Basic Human Research

Autism Genetics

Site Principal Investigator: Dr. Sophie Molholm

Project PI: Daniel Geschwind, M.D., Ph.D., UCL


Autism is a common neurodevelopmental condition with largely unknown pathophysiology, but with a substantial genetic contribution. The investigators in this Autism Center of Excellence Network headed by Daniel Geschwind, M.D., Ph.D., at UCLA, are taking an important new direction to fill a critical gap in ASD research by recruiting subjects of self-reported African ancestry, a group not previously represented in ASD genetics research.

 

Under the leadership of Dr. Molholm, at the Einstein site we are recruiting participants and collecting genetic information to contribute to the first comprehensive assessment of the coding and non-coding genome via whole genome sequencing (WGS). This effort involves six research sites, and systematically investigates the genetics of ASD to identify rare single nucleotide variation (SNV), structural variation (SV), and common variation contributing to ASD susceptibility in this population. Diagnosis is delayed in Black and Hispanic individuals relative to Whites, and a critical part of this study is to understand the basis of this delay so that it can be remedied.  

 

So far our work on these health disparities confirms significant diagnostic delays despite well-articulated parental concerns. With these data we are working to improve early diagnosis, facilitated by the application of a novel heritable, quantitative biomarker, which we hypothesize will improve access to care.

 
 

SPARK for Autism

The number of children identified with autism has increased substantially over the last few decades and specific causes of autism are currently unknown for the majority of individuals with autism. Environmental factors and infections, especially during the prenatal period and infancy may play a role in some individuals. It is also possible that interactions between genes and exposures/environment cause autism in some individuals. Twin and family studies suggest a strong role for genetics, but the genetic architecture may be complex in many.

 

The purpose of SPARK (Simons Foundation Powering Autism Research for Knowledge) is to recruit, engage and retain a community of 50,000 individuals with autism along with their family members in the United States, to identify the causes of autism, accelerate clinical research by providing the autism research community with a genotyped cohort of consented participants, and establish a research cohort of individuals and families with autism.

 

Individuals and their families participate in SPARK by completing online registration and providing a genetic sample through saliva. The information provided by individuals and families affected by autism will power important research that advances the understanding of autism. The results of genetic testing are shared with families.

 
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Interventions for Autism

Principal Investigators: Dr. Maria Valicenti-Mcdermott & Dr. Lisa Shulman

Additional Investigators: Tammy Fried MSW & Risa Battino SLP

No cure exists for autism, and there is no one-size-fits-all treatment. The goal of treatment is to improve social communication and other language/learning impairments and to modify behaviors to optimize the child’s functioning and quality of life. This pilot study aims to evaluate a set of interventions for preschool and school aged children with Autism, who live in the Bronx including Social Cognitive/Skills Intervention using the Social Thinking methodology and Parent support groups to assist families with the stresses inherent in parenting a child with ASD.

 

This proposal includes direct services for patients with autism and intellectual disabilities, as well as a program for monitoring response to intervention and compliance. The goals of this study are to assess feasibility and acceptability of interventions to address social impairment and maladaptive behaviors in an ethnically and language diverse group, to examine the impact of these interventions on parental stress and to provide preliminary data of efficacy of these therapeutic interventions. Eligible children will participate in weekly interventions. Outcome assessments, which includes scales of social responsiveness and parental stress, occur at baseline, at 3 and 6 months of intervention.  

Predictive Processing in Autism

Principal Investigator: Dr. Sophie Molholm

Additional Investigators: Dr. Shlomit Beker (Research Fellow), Seydanur Tikir (Ph.D. Student)

 

In individuals with autism, reduced behavioral flexibility, insistence on sameness, and rigidity of routines are prevalent symptoms. In recent years, data from behavioral, physiological, and computational modeling suggest that children and adults with an autism are impaired in applying predictive information to generate expectations. However, which aspects of predictive processing are impaired is unclear.

We use non-invasive electrophysiological recordings, eye-tracking, computational modeling, as well as clinical & cognitive assessments on a cohort of higher functioning children, adolescents, and adults with autism and age- and IQ-matched controls. Our experiments are directed at answering the following questions about predictive processing in autism:

  • Can individuals with autism calibrate the confidence in predictions based on changes in environmental uncertainty?

  • Can they update their confidence to reflect changes in the environment?

