Projects Aided by the HCP Current Projects PI: Sophie Molholm, Ph.D. Multisensory Processing and Integration in Autism Atypical integration of multisensory inputs has been suggested as a major component of autism, and indeed there is clinical and behavioral support for this view. Where and when in the neural processing stream sensory integration deficits occur is as yet unknown, and gaining an understanding of this will be essential in defining the neuropathology of autism. In fact, there is precious little understanding of the basic development of healthy sensory integration mechanisms in typically developing children, although recent work in animal models is beginning to shed some light. Under this project, we use established electrophysiological metrics of multisensory integration that we have developed in our laboratory in healthy adults, to test the hypothesis that multisensory integration is impaired in autism. The high-density electrical recordings of neural activity that we record provide a precise measure of when in the information processing stream sensory integration differs from typically developing matched controls, as well as a good model of the underlying brain processes that are affected. Specific hypotheses about when and where multisensory processes are affected in autism stem from the thesis that there is impoverished connectivity between distant cortical regions in this population. The data acquired under this project will provide a strong empirical test of deficits in multisensory integration processes in autism. Understanding how multisensory integration develops and changes over childhood will significantly inform models of multisensory integration, and provide an initial benchmark against which predictions about possible disordered multisensory integration in a host of developmental disorders can be made. Cognitive Neurophysiology Lab website Cognitive Neurophysiology Lab Facebook Page PI: John J. Foxe, Ph.D. and Sophie Molholm, Ph.D. Assistant Professor: Lars Ross, Ph.D Brain Imaging in Autism Spectrum Disorders This study consists of a variety of experiments that use different techniques to investigate the brain mechanisms underlying the behavior of individuals diagnosed with ASD. One prominent idea about the possible causes of ASD behavior is that some of the many different parts of the brain do not communicate with one another as they do in typically developing individuals. This brain abnormality may give rise to the difficulty of individuals with ASD to effectively integrate information from different senses. This important function called "multisensory integration" is essential for interpersonal communication and social behavior both well known to be impaired in ASD. We use advanced technology called Magnetic Resonance Imaging (or MRI) to assess the structure of the brain and how different parts of the brain are connected to one another. We also investigate the activity of the brain when engaged in a task requiring the integration of information from different senses. In an effort to understand the relationship between brain structure/function and behavior we relate our MRI data to those gathered in related experiments and neuropsychological assessments outside the scanner. In these experiments we engage our participants in different multisensory tasks. Finally, we collect genetic information from our participants to investigate a possible connection between genetic makeup, brain structure/function and behavior. Using this variety of technological and experimental approaches will provide a more comprehensive understanding on the brain mechanisms underlying ASD behavior and will therefore allow unique and new insights into the etiology of Autism which are particularly relevant for therapeutic intervention. Cognitive Neurophysiology Lab website Cognitive Neurophysiology Lab Facebook Page PI: Sophie Molholm, Ph.D. Autism Genetics Network, Phase II: Increasing Representation of Human Diversity Although Autism Spectrum Disorder (ASD) has a multifactorial etiology, it encompasses a large genetic component. We are part of a collaborative effort lead by Daniel Geschwind (at UCLA) to significantly advance understanding of ASD by identifying rare and common ASD susceptibility alleles, defining models of ASD genetic susceptibility, and providing evidence for convergent pathophysiology. With this project we aim to fill a significant gap in ASD research, by recruiting underserved subjects of self-reported African ancestry (African-American; AA), an important population that has not previously been well-represented in ASD genetics research. The Network involves six research sites including Einstein, and the AGRE DCC. We will enrich existing resources by recruiting at least 600 AA probands across sites and their biological