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Note to Users NOTE TO USERS This reproduction is the best copy available. Université d'Ottawa University of Ottawa Nicotine & Tourette Syndrome I Clinical and Attentional Effects of Acute Nicotine Treatment in Tourette Syndrome Anne L. Howson, B.A., M.B.A. A dissertation submitted to the School of Graduate and Postdoctoral Studies of the University of Ottawa as partial filfilment of the requirements for the degree of Doctor of Philosophy Dissertation Supervisor: Vemer J. Knott, D.Phi1. Ottawa, Canada, 2000 0 Anie L. Houson, Ottawa, Canada, 2001 National Library Bibliothèque nationale du Canada Acquisitions and Acquisitions et Bibliographie Services services bibliographiques 395 WeMington Street 385, nre Wellington OltawaON K1AOFU ûüawaûN K1AW CanadB cenada The author has granted a non- L'auteur a accordé une licence non exclusive licence allowing the exclusive permettant à la National Library of Canada to Bibliothèque nationale du Canada de reproduce, loan, distn'bute or sell reproduire, prêter, distribuer ou copies of this thesis in microform, vendre des copies de cette thèse sous paper or electronic formats. la forme de microfiche/film, de reproduction sur papier ou sur format électronique. The author retains ownership of the L'auteur conserve la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts fiom it Ni la thèse ni des extraits substantiels may be printed or otherwise de celle-ci ne doivent être imprimes reproduced without the author' s ou autrement reproduits sans son permission. autorisation. Nicotine & Tourette Syndrome t Acknowledgements Professiondly, 1 would like to thank my thesis supenisor, Vemer Kaott, for welcoming rny ideas and helping to create a research projec t that was interesthg and rewarding for us both. As an exceptional teacher and true mentor, Vemer has shown patience, encouragement and guidance, through the modelling of exemplary professionalism throughout. I am also extrernely thankful for his support in applying for a gant to the Tourette Syndrome Association, the receipt of which provided the financial support for the running of this study. in addition, 1 would like to express my gratitude to Colleen Mahoney, Vemer's former research assistant, who helped navigate through the numerous logistical, statistical, and seemingly mystical challenges associated with this research process, always with patience, encouragement and a srnile. 1 would like to thank Ken Campbell, Mario Cappelli and Clarissa Bush for their participation as memben of my thesis comrnittee, as well as for their insightful and encouraging comments. 1 would like io thank the libmians at the Rhodes Chalke Library of the Royal Ottawa Hospital, who taught much and helped trernendously with the research component of this project. I would also Wre to thank the physicians, who refmed patients to this st~dy,as well as the parents of the study subjects for the significant investment in the they made. Most of al1 1 would like to thank the children and adolescents with TS who took part in the study, giWig of their time and of themselves, to the demanding, and often ''h~g"requirements of repeated assessrnent on sustained attention tasks. Spending time with them during testing and waiting periods was a great pleanire and a lot of fuo. Nicotine & Tourette Syndrome 3 On a more personal note, 1would like to thank my farnily for their encouragement and support throughout this endeavour, and in particular, my mother, Mary Howson, who always encouraged us to follow our dreams. 1 am thanfil to my fnends, Charles Lepage, Kathryn Campbell, and Douglas Schmidt, who led the way and showed that it was possible to complete a seemingly intemiinable PhD thesis! Most importantly, I would like to express my extreme gratitude and appreciation to my partner, Natasha Tay Lyons, who has seen this thesis through f?om beginniag to end. Without her encouragement and support, 1 don? believe 1 would have enjoyed the oft-daunting process of completing this PhD thesis as much as I have. I am forever gratehil for her continued belief in the validity and achievability of my dreams. Nicotine & Tourette Syndrome 4 In loving memory of my father, Hugh Riddock Howson, C.A., Ph.D. "remember, Anne-Louise, the three keys to a successful Pm....focus, focus, focus" and ...as told to a dear philosopher niend of mine, "remember Charles, a PhD is not a career". Nicotine & Tourette Syndrome 5 ABSTRACT Tourette Syndrome (TS) is characterized primarily by multiple motor and vocal tics. Additionally cognitive deficits, such as problems with attention, may also exist, in those both with and without CO-morbidAttention Defici~HyperactivityDisorder (ADHD). Although neuroleptics, which block dopamine receptots, are ofien the treatment of choice for