Cognitive Development

A longitudinal study examining three RDoC constructs in adolescents with non-suicidal self-injury

Principal Investigator:

Kathryn Cullen, MD (Department of Psychiatry)

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Collaborators:

Bonnie Klimes-Dougan, PhD (Department of Psychology), Kelvin Lim, MD (Department of Psychiatry), Karina Quevedo, PhD (Department of Psychiatry), Katie Thomas, PhD (Institute of Child Development)

Abstract:

Non-Suicidal Self Injury (NSSI) is a common clinical problem that cuts across many different psychiatric diagnoses, leads to severe negative outcomes, and has limited treatment options. Advancement of new interventions for NSSI is hindered by a lack of knowledge about its neural mechanisms. NSSI usually emerges during adolescence, a time period notable for significant developmental changes in brain and behavior. Characterizing the developmental trajectories of key aberrant neural systems would enhance our understanding of the pathophysiology of NSSI. The current study will be instrumental in guiding foundational knowledge necessary for creating targeted early interventions for adolescents with NSSI that are designed to promote healthy neurodevelopment.

A phase I, multicenter, open-label, single-dose, dose ranging study to assess the safety and tolerability of SB-318, a rAAV2/6-based gene transfer in subjects with mucopolysaccharidosis I (MPS I)

Principal Investigator:

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

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Collaborators:

Julie Eisengart, PhD (Department of Pediatrics), Bradley S. Miller PhD, MD (Department of Pediatrics)

Abstract:

Current therapies for MPS I include hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT). HSCT can prevent or reverse most clinical features, and is recommended for those with the severe form of the disease (Hurler syndrome [MPS IH]). However, the reported mortality rate after HSCT is 15%, and the survival rate with successful engraftment is 56%. Patients with the attenuated forms of the disease (Hurler-Scheie syndrome [MPS IHS], Scheie syndrome [MPS IS]) are treated with ERT using laronidase (recombinant human α-L-iduronidase; Aldurazyme). Laronidase has been shown to improve pulmonary function, hepatosplenomegaly, and exercise capacity. However limitations of ERT include the need for life-long treatment; development of neutralizing antibodies; inability to cross the blood brain barrier; continued cardiac, orthopedic, and ocular complications; and the inconvenience of weekly intravenous (IV) infusions.

The current proposed study uses ZFN gene-specific targeted insertion of a/6 hIDUA transgene into the liver albumin genome locus to provide long-term production of hIDUA in patients with the attenuated forms of MPS I.The objective and rationale for the proposed SB-318 investigational therapy is to remove or decrease the need for enzyme replacement therapy by in vivo genome editing.

A phase II multi-center, randomized, doubleblind, 24-week, 3-ARM, parallel group, placebo-controlled study to investigate the efficacy and safety of RO5285119 in children and adolescents Age 5-17 with autism spectrum disorder (ASD)

Principal Investigator:

Suma Jacob, MD, PhD (Department of Psychiatry)

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Collaborators:

Bradley Miller, MD, PhD (Department of Pediatrics), Rebekah Hudock, PhD (Department of Pediatrics)

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 summary, 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. In conclusion, a V1a antagonist may provide a novel and first approach to treat the core social and communication deficits in ASD.

Event-related potentials for early detection of the cerebral form of X-linked adrenoleukodystrophy: a feasibility study

Principal Investigator:

Rene Pierpont, Ph.D., L.P. (Department of Pediatrics)

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Collaborators:

Julie Eisengart, Ph.D. (Department of Pediatrics), Weston Miller, MD (Department of Pediatrics), Paul Orchard, MD (Department of Pediatrics), Michael Georgieff, MD (Department of Pediatrics)

Abstract:

Adrenoleukodystrophy (ALD) is a devastating childhood neurodegenerative disease for which the onset of central nervous system (CNS) involvement is unpredictable, although previous research has shown that thirty-five percent of affected boys develop clinically evident cerebral involvement (cALD) between 4-10 years of age (1). The disease is characterized by progressive cerebral demyelination and inflammation. Devastating neurological and cognitive decline is associated with cALD, with death occurring a few years following the onset of clinically-evident disease.  Patients with cALD have a fairly predictable, consistent pattern of white matter disease progression.  Previous studies in other at-risk populations have demonstrated the ability of scalp-recorded event-related potentials (ERPs) to detect brain functional abnormalities prior to the onset of behavioral symptomatology. Early detection of the cerebral form of ALD would revolutionize treatment outcomes for patients with this condition. Given the fairly consistent pattern of cerebral disease progression within white matter tracts, and the fact that latency of ERP components are sensitive to changes in myelination and synaptic efficiency, we hypothesize that ERPs may enable more reliable prediction of disease onset than traditional behavioral measures, for which performance may be vulnerable to non-disease influences such as fatigue or anxiety.

