Work in the current set of projects has major public impact because it shapes understandings of the boundaries of normal development. In the absence of such understanding, it is impossible to precisely demarcate the boundaries of abnormal development. This set of projects relies on functional magnetic resonance imaging (fMRI) technology, one of the most promising scientific tools for research on development in brain-behavior relationships. There is a particular interest in using the most up-to-date techniques in this area, such as functional connectivity and psychophysiologic interaction analysis approaches. Our group continues to make progress in these areas over the past three years. Moreover, there also is an additional need to incorporate data from novel approaches, such as those that rely on magnetoencephalography and eye-movement technology. The past two years involved considerable success in integrating data from these two novel techniques with data from techniques used in prior years. These studies have focused largely on defining differences among adolescents and adults separated by many years. For the comming year, the plan is to attempt to understand differences that manifest in individuals that are closer in age. Considering the full range of techniques used, the work completed under this protocol is highly important, as considerable work suggests that changes in emotional experience around adolescence relate to changes in the brain. Based on developmental continuities in the relevant psychological processes, we anticipate considerable similarity across age groups in the topography of brain regions engaged by relevant tasks. In fact, work already completed in this protocol supports this possibility, and ongoing work using novel, state-of-the-art approaches is extending these previously-reported findings. Specifically, emerging findings are documenting such similarities through a series of publications. In the past year, some of the most exciting work has focused on the amygdala and amygdala-frontal interactions. We have found consistent differences among children, adolescents, and adults in terms of functional aspects of these various brain regions, regions involved in cognitive and emotional processes. These findings are consistent with our hypotheses that developmental differences in cortico-limbic circuits of adolescents and adults are reflected in patterns of fMRI activation. Finally, during the past year, we specifically extended our work on amygdala-frontal interactions through research on fear conditioning, one of the more important but also more difficult emotional processes to study in children. Such difficulties arise since fear conditioning involves aversive states in children. Specifically, we hypothesize in both adults and adolescents that attention, threat perception, and memory tasks involving the processing of emotionally salient stimuli will engage the amygdala, cingulate gyrus, and association cortex of medial/inferior prefrontal cortex and temporal regions. These findings have been confirmed in initial work. They most recently have been extended through research on fear conditioning. Nevertheless, height of task-associated activation is hypothesized to differ between adolescents and adults within these regions. Moreover, prior studies distinguish puberty vs. age-related aspects of cognitive development: some aspects of attention, threat perception, or memory development relate to changes in chronological age whereas other aspects, particularly those involving emotional processes, relate to pubertal status. Therefore, we expect eventually to use emotion-evoking fMRI tasks to test hypotheses on the presence of complementary, distinguishable puberty vs. age-related components of brain development. For this work, we are adopting an approach that focuses on children, adolescents, and adults with endocrinological changes that impact on puberty. Unlike many other findings in the current protocol, relatively few pieces of data have emerged to support these hypotheses, either in the current protocol or in work being performed by others outside or inside the NIMH-IRP. Due to the limited fMRI database on neurodevelopmental aspects of emotional processes, one initial goal of the current project had been to compare brain activation patterns in adults and adolescents, irrespective of pubertal status. As noted above, aspects of this goal already are being met. A second initial goal is to generate behavioral data in adults and adolescents designed to inform the implementation of future fMRI tasks. This goal, too, is actively being met, although implentation of new tasks remains an ongoing goal. Studies accomplishing both goals will facilitate eventual studies designed to distinguish puberty vs. age-related aspects of brain development. To meet these initial goals, the current project implemented a series of initial studies, resulting in a series of publications appearing through 2005. In these previous fMRI studies, brain activation profiles were examined to four sets of emotionally evocative stimuli. This included evocative faces, standardized emotion-inducing picture sets, monetary feedback during a decision task, and threat of a mildly aversive air-puff. In total, an initial set of fMRI studies were completed in samples of psychiatrically healthy adults and adolescents. The publications appearing in 2008, 2009, and 2010 have been particularly noteworthy. Moreover, very high citation rates for publications appearing in previous years have continued to increase the impact of the work performed in this protocol. During the past year, these experiments have been replicated in additional cohorts of healthy adolescents and adults. Moreover, the novel techniques mentioned above also have been implemented into our studies. The most significant breakthrough during the past year represents the detailed focused on fear conditioning, an extension of the approach used in prior years. As such, refinements of previously used paradigms have been successfully implemented;novel methods are being developed;and these refinements have led to data collection in increasingly large samples. In each of these, hypothesized brain activation patterns emerged. Some of these tasks involve face emotion processing whereas others rely on simulated social interactions. Still other task utilize fear-conditioning approaches. As with other findings emerging from the current project, results from these studies are summarized in multiple publications from our group. In an effort to replicate these associations, we have acquired further data sets in other samples that are larger than the initial data sets. We continue to actively analyze these data. 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 each of these tasks, between 20-60 subjects were studied, including approximately equal numbers of adolescents and adults. This involves additional studies, in new groups of subjects in the past year, to meet recruitment needs for our new paradigms and techniques. Various new 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.

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