Psychotic disorders such as schizophrenia have been associated with both frontal lobe dysfunction as well as abnormal regulation of subcortical regions. An innovative theory suggests that deficits in the system linking these two areas (the frontal-subcortical circuits;FSCs) may account for the wide range of symptoms and characteristics seen in psychotic disorders. Recent research detecting abnormal grey and white matter development in the frontal and medial temporal regions during the prodrome, a period proceeding formal onset of psychotic disorders, suggests that maturational changes are highly relevant in the etiology of psychotic disorders. Despite the evidence suggesting a prominent role of maturational factors in etiological conceptualizations of psychosis, it is unclear how neuromaturation in the FSC system may contribute to symptoms or characteristic behaviors of psychosis;to date no published studies have examined longitudinal grey and white matter changes in high-risk participants in this critical system. However, understanding the neural-reorganization preceding illness is integral as it stands to elucidate underlying pathogenic mechanisms prior to when widespread medication usage and neurotoxicity may confound clear understanding and further, within the context of detecting and treating high-risk adolescents, can lead to identifying biological markers of vulnerability- indicating which high-risk individuals are most likely to convert to psychosis. A strong line of evidence implicating that developmentally based FSC changes are tied to emerging psychosis, indicates that spontaneous movement abnormalities (SMAs) (i.e., dyskinesia and Parkinsonisms), presumed to reflect a compromised FSC system, become salient during adolescence, continue to progress in frequency/severity with age, are associated with symptoms, and predict eventual conversion to formal psychosis. However, to date it is unclear which particular maturational changes may underlie SMAs, or if these movements do indeed serve as a marker of progressive FSC dysfunction. Further, to date SMAs in high-risk populations have only been assessed with observer-based measures, and recent studies in psychotic populations, suggesting that instrumentally based measures of SMA are significantly more sensitive, hint at promise for a viable biomarker. The proposed study will test the hypothesis that irregular development in grey and connective white matter tracts among prodromal adolescents contributes to alterations in FSC, resulting in SMAs, prodromal symptoms, and eventually the onset of psychosis. We propose to utilize instrumental measures of SMAs (i.e., Force Variability and Velocity Scaling), magnetic resonance imaging (MRI), and diffusion tensor imaging (DTI), to examine structures and connective tracts comprising the FSC system, following groups of 75 adolescents with a prodromal syndrome (age 12-21), and 75 matched healthy controls over the period of one-year (baseline and on year follow-up) to determine the neurodevelopmental underpinnings of SMAs (if specific developmental patterns of grey and white matter in the FSC system characterize prodromal populations and result in dyskinesias and/or Parkinsonisms) and if developmental abnormalities in this system and SMAs (a potential biomarker that may directly reflect this pathology) predict a poorer course of illness.

Public Health Relevance

Understanding how the brain changes during adolescence, a period that is characterized by significant neural- restructuring and also immediately precedes the typical age of onset for psychotic disorders such as schizophrenia, is necessary for improving our conceptions of what causes the disorders, and may help efforts to identify, provide early treatment, and subsequently improve the course of illness for adolescents at heightened risk for developing these disorders. The proposed research investigates adolescents at high-risk for developing psychotic disorders, for a period of one-year, to determine if brain development in the frontal subcortical circuit system, linking frontal and subcortical brain regions (both highly implicated regions in adults with formal psychotic disorders) contributes to developing psychosis, and if movement abnormalities (also characteristic of adults with psychosis) reflects abnormal development in the frontal subcortical circuit system, and can thereby be utilized as a readily detectable marker to improve identification, implicating those high-risk adolescents at heightened vulnerability for developing psychosis.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZMH1-ERB-L (04))
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Garvey, Marjorie A
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University of Colorado at Boulder
Schools of Arts and Sciences
United States
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