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.
Choline supplementation as a neurodevelopmental intervention in fetal alcohol spectrum disorders
Jeffrey R. Wozniak, Ph.D., L.P. (Department of Psychiatry)
Michael K. Georgieff, M.D. (Department of Pediatrics), Stephanie Carlson, Ph.D. (Institute of Child Development)
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.
Emotion regulation in the transition to adolescence
Shreya Lakhan-Pal, Graduate Student (Institute of Child Development)
Kathleen Thomas, PhD (Institute of Child Development)
The capacity to regulate one’s emotions is a critical skill that develops into adulthood. Adolescence is a period of emotional vulnerability and hypersensitivity, and is marked by a rise in the onset of affective disorders like depression and anxiety. Problems with emotion regulation (ER) are implicated in most forms of psychopathology and in decreased socioemotional health, suggesting that successful ER may be a key protective factor during adolescence. Despite its significance in psychopathology and emotional development, little is known about changes in ER in this time.
While social regulation plays an important role throughout the lifespan, evidence suggests that it becomes less effective during adolescence. Social structures and expectations are in dramatic flux, and emotions are more volatile. During stressful situations, neither parent nor friend presence effectively regulates stress hormones or emotion-related neural activity,and neural networks for self-regulation are still developing. Thus, it seems likely that there is a period of emotional vulnerability when social regulation wanes while self-regulation is still maturing. In the proposed study, I aim to address this gap by jointly examining social and self-regulation efficacy during the transition to adolescence, and by determining how the two are associated with caregiver emotional styles.
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.
Longitudinal studies in MPS disorders: a multicenter study of the lysosomal disease network, longitudinal studies of brain structure and function in MPS disorders
Chester B. Whitley, PhD, MD (Department of Pediatrics)
The purpose of this study is to examine the changes in the central nervous system over time in patients with MPS I, II, IV, VI, and VII in both structure and function. We have determined that localization in the brain of abnormal cognitive and behavioral attributes varies by the type of MPS disorder. We will be examining how changes in the brain over time reflects the natural course of the disease or the effects of past or currently administered treatment such as hematopoietic cell transplant, systemic enzyme replacement or intrathecal enzyme replacement.
We hypothesize that specific and localized neuroimaging, neuropsychological and neurobehavioral findings and their relationship will be distinct for each MPS disorder. Further, without appropriate treatment, functions will decline and structure will change over time specific to each disease and stage of disease. We hypothesize that treatments such as ERT, HCT, HCT+ERT, and palliative and rehabilitation therapies, will differentially affect brain structure, functions and quality of life. Finally, we hypothesize that for each MPS type, variables such as age at first treatment, severity of disease, medical events related and unrelated to the disease, mutation, family and environmental factors, sensory abnormalities, and sociodemographic variables will influence brain functional and structural outcomes as well as quality-of-life.
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.
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.
Neurobehavioral functioning in youth
Christine Conelea, PhD (Department of Psychiatry)
Suma Jacob, MD, PhD (Department of Psychiatry)
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.
Screening for profiles of risk associated with ASD and other emerging atypical phenotypes
Jed Elison, PhD (Institute of Child Development)
Suma Jacob, MD, PhD (Department of Psychiatry), Amy Esler, PhD, LP (Department of Pediatrics), Jason Wolff, PhD (Department of Educational Psychology)
There is a great need for improved screening approaches and improved implementation of screening procedures to identify children who will need early intervention for ASD. New screening approaches are needed to capture the heterogeneity of the disorder(s), which includes identifying children who are likely to access services in the community even though they may not meet strict research criteria for an autism spectrum diagnosis.
In the current application, we propose to test a new screening approach that we refer to as pheno-screening. We ask parents to complete online versions of standardized questionnaires that are designed to capture individual differences in highly dimensional traits relevant to the early emergence of clinically impairing behaviors that constitute ASD. We use data driven approaches to derive clusters or latent classes of children that represent a continuum of risk. Next, based on a given cluster’s profile, we invite children into the laboratory for direct phenotypic assessment that also includes measurement of biomarkers hypothesized to help us parse the heterogeneity of behavioral profiles encapsulated by an ASD diagnosis. Improved screening procedures promise to advance early identification, and improved characterization of biomarkers associated with risk promises to advance new interventions designed to target specific mechanisms associated with behavioral symptomatology.