The purpose of this study is to better understand the neural correlates of selective attention deficits in schizophrenia and determine how these mechanisms can be pharmacologically modulated by nicotine. Patients commonly report being overwhelmed by sensory stimuli in the environment, causing difficulties at work and social situations and thereby lowering quality of life. Neurobiologically, this phenotype is partially due to reduced efficacy of nicotinic receptor systems that modulate inhibitory circuitry, and may be demonstrated in fMRI studies showing cortical hyperactivity in response to noise. Sensitivity to noise may have deleterious effects on attention-related neuronal response when the noise is task-irrelevant, although this has not been conclusively demonstrated. The proposed study will include two specific aims. In the first aim, the effects of distracting environmental noise on auditory attention task-related neuronal activity and behavior will be studied in schizophrenia patients and healthy controls using fMRI. It is hypothesized that a distraction condition (noise or silence) by diagnosis (patient or control) interaction will be observed, driven by a relative decrease in activity associated with attention networks in patients during noise (relative to silence), but the reverse effect (a relative increase) in activity in controls.
The second aim will determine if response abnormalities during (a) passive listening and (b) the auditory attention task with noise distraction can be improved by a nicotinic agonist (nicotine). In the first task, subjects will listen to environmental noise or cued silence. It is expected that relative to placeb, nicotine will normalize (i.e. reduce) response to noise in the hippocampus in patients. In the second task, subjects will perform the same auditory attention task as in the first aim; it is hypothesized that relative to placebo, noise-induced change in neuronal response and performance will be similarly normalized by nicotine. The current study will be the first to examine the neuronal effects of cholinergic modulation on selective attention in schizophrenia, and has methodological and pharmacologic implications for therapeutic development. Through completion of this research, in combination with additional activities including coursework, participation in an active clinical research group, and the University of Colorado research community, the NRSA will enable Mr. Smucny to achieve the following goals of his predoctoral training: 1) To acquire expertise in the neurobiology of schizophrenia 2) to expand his knowledge of fMRI experimental design, data acquisition, and statistical analyses, and 3) to become proficient in presenting his work in journals and at conferences. Achievement of these goals is an important step towards Mr. Smucny's long-term goal of becoming a productive independent researcher in the mental health field, with a focus on using neuroimaging to better understand the neurobiology and neuropharmacology of schizophrenia.
Although cognitive deficits (including distractibility and problems with attention) are the greatest predictor of poor quality of life in schizophrenia, they are not clinically well-managed. The aim of this study is to use functional magnetic resonance imaging to examine brain function during an attention task with noise distractors, and to determine if atypical brain activity in patients during the task can be improved with nicotine. The study is expected to yield knowledge that will be used help develop better drugs to treat cognitive symptoms of schizophrenia.
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