Kiki Chang - US grants

DESCRIPTION (provided by the applicant): The long-term objective of this Mentored Patient-Oriented Research Career Development (K23) Award is to develop the candidate's skills in patient-oriented clinical research so that he may become an independent researcher in the field of child mental health. Dr. Chang's specific goal is to gain proficiency in pediatric mood disorders research, specifically in the area of utilizing brain imaging techniques to elucidate neurobiological data correlated to clinical presentations of children and adolescents with bipolar disorder (BD). To accomplish this goal, the candidate will be mentored by experts in the field of neuroimaging, childhood and adult BD, and statistics and research design. The candidate furthermore will participate in educational activities in his department as well as formal coursework in the areas of cognitive neuroscience, brain imaging, and statistics. Finally, the candidate will carry out a research project closely aligned with his research training plan. The goal of the proposed research project is to gather longitudinal phenomenological and brain imaging data on child and adolescent offspring of parents with BD, who are at high risk for developing bipolar disorder. These at-risk children, some already with BD, and healthy controls will be assessed longitudinally over three years by brain functional magnetic resonance imaging (fMRI) and proton magnetic resonance spectroscopy (MRS). fMRI tasks will be related to emotion and attention, and proton MRS will be of bilateral dorsolateral prefrontal cortices (DLPFC), specifically assessing n-acetyl aspartate/creatinine (NAA/Cr) ratios. Phenomenology will be assessed through structured diagnostic interviews, clinician-rated scales, and patient-rated questionnaires. We hypothesize that (1) at-risk offspring already with BD at baseline will have differing areas of activation and deactivation than healthy controls, primarily in DLPFC and anterior cingulate cortex (ACC), (2) at-risk offspring with BD will have lower NAA/Cr ratios in bilateral DLPFC compared to healthy controls, and (3) at-risk offspring who develop BD in the course of this study will demonstrate a greater decrease in DLPFC NAA/Cr from baseline than controls and patterns of brain activation similar to those subjects already with BD, either at baseline or at three-year follow-up. Through conducting this research project and implementation of the research training plan, Dr. Chang plans to become an independent investigator in the field of pediatric BD and thus contributing to the current knowledge of the neurobiology and development of BD.

Abstract Not Provided.

0-11 years old; 21+ years old; Accounting; Adolescent; Adolescent Youth; Adult; Affect; Affective Psychosis, Bipolar; Amygdala; Amygdaloid Body; Amygdaloid Nucleus; Amygdaloid structure; Anisotropy; Area; Articulation; Autism; Autism, Early Infantile; Autism, Infantile; Autistic Disorder; Bipolar Disorder; Body Tissues; Body of uterus; Brain; CRISP; Causality; Cerebellum; Child; Child Youth; Childhood; Children (0-21); Cognitive deficits; Communication; Computer Programs; Computer Retrieval of Information on Scientific Projects Database; Computer software; Corpus; Corpus Callosum; Corpus Callosums; Corpus Uteri; DP; DP protein, human; Data; Deep; Depth; Diagnosis; Diffusion; Diffusion MRI; Diffusion Magnetic Resonance Imaging; Diffusion Weighted MRI; Disease; Disorder; Disruption; Drugs; Dysfunction; Echo-Planar Imaging; Echoplanar Imaging; Encephalon; Encephalons; Etiology; Event; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Grant; Height; Hour; Human, Adult; Human, Child; Image; Inferior; Institution; Investigators; Joints; Kanner's Syndrome; MR Imaging; MR Tomography; MRI; MRI, Functional; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Magnetic Resonance Imaging, Echo-Planar; Magnetic Resonance Imaging, Echoplanar; Magnetic Resonance Imaging, Functional; Maps; Masks; Measures; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Medical Imaging, Planar; Medication; Memory; Mental disorders; Mental health disorders; Method LOINC Axis 6; Methodology; Methods; NIH; NMR Imaging; NMR Tomography; National Institutes of Health; National Institutes of Health (U.S.); Nervous System, Brain; Neuropsychologies; Neuropsychology; Noise; Nuclear Magnetic Resonance Imaging; Numbers; PTGDR protein, human; Parents; Parietal; Patients; Pattern; Performance; Pharmaceutic Preparations; Pharmaceutical Preparations; Physiologic; Physiologic pulse; Physiological; Physiopathology; Prefrontal Cortex; Probability; Process; Psychiatric Disease; Psychiatric Disorder; Psychiatry; Psychosis, Manic-Depressive; Publishing; Pulse; Pulse taking; Relative; Relative (related person); Reporting; Research; Research Personnel; Research Resources; Researchers; Resources; Role; Sample Size; Sampling; Scanning; Score; Severity of illness; Side; Slice; Snow; Software; Source; Structure; Tail; Test Result; Thick; Thickness; Time; Tissues; United States National Institutes of Health; Unspecified Mental Disorder; Uterine Body; Visuospatial; Weight; Zeugmatography; adult human (21+); amygdaloid nuclear complex; base; bipolar affective disorder; cardiovascular risk; cardiovascular risk factor; children; computer program/software; diffusion tensor imaging; disease causation; disease etiology; disease severity; disease/disorder; disease/disorder etiology; disorder etiology; drug/agent; emotion regulation; fMRI; human prostaglandin D2 receptor; imaging; juvenile; juvenile human; manic depressive disorder; manic depressive illness; mental illness; neuroimaging; neuropsychologic; neuropsychological; pathophysiology; pediatric; prostaglandin D2 receptor proten, human; prostaglandin D2 receptor, human; psychological disorder; size; social role; substantia alba; visual spatial; white matter; youngster

