Cognitive Development

A phase III, randomized, double-blind, placebo-controlled, efficacy and safety study of balovaptan in adults with autism spectrum disorder with a 2-year open-label extension

Principal Investigator:

Suma Jacob, MD, PhD (Department of Psychiatry)

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Abstract:

To date, few studies have investigated the effect of pharmacological treatments on the social and communication deficits in ASD, and no agent has received marketing approval for treating these core symptoms. Currently in the US, the only two approved medications for ASD are the atypical antipsychotics risperidone and aripiprazole, which only target irritability associated with ASD, but not core symptoms. In sum, there is no pharmacological treatment available for the social and communication deficits in individuals with ASD, and as a consequence there is a high unmet medical need for effective pharmacological therapies in the treatment of core symptoms in ASD.

The V1a receptor has been shown to modulate key social behaviors in both human and animal studies. Chronic administration of RO5285119 has been shown to normalize the social behavior and cognitive impairments induced in rats by prenatal valproate (VPA) exposure, an animal model that reflects some of the behavioral changes seen in ASD patients. Also, in the CNTNAP2 KO genetic mouse model of autism, V1a antagonism has been shown to rescue social impairment and repetitive behavior. A V1a antagonist may provide a novel and first approach to treat the core social and communication deficits in ASD.

An open-label, single-arm, multicenter study of intracerebral administration of adeno-associated viral vectors serotype rh10 carrying the human N-sulfoglucosamine sulfohydrolase (SGSH) cDNA for the treatment of mucopolysaccharidosis type IIIA

Principal Investigator:

Julie Eisengart, PhD, LP (Department of Pediatrics)

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Collaborators:

Chester B. Whitley PhD, MD (Department of Pediatrics), Amy Esler, PhD (Department of Pediatrics)

Abstract:

Mucopolysaccharidosis IIIA (MPS IIIA), also known as Sanfilippo Syndrome Type A, is a rare pediatric disease that is a uniformly fatal childhood disease. This autosomal recessive lysosomal storage disease is caused by a missing or dysfunctional catabolic protein, leading to the subsequent accumulation of substrates in the cell, resulting in very severe cellular and organ dysfunctions, particularly prominent in the central nervous system. Severe behavior dysregulation, sleep disturbance, and cognitive decline are the phenotypic hallmarks of MPS IIIA.

MPS IIIA has an incidence of 0.44-1.16 per 100,000 births and is caused by autosomal recessive genetic defects of the N-sulfoglucosamine sulfohydrolase (SGSH) gene localized to 17q25.3. SGSH is a secreted enzyme involved in the stepwise degradation of heparan sulfate (HS). A  deficiency in SGSH leads to an accumulation of HS in cells and affects cellular functioning  including lysosomal clearance. Currently, there ae no disease-modifying treatment(s) available or MPS IIIA.

The treatment proposed here, using Lysogene's in-vivo gene therapy LYS-SAF302 product (adeno-associated viral vector serotype rh.10 canying the human N-sulfoglucosamine sulfohydrolase cDNA)  consists of an intracerebral multi-injection site administration performed in a single operation.  It is hoped that treated patients would maintain existing cognitive and neurodevelopmental capabilities and possibly would acquire new skills.

Autobiographical Memory and Social Problem Solving in Children and Adolescents

Principal Investigator:

Kathleen Thomas, PhD (Institute of Child Development)

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Collaborators:

Evren Guler, PhD (Augsburg University)

Abstract:

The ability to remember our personal past (autobiographical memory) is fundamental to our sense of self, our personality, as well as daily functioning in the world. Autobiographical memory is thought to serve multiple functions, one of which is planning for future behaviors and directing future goals. For instance, the ability to solve a current problem will likely be enhanced if one can recall a specific past event that is relevant to the current situation. Several studies have shown that autobiographical memory specificity predicts social problem solving in adults. To date, no studies have addressed whether individual differences in autobiographical memory recall relate to variation in problem-solving in childhood and adolescence. Given that both autobiographical memory specificity and problem solving improve with age, it is important to examine whether these two constructs are related in children and adolescents ages 8-17 years. 