TS, insufficient symptomatic control often requires the use of increased doses. In addition, undesirable side effects cm occur at high doses of neuroleptics, including detrimental effects on attention and concentration. Nicotine has been reported to effectively potentiate neuroleptic- induced catalepsy in rats and, when combined with neuroleptics, to reduce motor and vocal tics in TS patients. However, reported acute and sustained (Le. up to 8 weeks) nicotine-induced improvements in tic symptomatology in TS patients have corne fkom case reports, open and single blind studies. Nicotine alone has been shown to improve attention and cognition in both nomal and neuropsychiatnc populations. This double-bhd, placebo-controlled, crossover design study investigated the comparative efficacy, both acute and sustained, of placebo and a single test dose of transdennal nicotine patch (TNP) on clinical symptoms of TS (i.e. tics), evaluative ratings (by parents) of attention and maladaptive behaviours, as well as event-related potential (ERP) and behavioural performance measures extracted fiom a degraded stimulus continuous penormance task @S-CPT) of sustained attention. Twenty-three children and adolescents with TS (with and without CO-morbidADHD), aged 8-17, who were takuig conventional neuroleptics (i.e. dopamine D-2receptor antagonists) were entered into the study. Nicotine & Tourette Syndrome 6 Adjunctive nicotine, relative to placebo, failed to significantly alter tic symptomatology in either the acute (Le. 4 hours post-treatment) or follow-up (Le. 1 week post treatment) conditions. At follow-up but not at acute assessment, parents reported non-specific improvements in attention, and performance was found to have improved on Coding, a visuomotor task measuring keedom fiom distractibility, following nicotine treatment. Nicotine had a limited effect on area measures of the P300 component of the ERP, by preventing area decrements seen following placebo treatment. However, 0thperformance measures on the DS-CPT,including accuracy and speed of responding, and P300 amplitude and latency measures, failed to identify any significant effects of nicotine relative to placebo. Given the lack of initial significant effects of a single dose challenge of nicotine and the side eEect profile of the TNP,the clinical use of adjunctive nicotine in neuroleptically treated children and adolescents with TS appears premature. Nicotine & Tourette Syndrome 7 Table of Contents Page Acknowledgements 2 Abstract 5 Table of Contents 7 List of Tables 10 List of Figures 13 List of Appendices 14 1. INTRODUCTION 15 a, Tourette Svndmme i. History 16 ii. Epidemiology 18 M. Ciinical Cbaracteristics 1. Onset 21 2. Course 22 3. Prognosis 24 4. Co-morbidity 24 iv. Attentional Deficits 27 v. Pharmacological Treatment of TS 33 1. Cogn iriw Side Eficc~sof Neurolep ic Treatment in TS 37 vi. Nicotine Treatment of TS 38 1. Animal Studies 39 2. Human Studies 41 b. Nicotine 1. Pharmacology of Nicotine 42 1. Phannacokinetics 42 2. Pharmacodytiamics 44 .. II. Nicotine and Cognition: Animals 46 .*. 111. Nicotine and Cognition: Humans 50 iv. Nicotine and Cognition: Neuropsychiatrie Populations 53 v. Nicotine and Attention 55 c. Event-Related Potentials 64 i. P300 Wave 66 1. PhysiologicaI Characteristics of the P300 68 2. Psychological Aspects of the P300 68 a. P300 Amplitude Variations 68 b. P300 Latency Variations 72 ii. P300 and TS 73 iii. P300 and ADHD 74 iv. P300 and Nicotine 75 d. Summaw and Rmtionale 84 e. Hvwtheses 85 Nicotine & Tourette Syndrome 8 2. METHOD Studv Subiects i. Inclusion Criteria ii. Exclusion Criteria Studv Design Studv Procedure Nicotine ûosiaq Neurole~ticTreatment Ratinn %ales and Questioanaires Videota~ianof TS Svmptoms Continuous Performance Test Paradinm (CPT) ERP Recordhn/Measures Statistlcal Anal~sis 3. RESULTS a. Adverse Events b. Dro~Outs c. Acute Effects i, Clfnical 1. Tic Frequency ii. Attentional 1. Digit Span 2. Coding 3. CPT Peflormonce 4. CPT ERP: P300 Amplitude and Lotency S. CPT ERP: P300 Areas de FoUow-UPEffects i. CLIaicrl 1. Tic Frequency 2. YGTSS 3. TSSL-P 4. TSSL-C 5. Conners ü. Atteaüoaal 1. Digit Span 2. Coding 3. CPT Petjionnance 4. CPT ERP: P300 Amplimde und Latency 5. CPT ERP= P300 Areas c Su~~lementrnFindinns i. Clinical (subsct of subjects taking haloperidol) ii, Cornl+tional Analysis Nicotine & Tourette Syndrome 9 4. DISCUSSION a. Acute Effects i. Clinical ü. Attentional 1. CPT Perjonnance 2. CPTERP: P300 b. Foliow-up Effects i. Ciinical 1. Tic S'ptomatology 2. Conners ii. Attentional 1. CPT Perfîonnance 2. CPTERP:P300 c. Acute versus FoUow-UREffects d. Strenaths and Limitations of tbe Study e. Theoretical Implicrtions f. Clinical Im~lications g. Su~pestioasCor Future Rcsesrch h. Conclusions List
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