A longitudinal study examining three RDoC constructs in adolescents with non-suicidal self-injury
Kathryn Cullen, MD (Department of Psychiatry)
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)
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 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)
Suma Jacob, MD, PhD (Department of Psychiatry)
Bradley Miller, MD, PhD (Department of Pediatrics), Rebekah Hudock, PhD (Department of Pediatrics)
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.
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
Julie Eisengart, PhD, LP (Department of Pediatrics)
Chester B. Whitley PhD, MD (Department of Pediatrics), Amy Esler, PhD (Department of Pediatrics)
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.
Autism spectrum disorders and the gut microbiome
Suma Jacob, MD, PhD (Department of Psychiatry)
Jed Elison, PhD (Institute of Child Development), Amy Esler, PhD (Department of Pediatrics), Brittany Howell, PhD (Institute of Child Development)
Standard practice has not been established for the evaluation of possible GI morbidity when an individual with ASD presents with behavioral problems of new onset. In addition, it is hypothesized that gut-based processes may have a more direct pathophysiologic role in ASD due to 1) gut-based inflammatory processes that result in neuroinflammation and consequent alterations in brain function, 2) changes to the gut microbiota and the associated metabolome result in altered neurobehavioral function, or 3) dietary and nutritional mechanisms alter the relationship between GI and CNS function. This study aims to identify differences in gut microbiome composition between healthy controls, individuals with ASD diagnosis and those without, and to confirm that rigid-compulsive behaviors (RCB) in ASD are associated with GI symptoms and to examine if those with higher levels of these ASD behaviors have a distinct microbiome profiles.
Dyadic coordination of self-regulation and social engagement in infants and caregivers
Daniel Berry, PhD (Institute of Child Development)
Isabella Stallworthy, doctoral candidate (Institute of Child Development)
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.
Alicia Kunin-Batson, PdD, LP (Department of Pediatrics), Mike Troy, PhD, LP (Children's MN - Behavioral Health)
Jerica Berge, PhD, MPH, LMFT, CRLE (Family Medicine and Community Health), Rachel Hardemann, PhD, MPH (Health Policy and Management)
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
Kathleen Thomas, PhD (Institute of Child Development), Essa Yacoub, PhD (Center for Magnetic Resonance Imaging)
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.
Mindful breathing and neuromodulation for depression in young people
Kathryn Cullen, MD (Department of Psychiatry)
Bonnie Klimes-Dougan, PhD (Department of Psychology), Kelvin Lim, MD (Department of Psychiatry)
Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique that can modulate neural activity. If paired with Mindful breating training (MBT), tDCS may be able to enhance learning and neural changes associated with MBT. This study will test the efficacy of a novel treatment comprised of MBT and tDCS in adolescent depression. We propose that for patients with depression, where the core feature is persistent negative mood, a training task that engages the DLPFC’s role in regulating emotion may optimally reduce symptoms of depression. Mindful breathing training may be a suitable task to down-regulate negative affect and prime the fronto-limbic circuit. Further, this work will advance our understanding the synergistic effects of combining MBT with tDCS to target the connections between the DLPFC with the default mode network (DMN) and limbic regions. If successful, this study will aid in the development of novel treatments for adolescent depression and improve the ability of neuromodulation to treat depression.
Modes of Cognition and Arousal
Daniel Berry, PhD (Institute of Child Development)
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.
NET-Works 2 at the U
Alicia Kunin-Batson, PhD, LP (Department of Pediatrics)
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)
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.