Effects of nicotine on brain event-related potential and behavioural performance indices of auditory distraction in schizophrenia

Attention dysfunction is a hallmark of schizophrenia, a disorder in which smoking prevalence is double that of the general population. The main interest of this dissertation was in using behavioural performance (accuracy, reaction time or RT) and brain event-related potential (ERP) measures to examine the processing of distracting events in schizophrenic patients and control subjects, and to assess the effects of acute nicotine on this processing. This was accomplished in three experiments by comparing 12 minimally-tobacco-deprived control smokers with 12 outpatient smokers, the latter being assessed under double-blind, placebo-controlled (vs. nicotine) conditions. Experiment 1 used a passive, non-task paradigm to examine the mismatch negativity (MMN) ERP component, an index of early auditory deviance detection. Patients exhibited reduced MMNs to frequency and duration deviants compared to controls, and nicotine increased patients' duration MMN to a level comparable to that seen in controls. Experiment 2 used a novel auditory-auditory distraction paradigm that embeds task-irrelevant deviant features within task-related stimuli requiring location discrimination. Deviants caused RTs to be prolonged in patients and controls. Patients' MMN did not differ from controls' but attentional switching, reflected in the P3a ERP, was attenuated in patients. Nicotine increased patients' MMN to small deviants such that it was no longer smaller than the MMN to large deviants. Experiment 3 used an auditory-visual distractor paradigm requiring participants to discriminate visual letters vs. numbers preceded by task-irrelevant auditory stimuli of standard and deviant frequencies. Reaction times were prolonged by deviants in patients and controls and the MMN of patients to small deviants was diminished. Nicotine increased the MMN to small deviants and reduced RT prolongation and the involuntary attentional switching indexed by the P3a ERP associated with large deviants. Overall, these experiments demonstrated that nicotine can reduce distractibility and can normalize aberrant neural processing of distracting events in schizophrenic patients. Nicotine and schizophrenia iii Dedication and Acknowledgements I dedicate this thesis to my brother, Pierre Dulude, whose brilliant legal career was destroyed by schizophrenia when he was in his early thirties. In the thirty years that followed this diagnosis, Pierre has never been able to return to his beloved field of law. In spite of all the catastrophes he has endured, he is one of the kindest and most cheerful people I know. I have sometimes seen him sad, but I have never seen him bitter. He is my close friend and one of my heroes. I wish he could break his addiction to nicotine. I owe deep thanks to the members of my thesis committee, Drs. Ken Campbell, Helene Plamondon and Bob Stelmack. All three have been my teachers and mentors over many years and were there for me whenever I asked for their help. In particular, I am profoundly grateful to Dr. Ken Campbell, who put his encyclopedic knowledge at my disposal. Finally but not least, I thank my thesis advisor, Dr. Verner Knott. He took me on as a student even though my background in the sciences was much weaker than that of many other applicants. He fostered a congenial and egalitarian atmosphere in our lab at the Royal Ottawa Hospital in which there are no stupid questions and everyone helps everyone else. In the many jobs I have held in my life, I have rarely seen such a happy workplace. Most of all, Dr. Knott himself was always available, and very patient with this oldest and slowest of his students. Special thanks also to all those who participated in my experiments, and of course to my ever-supportive husband, Leonard Shifrin. Nicotine and schizophrenia iv