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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31MH102879-03
Application #
9030947
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Chavez, Mark
Project Start
2014-04-01
Project End
2017-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Psychiatry
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Tregellas, Jason R; Smucny, Jason; Rojas, Donald C et al. (2018) Predicting academic career outcomes by predoctoral publication record. PeerJ 6:e5707
Smucny, Jason; Tregellas, Jason R (2017) Targeting neuronal dysfunction in schizophrenia with nicotine: Evidence from neurophysiology to neuroimaging. J Psychopharmacol 31:801-811
Smucny, Jason; Wylie, Korey P; Kronberg, Eugene et al. (2017) Nicotinic modulation of salience network connectivity and centrality in schizophrenia. J Psychiatr Res 89:85-96
Smucny, Jason; Olincy, Ann; Rojas, Donald C et al. (2016) Neuronal effects of nicotine during auditory selective attention in schizophrenia. Hum Brain Mapp 37:410-21
Smucny, Jason; Olincy, Ann; Tregellas, Jason R (2016) Nicotine restores functional connectivity of the ventral attention network in schizophrenia. Neuropharmacology 108:144-51
Berman, Brian D; Smucny, Jason; Wylie, Korey P et al. (2016) Levodopa modulates small-world architecture of functional brain networks in Parkinson's disease. Mov Disord 31:1676-1684
Smucny, Jason; Visani, Adrienne; Tregellas, Jason R (2015) Could vagus nerve stimulation target hippocampal hyperactivity to improve cognition in schizophrenia? Front Psychiatry 6:43
Tregellas, Jason R; Smucny, Jason; Legget, Kristina T et al. (2015) Effects of a ketogenic diet on auditory gating in DBA/2 mice: A proof-of-concept study. Schizophr Res 169:351-354
Smucny, Jason; Olincy, Ann; Eichman, Lindsay S et al. (2015) Neuronal effects of nicotine during auditory selective attention. Psychopharmacology (Berl) 232:2017-28
Smucny, J; Stevens, K E; Olincy, A et al. (2015) Translational utility of rodent hippocampal auditory gating in schizophrenia research: a review and evaluation. Transl Psychiatry 5:e587

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