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Beth Israel Deaconess Medical Center, Boston, MA

Principal Investigator(s): Cliff Saper, MD, PhD, and Mouhsin Shafi, MD

Transcranial Magnetic Stimulation: Giving Epilepsy and Autistic Patients Increased Access to Pioneering Treatments

This grant will be used to purchase a transcranial magnetic stimulation (TMS) device for inpatient use. This device would be used therapeutically for patients with epilepsy, including those with autism and other brain disorders whose symptoms may include seizures. The device would also be used in research studies to benefit patients with these profiles. Currently, Beth Israel is limited to TMS devices for outpatient use and this additional device, for inpatient use, would expand its ability to provide treatment and to conduct research studies for the benefit of these patients.

TMS is a non-invasive technique that uses the principle of electromagnetic induction to focus currents in the brain and modulate the function of the cortex. TMS helps to treat a wide range of patients with neurological diseases and disorders. This tool is also helpful in treating epilepsy patients who are diagnosed with autism spectrum disorders (ASD). As many as 40 percent of individuals with ASD and intellectual disability have epilepsy. The treatment for this subpopulation is challenging because of difficulties with medication side effects. TMS is unique in that it can deliver targeted, non-pharmacologic therapy that works via a different mechanism than all known medications, and may be effective when conventional medications fail. Because it is targeted to a specific brain region, it also does not produce any systemic side effects. TMS can also be used in a variety of diagnostic and therapeutic research studies to benefit patients with neurologic diseases, including epilepsy and autism. For example, conventional electroencephalography (EEG), the test typically used to help diagnose epilepsy, is an imperfect tool that tries to capture brain activity as it occurs spontaneously. Since seizures are intermittent, EEG rarely captures them, and we rely on finding interictal "spikes" to help diagnose epilepsy. However, these spikes may not always be present in individuals with epilepsy, and can also be present in individuals with other neurologic disorders. For example, studies have suggested that up to 60 percent of individuals with ASD but without known epilepsy had interictal spikes. Consequently, better tools are needed, including a better biomarker for epilepsy. Because TMS enables us to stimulate the brain and assess how it responds, this technique may be a useful tool in this regard. TMS can be used in research studies of new treatments. For example, many individuals with ASD but without known epilepsy have interictal spikes on their EEG. In some cases these spikes are frequent, clearly associated with intellectual regression. Treatment with conventional seizure medications can significantly improve cognitive function. In the majority of cases, however, there is no such clear improvement. This may in part be because the seizure medications do not completely suppress the spikes, and because the seizure medications often themselves have cognitive side effects. Since TMS can be used to deliver treatment specifically to the spike focus, and without general cognitive side effects, TMS treatment could be helpful in improving cognitive function in individuals with ASD with interictal spikes.

A new TMS machine will enable BIDMC to expand services to inpatients with epilepsy, including those with autism, by giving physicians increased access to this pioneering treatment and expanding the ability to conduct related research.

Clifford Saper Laboratory

Mouhsin Shafi

Boston Jewish Film Festival, Boston, MA

Support for the 2014 ReelAbilities Film Festival

The NLM Family Foundation provided support for the ReelAbilities Film Festival which was held on January 20, 2014 through February 6, 2014 at various venues throughout the Boston area. The festival featured two autism-related films, “Son of the Stars” (about a family with autism in China) and “Wretches & Jabberers.” The Foundation also provided support which enabled Tracy Thresher, Larry Bissonnette, and their companions to travel to Boston to attend the “Wretches & Jabberers” screening where they participated in a Q&A with the audience.

REELABILITIES: Boston Disabilities Film Festival

Children’s Hospital Boston, Boston, MA

Principal Investigator: Isaac Kohane, MD, PhD

Delineating autism subtypes by phenotype-wide scan across genome-wide genotypes in a patient centric information commons