[unreadable] DESCRIPTION (provided by applicant): Bipolar disorder (BD) commonly begins during childhood or adolescence, and those with early onset typically have greater severity of illness and suicidality. Early identification of this disorder is paramount for implementing psychosocial and pharmacologic interventions that might prevent the full disorder. Due to the nonspecificity of early symptoms of BD, such as hyperactivity or depression, biologic markers that signify highest-risk for BD would aid in early identification as well as contribute to the understanding of BD pathogenesis. Children with BD have abnormalities in amygdalar volume and prefrontal-limbic circuits, but it is unclear if these abnormalities are present before the development of BD. Furthermore, polymorphisms of the serotonin transporter (5-HTT) and brain-derived neurotrophic growth factor (BDNF) genes may adversely affect these circuits and be risk factors for BD. In order to study the trait-status of these neurobiological abnormalities and their relationship to genetic polymorphisms, it is necessary to study a high-risk group of children before the development of BD, such as children of parents with BD ("bipolar offspring"). We propose to study 100 offspring from families having one or more parents with BD, comprised of 50 sibling pairs discordant for putative prodromal BD ("Prodromal Siblings"), and 30 singleton healthy controls. Prodromal Siblings will be children with depression and/or ADHD + moderate mood symptoms. All subjects will be carefully assessed by semi-structured interviews, clinician rated scales, and questionnaires relevant to family function and life stressors. Blood will be obtained from parents and siblings for genotyping polymorphism status of the 5-HTT and BNDF genes. Subjects will be scanned on a high-field (3T) magnet, obtaining amygdalar morphometric and functional MRI data in response to two separate affective probes designed to elicit activation of prefrontal-amygdalar circuits. Finally, subjects will be reassessed by interview 3 years after initial evaluation to assess for development of BD. By studying genetic and brain characteristics of high-risk discordant siblings before the development of full BD, we will be able to determine non-environmental risk factors for BD that are not caused by later events, such as substance abuse or recurrent mood episodes. We will also be able to determine possible gene-effects on brain structure and function in this cohort and create a repository for genetic and neuroimaging data that can be used for future longitudinal studies. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This proposal is one of two linked applications (UCLA [D. Miklowitz] and Stanford [K. Chang]) in response to PAR-09-153, Collaborative R01s for Clinical and Services Studies of Mental Disorders. Despite the considerable public health burden of bipolar disorder (BD), no psychosocial interventions have been systematically applied to youth at high risk for developing the illness. Research on youth who are genetically predisposed to BD has identified clinical states with considerable risk for conversion to full threshold BD I or II disorder. We propose a multisite RCT to test the efficacy of a multi-faceted family-focused treatment for high- risk youth (FFT-HR). The 4 month intervention consists of psychoeducation, communication training, and problem solving and aims to reduce affective arousal, increase stress resilience, and increase capacities for emotion modulation. In a treatment development study, we found FFT-HR to be highly effective compared to a brief psychoeducational intervention in reducing affective symptoms and enhancing functioning among youth at high risk for BD, particularly those in high expressed emotion families. We will enroll 150 youth ages 9-17 who meet operationalized high-risk criteria for BD: (1) a diagnosis of BD not otherwise specified or major depressive disorder, with active symptoms in the past 1-2 weeks; and (2) at least one biological parent has a history of type I or type II BD. Following a diagnostic and family evaluation, we will randomly assign subjects to: (1) FFT-HR (12 sessions in 4 mos), or (2) enhanced care (EC; 3 weekly family education sessions followed by monthly individual support sessions over 4 mos). Participants who require pharmacotherapy will be treated by psychiatrists applying best-practice procedures. A subset of 60 youths will undergo pre- and post-treatment fMRI scans while performing two tasks shown to activate prefrontal-subcortical circuitry: a standard facial affect task of implicit emotion perception and an emotion regulation task. We will compare the magnitude of pre/post treatment changes in affective symptoms and functioning between subjects randomized to the two treatment arms, and the stability of changes over 2-4 years. We hypothesize that FFT-HR will be more effective than EC in (1) reducing the acute severity of mood symptoms and maintaining mood stability over 2-4 years, and (2) reducing the hazard of a first (hypo)manic episode and enhancing functioning. We hypothesize that indicators of high emotional arousal - pretreatment levels of expressed emotion in parents, emotional dysregulation in youth, and activation in prefrontal-subcortical limbic circuits (amygdala, dorsolateral and ventral prefrontal cortex) in youth - will be associated with a greater magnitude of response to FFT-HR. Finally, we will examine the impact of FFT-HR vs. EC on pre/post treatment changes in activation of limbic circuitry, and correlations between neural changes and symptom improvement over 4 mos. Consistent with the NIMH Strategic Plan, this study will facilitate the translation of a novel early intervention in community settings and identify mechanistic factors at the neural, clinical, and contextual levels that can be used to refine future treatments.

DESCRIPTION (provided by applicant): 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.