In this project, our group is examining biological aspects of risk for mood and anxiety disorders in children. This project encompasses work that is being implemented in three protocols. In one protocol, we are examining the degree to which traumatic experiences predict perturbations in brain function among youth with or without mood or anxiety disorders. In a second protocol, we are examining neurocognitive profiles in a cohort of approximately 350 children and adolescents stratified with respect to personal and family history of mood and anxiety disorders. In a third protocol, we are attempting to acquire fMRI data from a subset of these 350 subjects. Adults with post-traumatic stress disorder (PTSD) or major depressive disorder (MDD) exhibit abnormalities in the structure and function of the amygdala and hippocampus. However, while these psychiatric disorders often emerge in childhood, the integrity of these neural structures have been minimally studied in psychiatrically impaired children and adolescents. In the current proposal on trauma, functional MRI (fMRI) will be used to evaluate the amygdala and the hippocampus in 1) healthy adolescents and those with the following conditions: 2) PTSD; 3) MDD; 4) PTSD and MDD; and 5) abuse without PTSD or MDD. The proposed study will be conducted in three separate experiments/phases. Experiment 1/Phase 1 was completed during the first year of this project; this led to an adaptation of the planned fMRI tasks for the project. For the pilot phase of Experiment 2/3, we will conduct a pilot study in healthy adolescents to examine the effects on the fMRI signal from repeat testing with the tasks described below for Experiment 2 and 3. We have begun this study during the second year of this protocol. Suitable data have been acquired in eight adolescent subjects. In Experiment 2/Phase 2, the functioning of the amygdala and hippocampus will be examined in healthy adolescents and those with the psychiatric conditions described above. During image acquisition, 2 cognitive tasks will be used to recruit medial temporal lobe activation: a face-emotion processing tasks and an attention orientation task. Behavioral data for these tasks document associations with trauma and other risk factors for anxiety. Ninety participants will be recruited for this study, 18 patients in each of the five groups. In Experiment 3/Phase 3, individually tailored open treatment will be provided to patients with either PTSD or MDD, and responsivity will be assessed. Following 8 weeks of treatment, all participants will return and fMRI will be used again to examine amygdalar-hippocampal functioning as participants perform the same tasks as in Experiment 2. Thus, irrespective of treatment, Experiment 3 will examine whether the effects found in Experiment 2 diminish in patients whose symptoms resolve. These results will provide preliminary data on the degree to which neurophysiological correlates of psychopathology in Experiment 2 represent state as opposed to trait markers for psychopathology. With respect to our implementing these aspects of our protocol on reactions to trauma, we have spent much of the initial period of work piloting fMRI protocols in psychiatrically healthy subjects and establishing ties with local authorities who work closely with children exposed to trauma. As described in our report on studies in healthy subjects, we have developed fMRI paradigms suitable for research with traumatized children. We also have established a strong alliance with local authorities that should insure ample flow of patients into our studies. During the previous year, we established procedures for the fMRI portion of this study. We have enrolled three traumatized patients into the protocol. Anxiety in children of parents with major depressive disorder (MDD) poses a particularly high risk for later-life MDD. In adults, MDD involves dysfunction in prefrontal brain regions that regulate attention to emotional stimuli. These abnormalities: i) have been found primarily in adults with specific familial forms of MDD; ii) persist after recovery from MDD, and iii) relate to anxiety. These findings raise the possibility that risk for MDD is tied to dysfunction in prefrontal regions involved in regulation of emotion, which possibly manifests as early-life anxiety. If this possibility were confirmed in never-depressed adolescents at high risk for MDD, the findings would provide key insights into the developmental neurobiology of MDD. The goal of this protocol is to study the neural substrate of risk for MDD in young people. This protocol tests the hypothesis that adolescents at high risk for MDD by virtue of childhood anxiety and parental history of MDD exhibit dysfunction in prefrontal cortex and amygdala, regions involved in emotion regulation. This goal will be accomplished through behavioral and fMRI studies of emotion regulation in high and low-risk adolescents. With respect to our research neurocognitive profiles in offspring of depressed and/or anxious parents, we have acquired data in 225 subjects, working closely with a group from New York University Child Study Center. This includes behavioral data on a face-viewing paradigm that we have also been using to conduct our fMRI studies. During the past year, we acquired fMRI data among 50 subjects in this same cohort of children. For this research, at-risk adolescents have been recruited from participants in an NIMH-funded extramural study at New York University (NYU) examining the biology of risk for anxiety and depressive disorders. Over a three-year period, 30 high-risk probands and 45 low-risk comparisons will be studied, including 20 comparisons from the NYU sample and 25 from the Washington DC metropolitan area. In the present protocol, to be conducted at NIH, subjects will undergo volumetric MRI scans to assess structural abnormalities in the prefrontal cortex and medial temporal lobe. They will complete a series of four out-of-scanner cognitive tasks and two fMRI-based cognitive tasks that measure modulation of attention to emotional stimuli. The fMRI tasks are hypothesized to differentially engage the prefrontal cortex and amygdala in low vs. high risks subjects. These tasks will be used to test the hypothesis that at-risk individuals exhibit enhanced amygdala and reduced prefrontal activation on the fMRI emotion/attention tasks. Finally, we also have developed a strong collaborative relationship with Dr. Nathan Fox at the University of Maryland. Dr. Fox has followed a cohort of approximately 200 infants as they passed from childhood into adolescence. These children have received repeated assessments of their temperament. Temperament classifications in the sample during infancy and early childhood have been shown to predict behavior later in life. We have initiated a protocol where we will collect fMRI and behavioral data on a sample of approximately 50 teenagers from this sample. We have completed studies in a total of 30 subjects from this cohort. Finally, for our behavioral studies, neuropsychological data were gathered to facilitate the development of new fMRI tasks. These included data on four additional tasks. In these tasks, between 20-60 subjects were studied, including approximately equal numbers of adolescents and adults. Three additional manuscripts using these data have been submitted and are under-review. We are also in the process of analyzing other data and preparing research reports for other tasks. Most importantly, we have initiated a series of studies using fear conditioning approaches. We have successfully demonstrated fear conditioning in both adolescents and adults using paradigms developed as part of this protocol. We plan to initiate studies using these methods in the fMRI scanner relatively shortly.

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