Choline supplementation as a neurodevelopmental intervention in fetal alcohol spectrum disorders

Principal Investigator:

Jeffrey R. Wozniak, Ph.D., L.P. (Department of Psychiatry)

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Collaborators:

Michael K. Georgieff, M.D. (Department of Pediatrics), Stephanie Carlson, Ph.D. (Institute of Child Development)

Abstract:

Recent data indicate that 2-5% of the U.S. population has Fetal Alcohol Spectrum Disorder (FASD) – a set of physical anomalies and neurodevelopmental deficits caused by prenatal alcohol exposure (May, Fiorentino et al. 2011). Despite the profound public health burden posed by FASD, there have been very few treatment studies of any sort in this population and no clinical trials that have attempted to directly address the neurodevelopmental deficits that are so debilitating for these individuals. There is, however, a promising line of translational research that suggests a potential role for micronutrient interventions. At the top of the list is choline, an essential nutrient for humans that is critical for normal brain development during gestation and early childhood. Although the human body produces choline, the demand cannot be met entirely endogenously and thus, some choline must be consumed in food. Extensive pre-clinical work has provided evidence that choline supplementation is effective in attenuating the neurodevelopmental deficits caused by prenatal alcohol exposure in animal models (Thomas, Biane et al. 2007, Ryan, Williams et al. 2008). Our group has taken the initial steps toward translating this work to humans. We first conducted a two-year pilot study to ensure the feasibility, tolerability, and safety of choline supplementation in 20 children with FASD (Wozniak, Fuglestad et al. 2013). Next, we completed a three-year pilot study of 40 additional children with the goals of establishing a target dosage for young children and testing efficacy in the domain of memory (Wozniak, Fuglestad et al. under review). Together, data from these two studies demonstrate that choline supplementation in 2-3 year old children with FASD improves explicit memory – a core function that is essential for normal cognitive development. Based on the time periods in which choline is effective in pre-clinical models of FASD and on the fact that the first years of human life represent a period of intense brain development, choline supplementation in young children appears to have significant potential as an intervention for neurodevelopmental disorders including FASD.

Dyadic coordination of self-regulation and social engagement in infants and caregivers

Principal Investigator:

Daniel Berry, PhD (Institute of Child Development)

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Collaborators:

Isabella Stallworthy, doctoral candidate (Institute of Child Development)

Abstract:

The ability to contingently and dynamically engage with others is critical for human functioning throughout life. In the first year, infants’ abilities evolve from simple social orienting to engaging in complex social interactions. This progression is foundational for their emerging social, self-regulatory, and learning abilities, and is driven in part by the developmental interplay of sensitive caregiving and infants’ nascent physiological reactivity systems. In infancy, when cortical control of behavior is immature, parasympathetic control of the heart is critical for infants’ abilities to regulate their internal states and engage with others (Bazhenova & Porges, 1997). Respiratory sinus arrhythmia (RSA), a measure of heart rate variability, indexes parasympathetic control of cardiac activity by the vagus nerve.

This study aims to examine: (1) how real-time changes in infants’ RSA relate to changes in infants’ social visual attention during a) social interaction and b) a naturalistic disruption to the interaction; (2) the extent to which infants’ social visual attention and RSA are coupled in time and relate to affect, within each infant; (3) how caregivers’ RSA coordinates with infants’ RSA; as well as (4) developmental changes in these associations over the first year of life.

Family Matters

Principal Investigator:

Alicia Kunin-Batson, PdD, LP (Department of Pediatrics), Mike Troy, PhD, LP (Children's MN - Behavioral Health)

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Collaborators:

Jerica Berge, PhD, MPH, LMFT, CRLE (Family Medicine and Community Health), Rachel Hardemann, PhD, MPH (Health Policy and Management)

Abstract:

The experience of discrimination and harassment due to race/ethnicity is a common and significant problem, with past studies suggesting 40-70% of people of color report such experiences. Evidence is accumulating that racism is a cause of health disparities and poor health outcomes in the United States. Most previous studies have focused on the direct experience of racism at the level of the individual and associations with adult health (e.g., hypertension, all-cause mortality).  However, research also suggests that racism-related stress can also be experienced indirectly, through exposure to the prejudice and discrimination experienced by others (e.g., parent to child) and the persistence of social structures which maintain racial discrimination by fostering inequitable systems (e.g., housing, employment). Few studies have examined the impact of parent-reported discrimination and harassment on children’s health and development and even fewer of these have included measures of exposure to structural racism at the community level.

There is an urgent need to learn more about avenues to disrupt the relationship between racism-related stressors and poor health outcomes. This is particularly true in the context of the current sociopolitical climate which many have argued has created a less accepting environment for immigrants and people of color, contributing to further discrimination and harassment and compounding structural inequality already present in many social systems. Drawing from previous empirical and conceptual studies, we propose that racism-related stressors will be related to important health, mental health, and cognitive developmental outcomes, and that children’s HPA-axis regulation is impacted through exposure to racism-related stress and associated with children’s health and wellness. Parenting behaviors and skills may also be impacted by exposure to racism-related stressors and provide potentially malleable intervention targets to impact children’s stress physiology as well as children’s health and development.

