The long-term objective of this Midcareer Investigator Award in Patient-Oriented Research (K24) Award is to provide time and resources to the candidate to continue and expand his mentoring activities of trainees in clinical research careers in the field of innovative methods for early identification and prevention of pediatric mood disorders. Furthermore, the candidate will develop his own career in the areas of advanced MRI methodologies and mindfulness-based therapies in order to use this knowledge to better investigate neural network abnormalities that create risk for early-onset bipolar disorder (BD) and how interventions can reverse these developmental abnormalities. The candidate will reach this goal through relevant coursework, scientific meetings, outside consultation, internal collaboration and mentoring, and completion of a proposed research project relating these fields to youth with BD, not otherwise specified (BD NOS). Bipolar disorder is a common, chronic, and often disabling disorder that carries significant public health burden and commonly begins in childhood or adolescence. Understanding how brain development leads to BD development would aid in developing targeted interventions for early intervention and prevention. Given the unclear adverse effects of psychotropic medications on developing brains, non-pharmacologic interventions in populations at risk for BD should also be explored. Mindfulness based therapies (MBT) have been successfully used to treat adults and children with depression, and adults with bipolar disorder. This application proposes examination of baseline resting state neural networks in youth at high-risk for BD, and the effects of a MBT intervention on these networks and on brain morphometry. First, we will study 30 adolescents (13-17 yo) who meet criteria for BD NOS, strictly defined per standardized research criteria. Subjects will also have a first- or second-degree relative with BD, creating a group at very high risk of progressing to bipolar I disorder within four years. We will use resting state-fMRI (rs-fMRI) to examine default mode networks (DMN) in these 30 subjects and compare with already acquired data from 20 healthy controls (HC). We hypothesize that youth with BD NOS will have altered subgenual anterior cingulate (sgACC) functional connectivity (FC) compared with HC: higher FC of sgACC with the DMN and lower FC of the sgACC with the dorsal anterior cingulate and dorsolateral prefrontal cortex. Second, these subjects will be treated with a 12-week Mindfulness Based Stress Reduction for Teens (MBSR-T) intervention, designed to increase daily mindfulness, meditation skills, and awareness of emotional dysregulation in response to stressors. We hypothesize that youth with BD NOS will experience decreases in depressive symptoms and degree of mood dysregulation, and increases in functioning and degree of mindfulness practice. Furthermore, we anticipate that FC of sgACC with DMN will decrease and FC of sgACC with dorsal structures will increase, as will left hippocampal volume. Consistent with the NIMH Strategic Plan, this study will examine neurobiological risk factors for mood disorder development in youth and neural mechanisms of a novel intervention that has potential for prevention, while creating additional opportunities for mentoring the next generation of clinical researchers in the field of pediatric mood disorder prevention.

Public Health Relevance

Bipolar disorder is a common, chronic, and disabling disorder that carries significant public health burden and commonly begins during childhood. Discovering biological pathways to BD development would lead to better targeted preventative and treatment efforts. This application proposes examination of resting state neural networks in youth at high-risk for BD, and effects on these networks of a mindfulness-based group therapy intervention. Identification of abnormalities in such systems and effects of novel non-pharmacological interventions in this population has the potential to interrupted in the natural progression of bipolar disorder in at-risk youth.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Midcareer Investigator Award in Patient-Oriented Research (K24)
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Interventions Committee for Disorders Involving Children and Their Families (ITVC)
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Wagner, Ann
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Stanford University
Schools of Medicine
United States
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Frankovich, Jennifer; Thienemann, Margo; Rana, Sonal et al. (2015) Five youth with pediatric acute-onset neuropsychiatric syndrome of differing etiologies. J Child Adolesc Psychopharmacol 25:31-7
Chang, Kiki; Frankovich, Jennifer; Cooperstock, Michael et al. (2015) Clinical evaluation of youth with pediatric acute-onset neuropsychiatric syndrome (PANS): recommendations from the 2013 PANS Consensus Conference. J Child Adolesc Psychopharmacol 25:3-13
Garrett, Amy S; Miklowitz, David J; Howe, Meghan E et al. (2015) Changes in brain activation following psychotherapy for youth with mood dysregulation at familial risk for bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry 56:215-20
Frankovich, Jennifer; Thienemann, Margo; Pearlstein, Jennifer et al. (2015) Multidisciplinary clinic dedicated to treating youth with pediatric acute-onset neuropsychiatric syndrome: presenting characteristics of the first 47 consecutive patients. J Child Adolesc Psychopharmacol 25:38-47
Singh, Manpreet K; Jo, Booil; Adleman, Nancy E et al. (2013) Prospective neurochemical characterization of child offspring of parents with bipolar disorder. Psychiatry Res 214:153-60