  • Are these impairments reflected in specific neural signals that are thought to encode confidence and surprise?

  • Do individuals with autism have intact and flexible entrainment of ongoing oscillations to external stimuli, which is critical for preparing for upcoming temporally predictable events?

  • How well does the predictive processing operate under the highly relevant everyday circumstance? Are they able to apply temporal and contextual priors in the neural processing of continuous speech?

 

Investigating the link between sensory-motor processing and autism symptoms using Mobile Brain-Body Imaging (MoBI)

Principal Investigator: Dr. Pierfilippo De Sanctis

We use a novel Mobile Brain-Body Imaging (MoBI) technology to yield new insights into the central control of gross-motor behavior in children diagnosed with autism spectrum disorder. The MoBI system integrates electroencephalographic (EEG) brain activity recordings with simultaneously acquired 3D infrared camera images to monitor brain activity, gait pattern, and body posture with millisecond precision. We combine MoBI recordings with virtual reality, exposing individuals to optic flow by projecting a full-field visual display of white dots emanating outward from a central focus of expansion. This allows for systematic manipulation of visual and proprioceptive information essential to control and maintain good posture while walking or standing.

Our collaboration between the Cognitive Neurophysiology Laboratory and the Human Clinical Phenotyping Core further strengthens a partnership bringing translational research to bear on a comprehensively phenotyped sample of children with autism spectrum disorder, applying state-of-the-art technology to investigate sensory integration, balance, and gait impairments utilizing an approach with high ecological validity.

Advancing MoBI to investigate sensory and motor dysfunctions in autism has the potential to not only to provide new insight into brain functions underlying locomotion and balance issues, but also to elucidate sensory-motor contributions to repetitive behaviors and difficulties with social communication and interaction.

This project represents a first step in a research program aimed at the discovery of objective brain measures of sensory-motor dysfunction and the evaluation of these brain measures in relation to core symptoms of autism spectrum disorder to enhance diagnostic and therapeutic assessments. 

 
 

Multisensory Processing

Principal Investigator: Dr. Sophie Molholm

 

Children with autism exhibit alterations in multisensory processing, which may contribute to the prevalence of sensory reactivity and social deficits in this population. We are investigating the role that altered sensory processing and multisensory integration plays in the autism phenotype. 


Amelioration of multisensory deficits has been observed in teenagers with autism for complex, social speech stimuli; however, whether this recovery extends to more basic multisensory processing deficits remains unclear. In a cohort of 364 participants we recently showed that deficits in multisensory processing recover in autism by adulthood. Computational modelling indicated that multisensory processing transitions from a default state of competition to one of facilitation, and that this developmental transition is delayed in autism. 


In another project, we are investigating the neural basis of multisensory speech deficits in children with autism, and its recovery in adolescence. We record multi-channel EEG from children and teenagers with and without a diagnosis of autism whilst they are presented with videos of an actress reciting children’s stories in audio, video and audiovisual format. Background noise is presented at different levels to modulate the intelligibility of the different videos clips. Using a novel EEG analysis framework, we probe multisensory speech processing at the level of acoustics, phonemes and words/meaning. We aim to establish where and when multisensory integration breaks down in the speech processing hierarchy. 

 

Cerebellar hypoplasia & Saccade adaptation

 

Principal Investigator: Dr. Sophie Molholm, Dr. John Foxe & Dr. Edward Freedman from the University of Rochester

 

There is significant individual variation in the types and severity of symptoms in autism, and it is almost certain that there are multiple neurodevelopmental pathways to these varied clinical presentations.

In a subset of people with autism, midline posterior cerebellum is hypoplastic and Purkinje cell numbers are reduced compared to typically developing (TD) people. Degeneration or damage (or alteration via experimental intervention) of the posterior vermis significantly deteriorates visual orienting behaviors and adaptive plasticity in both human and non-human primates. Thus, differences in cerebellar vermis structure in autism could critically impact visuo-sensori-motor development in early infancy, which may in turn manifest as the visual orienting, communication and social interaction differences often seen in this population.

 

This project aims to distinguish a subpopulation of children with vermal hypoplasia, to establish whether this group manifests more severe deficits in visual orienting and in adaptation to persistent visual errors, and to establish whether this putative subphenotype of autism is associated with a specific and distinct clinical symptom profile. It makes use of eye-tracking, EEG, and structural MRI.​