Mapping the Human Connectome During Typical Development

Principal Investigator:

Kathleen Thomas, PhD (Institute of Child Development), Essa Yacoub, PhD (Center for Magnetic Resonance Imaging)

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Abstract:

The major technological and analytical advances in adult human brain imaging achieved as part of the Human Connectome Projects (HCP) have allowed unprecedented examination of structural and functional brain connectivity at previously impossible levels of spatial and temporal resolution. While this information has proven crucial to our understanding of normative variation in adult brain connectivity, little is known about the developmental processes through which this variation arises. In this project, we apply the tools and analytical approaches developed by the HCP to understand how structural and functional wiring of the brain develops. This work is conducted through a consortium of five sites (Harvard University, University of California at Los Angeles, University of Minnesota, University of Oxford, Washington University in St. Louis), with extensive complimentary expertise in human brain imaging and neural development and including many of the investigators from the original adult and pilot lifespan HCPs. This group will acquire, analyze, and publicly share approximately 1500 high quality neuroimaging and associated behavioral datasets on healthy children and adolescents from 5–21 years of age. This unique protocol is designed to provide rich, multimodal data on several biological and cognitive constructs that are of critical importance to health and well-being across this age range and allow a wide range of investigators in the community to test a host of crucial hypotheses about brain development and connectivity.

Microstructural and functional MRI signatures of brain alterations in patients with mucopolysaccharidosis

Principal Investigator:

Igor Nestrasil, MD, PhD (Department of Pediatrics)

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Collaborators:

Julie Eisengart, Phd, LP (Department of Pediatrics)

Abstract:

We intend to employ a non-invasive technique using brain magnetic resonance imaging (MRI) along with analysis of microstructural and functional MRI signatures of these regions to measure and determine the alterations and their impact on clinical variability in mucopolysaccharidosis (MPS) patients. The study aims to identify the neuronal and functional signatures in MPS patients who have been scanned longitudinally. To accomplish this aim, we have established MRI parameters for detection of abnormalities in myelin content, microstructural integrity, and functional connectivity in the brain of MPS patients. The study also aims to determine the role of myelin abnormalities in cognitive deterioration in MPS subjects by relating comprehensive neurocognitive assessments to their respective MRI outcomes.

Modes of Cognition and Arousal

Principal Investigator:

Daniel Berry, PhD (Institute of Child Development)

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Developing the ability to regulate one’s thoughts and attention—or ‘executive functioning’ (EF)—is a central developmental milestone of early childhood. The benefits of EF development are well known.  These abilities support children’s burgeoning academic and social skills and successful transition to formal schooling. As such, there is a reasonable tendency to equate stronger EF as being 'better’ for learning. 

Notably, Life History models highlight the idea that many complex developmental phenomena are often more about adaptive trade-offs than they are about clear-cut deficits. From this perspective, ‘better’ learning is reframed as a relative question: ‘better,' to what end? For example, we know that EF deficits can undermine learning that requires organizing and integrating new and existing information —skills that are quite useful in stable, predictable contexts. Yet, there is increasing reason to suspect that such top-down control may also bias thinking toward known heuristics and, thus, away from richer sets of cognitive alternatives. As such, EF may provide an incredibly useful tool for efficiently building upon what we know, yet come at the cost of increasing inflexibility in our receptiveness to novel information and alternative ways of thinking. This latter 'cognitive receptiveness' is fundamental to inductive reasoning, creative thinking, and implicit/conventional learning—abilities that that are quite adaptive in unpredictable environments that require rapid, qualitative shifts in thinking.

 Collectively, the aim of this study is to begin to test the trade-offs of EF in the context of different types of cognitive tasks.

Quantifying eye tracking and EEG metrics of social perception during infancy

Principal Investigator:

Charisse Pickron, PhD (Institute of Child Development)

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Collaborators:

Jed Elison, PhD (Institute of Child Development)

Abstract:

The healthy development of key neurocognitive functions, such as face recognition and social cognitive function, is essential for learning to navigate one’s environment. Individual differences in these functions predict important developmental outcomes including successful social communication skills, school readiness, and interpersonal relationships. Several recent investigations have focused on understanding how early perceptual experience influences the behavioral and neural specificity of face processing during the first year of life. Research in this area has revealed several perceptual biases arising within the first year of life, including the other-race effect. These findings indicate that infants’ ability to readily differentiate among face identities is narrowed to the race and gender groups that they have the most experience with.

This indicates that being able to attend to and possibly learn from faces is influenced by familiarity with facial features such as race and gender. Attentional biases for social information may be relevant to these changes in face processing capabilities. The ability to characterize the microarchitecture of looking patterns and neural activity responses during passive viewing of social and non-social stimuli has markedly advanced the study of infant cognition and social cognition.

To date, very few studies have recorded electrical brain activity while simultaneously recording looking patterns in developmental populations. Thus more research is needed to better characterize the relation between looking patterns and electrical responses measured from the brain. Together these methods will provide clearer characterization of changes in infants’ attentional and perceptual capabilities during the first years of life. Additionally, the current project will provide evidence for potential underlying neural and attentional mechanisms which drive changes in social information processing during the first year of life.