Tony Yang - US grants

DESCRIPTION (provided by applicant): Adolescent depression is a major public health problem that frequently recurs in the patient's life with significant costs to the adolescent and society. Presently, our understanding of the underlying neural substrates of adolescent depression is very limited. The number of pediatric functional neuroimaging studies is extremely sparse. The few functional magnetic resonance imaging (fMRI) studies of the amygdala in pediatric depression have reported opposite results. There are no published fMRI studies examining the subgenual anterior cingulate or dorsal lateral prefrontal cortex in depressed adolescents relative to matched, healthy adolescents except for the recent publication by the Principal Investigator (Dr. Yang). Furthermore, there are no published functional neuroimaging studies in depressed adolescents examining possible brain regions that might be predictors of future clinical response to treatment. Description: This proposal is both a cross-sectional and longitudinal follow-up study. In this application, we plan to: (1) recruit 64adolescents with major depressive disorder (MDD) and 64 healthy, control adolescents; and (2) follow the depressed adolescents longitudinally over 6 months after the initial assessment. MDD and healthy adolescents ages 13 to 17 years will participate in this study. Both genders and all ethnicities will be included. Recruitment will be through several major sources using the same approach as established in 5K23MH070791. Similarly, using the same approach established in 5K23MH070791, all adolescents will be carefully screened and undergo a series of interviews, questionnaires, and assessments to obtain information pertinent to this study. Adolescents will be scanned using fMRI tasks that activate the adolescent amygdala, dorsal lateral prefrontal cortices, and subgenual anterior cingulate cortex. A single fMRI scan will occur at baseline. Clinical assessments will occur at baseline, 3 months, and 6 months. The 6-month clinical assessment will be the primary time point of interest for the longitudinal study. The Children's Depression Rating Scale-Revised (CDRS-R) will be the primary clinical outcome measure. The Beck Depression Inventory II and Children's Global Assessment Scale will be the secondary clinical outcome measures. Aims: Aims of the current proposal are to: (1) contrast brain activation in the amygdala, dorsal lateral prefrontal cortices (DLPFC), and subgenual anterior cingulate cortex (sgACC) using fMRI between adolescents with MDD and matched healthy controls, and (2) evaluate the relationship between fMRI activation in the amygdala, DLPFC, and sgACC at baseline and the future clinical response to treatment in adolescents with MDD. Accomplishing these aims will advance the neurobiology of adolescent depression by: (1) contributing to an overall understanding and model of adolescent depression that can be used to develop clinically relevant tools, and (2) taking the necessary first steps towards the translation of basic functional neuroimaging findings into a useful clinical tool that can predict future treatment response in depressed adolescents.

Project Summary/Abstract Meditation training is a promising technique that can help improve emotional health of adolescents and facilitate treatment of adolescent depression. However, there is a fundamental gap in understanding the neural reorganization that takes place as a result of meditation training. Continued existence of this gap represents an important problem because, until it is filled, design of more effective interventions is highly unlikely. The long- term goal is to establish safe and effective methods of promoting emotional health in adolescents. The objective here is to study adolescents undergoing meditation training by using MRI connectomics to map changes in node strength (integrated connectivity) of the putamen. The putamen is a region previously associated with meditation practice and attenuated shrinkage with age in Zen meditators on the one hand, and with love, compassion, anticipation of pleasure, and responses to increasing intensity of happiness on the other hand. The central hypothesis is that structural connectivity of the putamen with other brain regions will increase in adolescents with mediation training and, in turn, positively affect their emotional health. This innovative model is rooted in preliminary results and previous literature. The rationale for the proposed MRI connectomics approach is that regular engagement of the putamen is expected to increase myelination of the white matter tracks connecting it to other regions, which can be probed by using diffusion MRI. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims, which entail studying changes in the putamen node strength and emotional health measured as internalizing problems and depressive symptoms in 1) a cohort of healthy adolescents with a 12-week meditation training compared to waitlist controls (R61 phase) and 2) a cohort of adolescents with mild to moderate depression with a 12-week meditation training compared to waitlist controls (R33 phase). The ?Go/No-Go Criterion? is a medium-large increase of the putamen node strength observed with meditation training in healthy adolescents in the R61 phase (Cohen's d>0.6). The optimization strategy for the R33 phase is based on the fact that anhedonia (diminished ability to experience pleasure) is a key characteristic of depression and preliminary results show that putamen structural connectivity is lower in adolescent depression. It is therefore expected that the mechanistic effect in the putamen will be amplified in the population of depressed adolescents, reflecting normalization of the putamen function. The proposed research is innovative, because it uses advanced MRI connectomics methods to map changes in brain networks of youth with meditation training and tests a novel mechanistic model. The proposed research is significant, because it is expected to greatly advance our understanding of the neural mechanism by which meditation improves emotional health of adolescents. Ultimately, such knowledge will inform treatment and prevention of adolescent depression.