With growing recognition that a number of psychiatric illnesses previously thought to be restricted to adulthood actually show their initial signs in childhood and begin to emerge fully during adolescence, NIMH mandated in its Strategic Plan that clinical research should, "compare trajectories of healthy development to those of mental disorders in order to better understand the first instance or instances, when development moves off course." Specifically, this objective involves the need to "map the trajectory of mental disorders using imaging technologies," and discovery of "early detection of risk factors for mental disorders." Consistent with these priorities, the current application involves a plan for th applicant to transform from an adult psychopathology researcher to a developmental cognitive neuroscientist with skills and expertise to study adolescence as a sensitive period in the development of psychotic disorders such as schizophrenia. Written in consultation with a team of clinical and developmental neuroscientists, as well as a developmental psychologist and clinical psychologist who both conduct basic research, and a statistician with expertise in longitudinal work, the proposal describes a one year-long investigation of cognition and neural connectivity in three groups of adolescents (ages 12-17 years) : help-seeking patients judged to be at clinical high-risk for developing schizophrenia (due to the presence of sub-threshold symptoms), patients who meet DSM-IV criteria for a first episode of schizophrenia, and matched community comparison subjects. At study enrollment and then again at 12 month follow-up, all participants will perform a set of experimental cognitive tests while event-related EEG data are recorded. EEG is capable of providing temporally-sensitive measures of synchronized activity in large-scale neural circuits. The proposed cognitive tests each recruit various subsets of prefrontal-posterior neural circuits. These particular neural circuits are critical for linking the prefrontal cortex to more posterior, earlier-maturing cortical regions (e.g., sensory and motor areas), and are the site of some of the most dramatic development and optimization that occurs in the brain during adolescence, as it transitions to stable, adult functioning. Therefore, the efficiency with which these neural circuits function under cognitive challenge should provide evidence of baseline dysfunction, and change in that efficiency over the year-long study should provide evidence of aberrant maturation if present. In fact, latent risk for developing schizophrenia is thought to dysregulate a subset of these functional connections (e.g., through selective pathology of pyramidal neurons synapses);however, exactly when these illness mechanisms arise with respect to the appearance of frank psychotic symptoms and with respect to landmarks in typical adolescent development remains unknown. Collectively, these results will provide a sensitive measure of the integrity of the neural connections that are thought to provide the substrate for both adolescent neurodevelopment and schizophrenia pathogenesis.
This study will help identify the neural changes that precede the onset of symptoms and decrease in real-world functioning that mark the first episode of schizophrenia. Detection of these critical neural changes will provide clinicians with tools to differentiate which help-seeking adolescents are most likely to go on to develop schizophrenia, so that treatment resources could be directed to them. Additionally, the training plan will provide the applicant with an opportunity to become an expert in the changes that occur in the brain during adolescence, which may in turn help him to discover indicators of vulnerability to developing the range of neurological and psychiatric illnesses that appear during that developmental stage.