parents. An embedded health disparities project seeks to evaluate access to care for AAs with ASD and clarify factors influencing participation of AA individuals in genetic research. The observation of new forms or different population frequencies of ASD-related variation in this sample as well as the sharing of most CNV and SNV with other cohorts are both outcomes that will have great significance for future studies and clinical care. The Network will make all phenotypic and genotype data accessible via the internet on a rolling basis, further enhancing the value of this resource to the community. Cognitive Neurophysiology Lab website Cognitive Neurophysiology Lab Facebook Page PI: John Foxe, Ph.D. and Sophie Molholm, Ph.D. Electrophysiological Assessment of Sensory Processing and Sensory Integration in Sensory Processing Disorder For most individuals sensory processing occurs automatically and is not disruptive to ongoing higher-order cognitive processing. For a small but significant subset of the population, however, sensory processing is disordered and obtrusive, disrupting normal cognitive-emotional functioning (e.g., Ben-Sasson, Carter, & Briggs-Gowan, 2009; Shalita, Vatine, & Parush, 2008). This current program of research is designed to test the hypothesis that the brains of children classified with a Sensory Processing Disorder (SPD) process sensory inputs differently. We use high-density electrophysiology to measure whether the SPD brain exhibits greater sensitivity to auditory and somatosensory stimulation, and correlate these brain responses with behavioral measures of sensitivity to auditory and somatosensory stimulation. Cognitive Neurophysiology Lab website Cognitive Neurophysiology Lab Facebook Page PI: Brett Abrahams, Ph.D. DNA Variation and Genetic Disorders Work in Dr. Brett Abraham's lab employs a blend of molecular genetics and developmental neurobiology to identify novel genes that may influence risk of autism and to understand how those genes function. Although some autism-related genes have already been identified, none show a specific relationship to the clinical diagnosis of autism. Instead, they appear to contribute to a range of related neurodevelopmental disorders, such as: intellectual disability, language impairment, schizophrenia, bipolar disorder and epilepsy. We hope to enroll subjects who are on the autism spectrum and/or have other disorders of cognition, as well as healthy subjects without any cognitive disorders. Characterization of genetic differences between individuals will allow us to uncover factors that may contribute to autism spectrum disorders and related disorders of cognition. Abrahams Lab webpage PI: Pierfilippo De Sanctis, Ph.D Predoctoral Fellow: Brenda Malcolm, Ph.D. Student Aging Study A general decline in executive control mechanisms is a common, and to a certain degree, a reluctantly accepted aspect of normal aging. Of course, there is great variance in the extent of this decline, ranging from severe debilitating in some adults, to the more acceptable mild-to-moderate decline that is the hallmark of a much larger cohort. Whereas these more subtle deficits may not be life-threatening, they nonetheless cause real distress and negatively impact general quality-of-life and sense of well-being. Yet, there are also those elderly individuals that we all encounter, who somehow manage to retain and perhaps even improve their mental “sharpness” and flexibility over their later years. What makes these individuals special? Are there fundamental neuroprotective aspects of their biological makeup? Do they by some means escape the structural changes in frontal cortex that seem to be a factor in the decline of executive functioning with? Recent work suggests that this is not the basis for their success; rather, one fundamental way in which these individuals stave off the negative effects of cognitive aging is by recruiting and reconfiguring executive control processes in the frontal lobes. We found clear functional evidence for additional recruitment of frontal circuits and that activity in these regions is often considerably amplified relative to that seen in healthy young adults during standard executive tasks. That there appears to be the possibility for large-scale functional plasticity during later life is surely encouraging. If it were simply the case that these adults were not as susceptible to basic structural changes, then the options for intervention in those who are susceptible might be relatively more limited. However, if cognitive strategies and neural network reconfigurations can compensate for basic structural decline, then the picture becomes more hopeful, for if we can understand these reconfigurations and perhaps the strategies that allow for them, we can potentially teach them