres