The raie of the prefrontal cortex in episodic memory: PET studies in normal subjects. Shitij Kapur A thesis submitted in conformity with the requirements for the Degree of Philosophy in the Institute of Medical Sciences University of Toronto. O Copyright Shitij Kapur, 1997. National tibrary Bibliothèque nationale 1*1 of Canada du Canada Acquisitions and Acquisitions et Bibliographie Services services bibliographiques 395 Wellington Street 395, rue Wellington OtiawaON K1AON4 OttawaON K1AON4 Canada Canada 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, distribute 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/nlm, 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 imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation. The role of the prefrontal cortex In eplscxlic memory: PET sWdles In normal rubjects. Shitij Kapur, PhD Thesis, 1997. Institute of Medicd Sciences, University of Toronto. This thesis documents the findings of a series of positron emission tomography (PET) experiments undertaken to elucidate the neural correlates of episodic memoxy - in particular, to understand the hctional contributions of the prefiontal cortex to episodic memory. Healthy young adults were scanned ushg [15~]-~fi-~~~imaging as they Camed out encoding and retrieval tasks. The data were analyzed using the cognitive subtraction paradigrn and Statistical Parametric Mapping technique of image analysis. The results clearly doaunent a dflerentiai involvement of the left and right prenontal cortex in encoding and retrieval respectively. The thesis firther suggests that the lefk prenontal activation is invoked by the task requirement of ''working with meaning" of the stimulus. The results are supportive of a role for the left prefiontal cortex in facilitating the formation of a retrievable engram, regardiess of the subject's intention. The right prefiontal cortex is invoked equdy in recall and recognition tasks when these tasks are equated for difnculty. The role of the right prefiontal cortex in retrievai, as reveaied by PET, is consistent with the concept of "retrieval attempt" and is distinguishable for the concept of "ecphory" which may be a medial temporal or posterior association cortex based process. The results are discussed in concert with neuropsychological findings and it is concluded that the prefionta cortex facilitates memory encodhg and retrieval processes - though it may not be the site where the engram resides. The discrepanq with established neuropsychological findings is discussed and directions for fiiture research are outlined. Page ii - -- - - - - Acknowledg ments 1 1 must Estacknowledge my gratitude to the late Dr. Cleghom - to work with whom 1 retumed to Canada. His absence is SMfelt - but would have been felt even more had it not been for the guidance and mentorship of my supervisor - Dr. Greg Brown. 1 owe a special debt to Dr. Brown for shepherding me through the pitfds and fdow penods which befall a doctoral pursuit. To Profs. F.1.M Cr& and Endel TulWig for inviting me to study the 'science of the rnind' and teaching me about memory - and making it a rnost mernorable experience. To Dr. Robert Zipursky for enwwaging me to undertake this joumey in leaming - at a tirne when many interesthg cliaical questions in schuophrenia stood waiting. And to Dr. Sylvain Houle for showing me how one can do wondemil things with a few detectors, mathematics and cornputers. To this group of talenteci and supportive mentors - a special thanks. As 1 have tried to synthesize the work done over the last three years, establishing the exact parentage of each idea is not possible. Therefore, whenever 1 refer to our experiments and pubiished papers 1 use the term "we" - for these papers and their underlying experiments refiect our efforts as a group. Thoughts which are being expressed for the first thne in the PET-memory context in this thesis are owned with an 'T' - though I am indebted to my cornmittee, and particularly Professor Cr& for help in artiailating them. Thanks to my fiiends in the trenches - Douglas Hussey, Corey Jones, Stephen Dobbin, Terry Bell, Randi Rose, Kevin Cheung and Drs. Alan Wilson and Jean DaSilva. Through a myriad of kind and intelligent acts they helped me first in getting the work done, and then goaded me on in the seemingly endless task of writing this thesis. Thanks to two outstanding Institutions - The Clarke Institute of Psychiatry and the Rotman Research Institute - for providing the support and the atmosphere without which work such as this can never be done. 1 have thanked but a few, of the many, who have contributed in ways too numerous to make note of here. 1 have been fortunate to have your help and support. 1 hope this work meets your expectations. Finu&, to Shi& and Am- who make this, and al2 else, rneunin~l]. The role of the prefrontal cortex in episodic memory: PET studies in normal subjects. Doctoral Thesis Shitij Kapur 1996. Table of Contents 1 Section Page 1 Preamble .. Abstract ..........................................................................................................ll Acknowledgments ......................................................................................III Table of Contents ....................................................................................... iv ûutline of research and organization of the thesis ..........................................vi Chapter 1 Introduction........................................................................................... 1-1 Memory processes and memory systems ................................................... 1-1 Neural buis of memory ....................................................................... 1-13 Chapter 2 Introduction.. ........................................................................................ II- 1 ûverview of PET methods .......................................................................II- 1 SPM Analysis .....................................................................................II-7 Assumptions and their implications .......................................................... II-9 Methodological studies .......................................................................... IL2 1 Chapter 3 Ratiode for the Experimental Plan ........................................................DX- 1 Article # 1 Kùpr et ai., Pra.Nd Acad Sei., 1994 ...............................III-8 Article # 2 Kqret al., Neuroreprt, 1994 ............................................ III-9 Article # 3 K#et al., Cog. Brain Research, In press 1996............... .III- 10 Article # 4 Kapur et al., Neuroreport, 1995..................................... - 1 1 Article # 5 Cabeza et al., J Cog. Neurosci., In press 1996.................... .ID42 Chapter 4 Hemispheric Enwding Retrieval Asymmetry (HERA) ..............................IV-1 Lefi prefkontal cortex in encoding ............................................................IV-9 The nght prefiontal cortex in retrievd...................................................... IV- 12 Page iv What leads to the hemispheric asymmetry in HERA mode1 ...................... IV21 Where's the hippocarnpus?....................................................................... IV24 A rudimentary neurocognitive mode1 of episodic memory ........................ IV-3 1 Contributions of this thesis, its major Limitations and fiiture directions ......IV-3 5 Appendices TuiMng et aL Proc. Nd. Acad Sc i... 1994...................................................... V-2 Tuh>ing et al . Proc . Nat . A& Sci.. 1994 ...................................................... V-3 Moswvitch et al . Proc. Nat . Acad Sci., 1995............................................... V-4 Kohler et al . NeuroReprî, 1995 ................................................................... V-5 Nyberg et al . NwoReprt. 1995 ................................................................... V-6 Bibliography.............................................................................. VI-1 Page v Outline of the research and organization of the thesis The thesis is organized in five chapters. Thefirst chopter provides a review of the relevant litemture. It focuses on the concept of memory systems and memory processes as seen from a cognitive perspective. The chapter also reviews the role of dinerent brain regions as revealed by classic neuropsychological studies. The second chapter focuses on the general experimentai methods. It outlines the methods of subject recruitment, image acquisition and data analysis that were foliowed in these studies. It also reviews the assumptions and caveats related to the use of regional cerebral blood flow (rCBF) imaging and to the use of the cognitive subtraction paradip. In addition, some of the original work done by our group to clwthe use of rCBF imaging is describeci. Chpter three is a compilation of articles (three published, two in press) describing the results of the studies that