to those who have not managed to learn them independently. Our goal is to build basic understanding of the cognitive processes and neural underpinnings that protect these high performing elderly, and also to understand what occurs in the average to low performing elderly who fail to maintain optimal performance. Cognitive Neurophysiology Lab website Cognitive Neurophysiology Lab Facebook Page PI: Pierfilippo De Sanctis, Ph.D Predoctoral Fellow: Brenda Malcolm, Ph.D. Student MS Study How do individuals with mobility limitations leverage their cognitive resources to most effectively organize their behavior as they ambulate through a complex and ever-changing environment? This question captures a central issue faced by individuals with neurologic diseases such as multiple sclerosis (MS). Most everyday activities relay on concurrent and integrated processing of sensory, cognitive, and motor information. Individuals with MS often present with impairments in all three domains, making it particularly challenging for patients to go about their daily living. Walking in the real world is a rather complex behavior, requiring attention to various environmental features and recovery from postural perturbations to avoid stumbles or falls. Often individuals are engaged in a secondary task which also demands attention while walking (e.g. walking while talking or texting), further burdening the limited cortical resources required for safe locomotion. Little is known about brain functions underlying our ability to divide attention while walking, largely due to difficulties to observe brain processes during ambulation. Our goal is to address this knowledge gap, using a newly developed Mobile Brain-Body Imaging (MOBI) system that integrates electroencephalographic (EEG) brain activity recordings with simultaneously acquired foot-force sensor data and 3D infrared camera images to monitor brain activity, gait pattern, and body posture while participants walk on a treadmill. We will test the hypothesis that mobility issues in multiple sclerosis are associated with a specific deficit in the flexible reallocation of attentional resources across sensory, cognitive, and motor processes during walking. The successful completion of this research represents a first step in addressing a little understood question about the cortical contribution to mobility issues in MS. Advancing our understanding in this area might lead to the discovery of objective brain measures to enhance diagnostic and therapeutic assessments of multiple sclerosis. The ultimate goal of this research effort will be to help improve mobility and quality of life in MS patients. Cognitive Neurophysiology Lab website Cognitive Neurophysiology Lab Facebook Page PI: Anne Murphy, Ph.D Co-investigators: Pierfilippo De Sanctis, Ph.D Exploring brain responses to affective images in mothers with high or low Adverse Childhood Experiences (ACEs) A history of childhood maltreatment and low parental protection increases individuals’ risk for future physical and mental health problems. In fact, childhood experience of four or more adverse childhood experiences (ACEs) is linked to impaired affective and social functioning. Little is known about the impact of ACEs on the neural processing of emotional information. This projects goal is to investigate whether individuals with high ACE scores show impaired processing of emotionally valenced stimuli relative to individuals with low ACE scores. Using high-density electrophysiology and functional neuroimaging, the neurodynamics of processing of emotionally valenced versus neutral images will be compared between the two groups. It is predicted that emotional processing will be impaired in individuals who have high levels of adverse childhood experiences. PI: Sophie Molholm, Ph.D and Roseann C. Schaaf, Ph.D, OTR/L, FAOTA Co-investigators: John Foxe, Ph.D Sensory Integration Therapy in Autism: Mechanisms and Effectiveness Autism Spectrum Disorders (ASD) affect 1 in 68 children and frequently result in impairments in the functional skills necessary for independent living. It has been shown that 45-90% of persons diagnosed with ASD experience sensory issues (ASD+SI), including difficulty with sensory processing and integration. This can largely impact functional skills, and interventions for sensory issues are the most highly requested by parents. In this randomized controlled study, we will compare Sensory Integration Therapy (SIT) to focused behavioral interventions on the improvement of functional skills for children with ASD+SI between the ages of 6 and 8.5. Participants will be evaluated to determine whether cognitive level, severity of autism and/or sensory issues moderate intervention outcomes. We predict that children who receive SIT will show greater improvement