Impact of the intestinal microbiome on infant neurodevelopment

Principal Investigator:

Ellen Demerath, Ph.D. (Department of Epidemiology and Community Health)

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Collaborators:
Abstract:

Today the majority of pregnant women in the United States are either overweight or obese at conception with their offspring having greater adiposity at birth, a 2-fold greater risk of later obesity, and neonatal insulin resistance.  Animal models indicate that maternal obesity may have deleterious effects on brain development in offspring. Preliminary data from our laboratory suggest that infants born to mothers with high pre-gravid BMI have altered cognitive processing of visual and audio stimuli compared to infants born to mothers with normal BMIs. Maternal obesity can also cause changes in the intestinal microbiome of offspring, both pre- and postnatally.  Intestinal microbial communities are thought to affect the development immunity, metabolism, and brain function, with effects that extend across an individual’s lifespan. Our main objective is to determine how variations in microbiome signatures early in life correlate with variations in hippocampal development as indexed by ERPs. The specific aims are to 1) Examine the variation in the infant biome at one month and six months of age; and 2) Determine whether these variations are associated with poorer hippocampal-based electrophysiology outcomes and behavior, and slower myelination-dependent speed of processing not only at in the neonatal period but six months later as well.

Long-term follow-up of term survivors of hypoxic-ischemic encephalopathy: an evaluation of brain function and structure

Principal Investigator:

Katie Pfister, MD (Pediatrics, Division of Neonatology)

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Collaborators:

Elizabeth Zorn, MD (Pediatrics: Division of Neonatology), Christopher Boys, PhD, LP (Department of Pediatrics), Katie Thomas, PhD (Institute of Child Development)

Abstract:

A prospective observational cohort study design will be used to determine whether survivors of HIE who were treated with therapeutic hypothermia have deficits in memory or executive function at age 4-5 years, and whether there are observable changes in brain structure or connectivity. MRI with diffusion tensor imaging will be used to assess brain volumes, structure, and white matter connectivity. Behavioral assessments (WPPSI-IV and NEPSY-II) and parental questionnaires (BRIEF-P) will be used to assess overall intellectual function, executive function, and memory.

Longitudinal assessment of asymptomatic congenital CMV infection in Minnesota infants identified by universal screening: what is risk of sequelae?

Principal Investigator:

Mark Schleiss, MD (Department of Pediatrics)

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Collaborators:

Jed Elison, PhD (Institute of Child Development), Igor Nestrasil, MD, PhD (Department of Pediatrics), Erin Osterholm, MD (Department of Pediatrics)

Abstract:

Symptomatic congenital CMV (cCMV) infections are commonly encountered in clinical practice, affecting approximately 0.65% of all newborns. Such infections - in symptomatic newborns - carry a substantial risk for long-term neurodevelopmental sequelae including developmental delay, mental retardation, seizure disorders, cerebral palsy, and sensorineural hearing loss. Nucleoside antiviral therapy is associated with only modest improvements in audiological and neurodevelopmental outcomes. It is much less clear how to manage infants identified with asymptomatic cCMV infection. These infants have in the past essentially escaped clinical recognition, precisely because these children are asymptomatic at birth, and there is no universal newborn cCMV screen. However, the landscape of cCMV screening is rapidly evolving, and there is increasing interest in implementation of universal cCMV screening programs.  In spite of recent progress, universal newborn screening for congenital CMV in many ways remains an area of scientific uncertainty. The optimal screening methodology remains uncertain. We don’t know if asymptomatic infants should undergo full laboratory and neuroimaging evaluations, or whether treatment of infants with asymptomatic congenital CMV with antivirals should be considered. Our proposal will conduct neurocognitive and neuroimaging studies in asymptomatic infants identified with congenital CMV infection in the context of a universal screening program to address these important areas of knowledge deficit. 