This grant is for a one-year study that would result in a phenome-wide scan across all genotypes measured by SNP array. This will likely generate novel insights about the substructure of the different autisms. The involvement of genetic factors in ASD is demonstrated. Several genome-wide association studies (GWAS) of common single nucleotide polymorphisms have been performed but the effect sizes remained modest. New approaches, with a better integration of phenotypes and genotypes, such as pathway and network analyses could help to unravel the genetic mechanisms of ASD.  Stessman et al. suggested a “genotype-first” approach. In this approach, the selection criterion is no more phenotypic but genotypic: the variants of an identified gene of interest. Then, systematic associations of phenotypes with the variants of this gene are assessed. This new approach could allow the discovery of new subtypes of ASD. This genotype-first approach is similar to another method described by Denny et al: Phenome-wide association studies (PheWAS). Dr. Kohane’s group demonstrated in a previous work on thiopurine methyl-transferase enzymatic activity in the field of thiopurine therapy that this method could help to describe new subgroups of patients with specific characteristics. The PheWAS approach might allow the linkage of genes variants to specific sub-phenotypes of ASD. Some of these subgroups could benefit of a specific therapy, given that an earlier treatment can improve the situation. This kind of study requires large amounts of genotypic and phenotypic data. Big cohorts of ASD patients and families exist. They gather genetic and phenotypic data from thousands of patients, representing a promising source of data. One of the issues preventing wide research programs over these cohorts is the heterogeneity of the assessment tools for ASD phenotyping. Dr. Kohane argues that integrating genotypic and phenotypic data these cohorts into a single patient centric information platform enabling the unification of the different sources of data would allow a more effective use of their data for research purposes. One of the challenges preventing an effective use of this knowledge gold mine is the fragmentation of the data. Indeed, it is difficult to analyze phenotypic data fragmented over several different tools, representing thousands of questions and answers that may or may not overlap between the tools. Dr. Kohane’s group thinks that the unification and the harmonization of all these phenotypic data into single concept based ontology might enable its effective use in research. Collecting phenotypic data is expensive and time consuming. Lots of phenotypic data are collected on a daily basis but are difficult to access for research purposes. Therefore, clinical data warehouses (CDW), like i2b2, were designed to enable second use of data collected for health care for research purposes. The Children’s Hospital Boston (CHB) is equipped with such CDW and a significant part of ASD children from SSC are also treated in this hospital. With this grant, Dr. Kohane’s group will integrate anonymized data from CHB CDW to SSC phenotypic data, augmenting the number of phenotypic data available for analyses by performing a phenotypic expansion.

Isaac Kohane

Massachusetts Advocates for Children, Boston, MA
2002, 2003, 2004, 2005, 2006, 2007, 2008, 2009, 2010, 2011, 2012, 2013, 2014

Establishment and Support of the Autism Special Education Legal Support Center

The goal of this project is to provide training, technical assistance, and advocacy services necessary to ensure that children with autism receive equal educational opportunities. Goals include: Providing parents with information about state-of-the-art services and programs available to meet individual needs of students with disabilities; Insuring that children with autism receive special education services necessary to reach their potential in areas impacted by their disability; Increasing public awareness and understanding of the potential and competency of individuals with autism, targeting policy makers, media, educators, service providers, as well as the general public. The Autism Special Education Legal Support Center will accomplish these goals by: providing community-based workshops for parents, educators, and medical professionals regarding legal rights and range of service options available for children with autism; providing a hotline to give legal and technical assistance to families of children with autism; training attorneys to increase representation of low-income students with autism to ensure that children receive legally mandated special education services; and providing information to the media, the legislature, and other policy makers regarding changes necessary to ensure children with autism receive services that reflect their potential.

Click here to read the NLMFF Interview with Massachusetts Advocates for Children

Massachusetts Advocates for Children

Massachusetts General Hospital, Boston, MA

Principal Investigator: Martha Herbert, MD, PhD

Magnetic Resonance Pilot Study of Brain Tissue Pathophysiology and Perfusion in Autism

This project addresses how we can learn about ways that several different aspects of the brain interact with each other, and how these interactions may be different in people with Autism Spectrum Conditions (ASCs) as compared with people who have had typical development (TDs). Specifically, the brain is both a physical organ with cells, blood flow, fluids and metabolic processes – and also an information-processing system that generates, relays and coordinates signals.

This study is designed to test whether there is a relationship between problems with the physical functions of the brain and problems with the signaling functions of the brain in ASCs. The reason Dr. Herbert’s team thinks that such a relationship exists is that the physical brain is responsible for generating the brain’s electrical signals, and if there are problems with the health of the brain tissue, this is likely to compromise the quality of the signals the brain is able to generate. There are ways of measuring each aspect of brain function in living individuals using non-invasive scanning methods, which do not require any injections and are not known to carry health risks. Dr. Herbert’s group can use the magnetic resonance (MR) scanner to measure the density of various chemicals in the brain, the quality and density of the fibers connecting the neurons, and the rate and intensity of blood flow.  They can use electroencephalography or magnetoencephalography to measure the intensity and patterns of signals in the brain. They will use several MR scanning techniques to measure physical properties of the brain including 31Phosphorus Spectroscopy, Proton (1H) Spectroscopy, Glutathione Spectroscopy, GABA Spectroscopy, and Arterial Spin Labeling.

All of the children in this study will be part of a study where their brain signaling is measured by MEG. Therefore Dr. Herbert’s group will be able to compare the brain tissue and brain chemistry measures from Magnetic Resonance scanning with the brain signaling measures from MEG. This study is the first time these various measures have been combined. If correct in their predictions, Dr. Herbert’s group will proceed with using this collection of measures to evaluate the impact upon the brain of treatments, particularly those that target either metabolism or electrical brain signaling. They may find stronger effects in some measures than others, and this will help them to sharpen the studies that follow this pilot study.