in functional skills and greater decreases in maladaptive behaviors, especially those with higher IQ and more severe autism and sensory symptoms. We will also assess whether the treatments will have differential effects on sensory processing and integration using electrophysiological recordings to monitor brain activity. We hypothesize that children in the SIT treatment group will have increased performance on a multisensory task and greater differences in brain activity pre and post SIT. PI: Joan W. Berman, Ph.D and Kami Kim, M.D. Co-investigators: Sophie Molhom, Ph.D, Juliana Bates, Ph.D, and Michael Rosenberg, M.D. Is increased surface CCR2 on mature monocytes from perinatally HIV infected and perinatally HIV exposed children a biomarker of neurocognitive impairment? An estimated 40-70% of adults infected with HIV experience HIV associated neurocognitive disorders (HAND). Previous studies have identified a mature CD14+CD16+ monocyte subset that is highly susceptible to HIV infection and has been implicated in the development of HAND. Most research examines this CNS disease in infected adults, but fails to address the 3.5 million children worldwide that have been infected with HIV and are at risk for HAND. This pilot study examines the cognitive status of perinatally HIV-infected and HIV-exposed but uninfected (HEU) children, as well as the percentage of CD14+CD16+ monocytes in their blood and of a specific surface protein, the chemokine receptor CCR2, on this monocyte subset. We hypothesize that fewer HEU adolescents will have cognitive impairment, and that increased numbers of CD14+CD16+ monocytes and/or high CCR2 surface expression on these cells will correlate with cognitive deficits in HIV infected children. Complete Projects PI: John Foxe, Ph.D. and Alexandra Djuick, Ph.D. Postdoctoral Fellow: Hans-Peter Frey, Ph.D. Neurophysiology of Receptive Speech in Rett Syndrome Rett Syndrome, a neuro-developmental disorder that affects about 1 in 10,000 females, is characterized by a regressive loss of acquired spoken language and motor capabilities during the first two years of life. In patients who do not produce speech and lack motor abilities to respond to spoken words in a controlled manner, it is all too common to assume a more general lack of speech capabilities. However, recent evidence suggests that this is likely not a valid assumption for patients with Rett syndrome. There are now several anecdotal reports indicating altogether greater receptive language processing skills in RETT children. This project therefore aims at developing widely applicable quantitative tests of the most important aspects of receptive speech processing using objective neurophysiological methods. The goal is to determine just how intact the receptive speech system is in RETT, with important implications for the development of assistive communication devices for these oft-neglected children. PI: John Greally, Ph.D. Predoctoral Fellow: Esther Berko, MD/Ph.D. Student Advanced Parental Age and Autism: The role of aneuploidy and uniparental disomy in ASD pathogenesis Numerous studies have demonstrated that rates of autism spectrum disorders (ASDs) rise with older ages of the parents. Researchers are currently investigating the ways an aging paternal germline can contribute to Autism Spectrum Disorders (ASDs), namely through increased rates of mutation of the DNA sequence. Although the effects of paternal age, namely higher rates of mutation and copy number variation in offspring, have indeed been linked to ASDs, no study has determined the potential role of maternal age. We propose that maternal nondisjunction and resulting aneuploidy could cause ASDs and remain undetected. Since most aneuploidies are lethal embryonically, surviving offspring often undergo a "rescue" event that restores normal chromosome number. Depending on when an aneuploidy rescue occurs and which chromosome is lost, offspring exhibit either covert mosaic aneuploidy in sub-populations of cells or heterodisomic uniparental disomy (UPD). These defects have been implicated in other genetic disorders and may contribute to the molecular basis of ASDs, but are, surprisingly, unlikely to have been detected by current approaches that utilize cultured blood, a tissue that demonstrates low or absent levels of aneuploidy in mosaic individuals. In this study, we will perform comprehensive analysis of the genomes of children with ASD born to parents of advanced age, employing DNA isolated from buccal epithelium. By comparing children's genotypes with their parents and applying computational analysis on SNP array signal intensities, this study has the potential to identify the prevalence of covert mosaicism and heterodisomic UPD in children with ASDs. Greally Lab website More information on this project