NET-Works 2 at the U

Principal Investigator:

Alicia Kunin-Batson, PhD, LP (Department of Pediatrics)

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Collaborators:

Lauren Crain, PhD (Health Partners Institute), Simone French, PhD (School of Public Health), Megan Gunner, PhD (Institute of Child Development), Aaron Kelly, PhD (Department of Pediatrics), Elyse Kharbanda, MD, MPH (Health Partners Institute), Nancy Sherwood, PhD (School of Public Health)

Abstract:

Heart disease accounts for 1 in 4 deaths in the US with obesity as a leading risk factor. While prior studies have linked early environmental stressors such as socioeconomic disadvantage to childhood obesity and later cardiovascular disease risk some youth will be resilient and will not develop disease despite risk exposure. Developing optimal interventions requires understanding the protective factors that foster resilience, the pathways through which early environmental stressors contribute to emerging dysregulation in cardiometabolic processes, and the timing during childhood when impacts are observed. There is a significant gap in our knowledge; specifically, a relative dearth of information on the pathways, timing, and risk and protective factors that translate early environmental stressors into emerging cardiometabolic risk during childhood. Prior studies have been hampered by limited assessment of environmental stressors, lack of assessment of biologically plausible pathways (e.g., activity of the hypothalamic-pituitary-adrenocortical (HPA) axis) and a lack of use of sufficiently sensitive measures to detect important cardiometabolic domains in childhood. Most importantly, prior studies have not rigorously examined parenting and child behavioral factors as moderators of the relationship between psychosocial stressors and cardiometabolic risk and resilience. Identification of these potentially modifiable protective factors is crucial for optimizing interventions to prevent the development of cardiovascular and metabolic diseases. The NET-Works 2 at the U study will address this knowledge gap using a unique cohort of racially/ethnically diverse, low income children who participated in a two-arm randomized controlled obesity prevention trial.

The goal of this prospective study and the next logical step in our work is to characterize the emergence of dysregulation in cardiometabolic processes in this high-risk cohort of children at 7-10 years of age, and identify the malleable factors that mitigate the deleterious impact of early environmental stressors on later cardiometabolic risk.

Neurobehavioral functioning in youth

Principal Investigator:

Christine Conelea, PhD (Department of Psychiatry)

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Collaborators:

Suma Jacob, MD, PhD (Department of Psychiatry)

Abstract:

Despite the recognition of high comorbidity rates and overlapping features among neurodevelopmental disorders, studies assessing neurocognitive functioning have typically only included youth within one diagnostic category (e.g., compare ASD vs. healthy controls). The current study will use a transdiagnostic approach to examine patterns of neurocognitive functioning in a sample of youth with a variety of neurodevelopmental disorders (ASD, OCD, ADHD, and tic disorders (TDs)). Identifying patterns of neurobehavioral functioning in a diagnostically heterogeneous sample has the potential to improve our ability to match youth to appropriate treatments and to inform development of new treatments.

Neuromodulation augmented cognitive remediation to improve executive dysfunction in fetal alcohol spectrum disorder

Principal Investigator:

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

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Collaborators:

Christopher J. Boys, Ph.D. (Department of Pediatrics), Kelvin Lim, MD (Department of Psychiatry)

Abstract:

Prenatal alcohol exposure (PAE) has profound detrimental effects on brain development and, as a result, has permanent consequences for cognition, learning, and behavior. Individuals with Fetal Alcohol Spectrum Disorders (FASD) commonly have a range of neurocognitive impairments that directly lead to practical problems with learning, attention, working memory, task planning/execution, and decision making, among other areas of functioning. Despite the profound public health burden posed by FASD, there have been very few treatment studies of any sort in this population. Our group conducted the first randomized controlled trials of the nutrient choline as a neurodevelopmental intervention in 2-5 year old children with FASD, in which we demonstrated effects on sequential memory.  For older children, a very different neurodevelopmental target is needed, and for this we have narrowed our focus to “plasticity” (the brain’s ability to adapt).  We propose to conduct a novel pilot study to examine the effects of cognitive remediation training augmented with tDCS in children and adolescents with FASD. Functional magnetic resonance imaging will be collected to provide preliminary data of brain circuitry changes created by this intervention.

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