TRANSCEND Research Laboratory- Martha Herbert

Project Stretch, Natick, MA

Updating the “D-Termined Program of Repetitive Tasking and Familiarization in Dentistry”
Training Video

Principal Investigators: David Tesini, DMD and Carolyn Fetter, Specialized Care Co.

The D-Termined Program of Repetitive Tasking and Familiarization in Dentistry (DTP) is a training program for dentists, first published in 2004 with grant funding from the NLM Family Foundation. This grant is aimed at bringing this 8-year old training video and program material up to date. This unique program provides dental professionals with a dedicated approach to helping patients with autism to go beyond the strange noises, lights and odors of a dental office, to arrive at a point of accepting dental services with no special supports. This program is based on the philosophies and experiences of Dr. David Tesini in his private dental practice. Over a period of years, Dr. Tesini had worked with children with autism who exhibited unsafe behavior when a dental appointment was attempted. Dr. Tesini developed a system for gradually introducing these children to the expectations of a dental visit, such that after a period of time, a good percentage of the children were successfully treated in the normal dental office. These success stories were documented on video and became the basis for teaching others the techniques that he developed. Dr. Tesini’s approach was made into a DVD program for other dental professionals, and was also published on YouTube, with almost 71,000 hits. Based on the testimonials of academics and private practitioners, DTP has been successful in encouraging other dental professionals to open their practices to children with ASD.

David Tesini, DMD

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


Stony Brook University, Stony Brook, NY

Conversation on Autism & Sign Language Conference (CASL)

The inaugural C.A.S.L. is a unique event designed to encourage bold new ways of thinking about how the drive and capacity for communication emerges. By considering the nature of communication in communities of individuals with Autism and those who use Sign Language, C.A.S.L. aims to improve the quality of life and humanistic appreciation of individuals for whom social communication can sometimes be difficult. The insights that will emerge from this workshop are meant to aid in decreasing social challenges for these groups. C.A.S.L. will feature three groups of world-renowned researchers from around the country: a group of linguists who devote their careers to the study of sign languages; a group of researchers who study communicative abilities in autism; and a group of scholars who have begun to explore the connection between the two areas of research. In addition, the workshop will engage and include members of the community (from New York and beyond) who themselves identify as having autism. Students will also attend this conference, which will excite their interest in service-centered applied research and learning.

Stony Brook Social Competence & Treatment Lab

Tufts University, Medford, MA
2014- 2015

Principal Investigator: Theoharis Theoharides, MD, Ph.D., Sackler School for Graduate Biomedical Sciences, Tufts University

Predoctoral Fellowship – Theoharides Laboratory, Tufts University

This grant provides support for a predoctoral fellowship for a student in Theoharis Theoharides’ lab at Tufts University. Despite the rise in Autism Spectrum Disorders (ASD), characterized by social and stereotypic disabilities, there remains a lack of knowledge regarding disease causes or treatment. Mounting evidence supports the involvement of brain inflammation due to genetic, neurohormonal and environmental factors, as well as the role of immune dysfunction. The affected brain regions are rich in mast cells and microglia, the critical immune cells, which regulate neuronal function in the developing ASD brain. The kinase mammalian target of rapamycin (mTOR), which regulates immune cell proliferation and proinflammatory mediator expression, and the downstream cytoskeletal regulator of secretion, moesin, have recently been linked to ASD. High risk of some ASD subtypes is associated with gene mutations, which increase mTOR signaling and lower the brain moesin levels.

Dr. Theoharides’ laboratory cloned moesin protein and showed that a phosphorylation pattern was linked to inhibition of mast cells. They also reported increased serum levels of neurotensin (NT) in some ASD children, a peptide secreted from neurons and present in the gut and brain. They showed that corticotropin-releasing hormone (CRH) secreted under stress can stimulate human mast cells through a synergistic action with NT leading to proinflammatory mediator release.

Their hypothesis is that hyperactive mTOR and lack of regulation by moesin in mast cells and microglia is the missing link for gene-environmental factor interactions and brain inflammation in some ASD. Their studies will determine if mTOR and moesin regulate mast cell and microglial activation in response to NT and CRH. Their in vivo studies will determine the presence of brain inflammation in normal and moesin-deficient mice treated with NT and CRH, and the ASD-relevant concentrations of these triggers. Results will be essential to develop a unique ASD-like mouse model for behavioral studies, to identify molecular targets for inhibition of irregular immune cell responses and for effective ASD treatments.

Theoharides Laboratory


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