Dissecting the Human Medial Temporal Lobe Memory System by functional MRI Von der Medizinischen Fakultät der Rheinisch-Westfälischen Technischen Hochschule Aachen zur Erlangung des akademischen Grades einer Doktorin der Theoretischen Medizin genehmigte Dissertation vorgelegt von Dipl.-Math. Christine Susanne Weis aus Kaiserslautern Berichter: Herr Universitätsprofessor Dr. rer. nat. Klaus Willmes-von Hinckeldey Herr Privatdozent Dr. med. Guillén Fernández Tag der mündlichen Prüfung: 9. November 2004 Diese Dissertation ist auf den Internetseiten der Hochschulbibliothek online verfügbar. 2 1 SUMMARY ................................................................................................................................................5 2 INTRODUCTION .....................................................................................................................................7 WHAT IS EPISODIC MEMORY?..................................................................................................................7 2.1 ANATOMY OF THE MEDIAL TEMPORAL LOBE ............................................................................9 2.2 EPISODIC MEMORY - EVIDENCE FROM FUNCTIONAL IMAGING ................................................13 2.2.1 Encoding.............................................................................................................................15 2.2.2 Retrieval .............................................................................................................................22 2.2.3 Event-related fMRI studies on Encoding and Retrieval of Source Memory .......................28 2.3 OVERVIEW OF THESIS...............................................................................................................33 2.4 LIST OF ABBREVIATIONS..........................................................................................................35 3 MATERIALS AND METHODS ............................................................................................................37 3.1 FUNCTIONAL MAGNETIC RESONANCE IMAGING ......................................................................37 3.1.1 Non-invasive neuroimaging techniques..............................................................................37 3.1.2 The physics of NMR and MRI.............................................................................................38 3.1.3 Image formation: frequency and phase encoding...............................................................42 3.1.4 Ultra fast MRI sequences: Echo-Planar Imaging ..............................................................44 3.1.5 fMRI and the magnetic properties of blood ........................................................................44 3.1.6 Neurophysiology and BOLD...............................................................................................45 3.2 FMRI DATA ANALYSIS WITH SPM ..........................................................................................46 3.2.1 Spatial preprocessing .........................................................................................................48 3.2.2 Statistical parametric mapping...........................................................................................49 3.3 EVENT-RELATED FMRI............................................................................................................55 4 NEURAL CORRELATES OF SUCCESSFUL DECLARATIVE MEMORY FORMATION AND RETRIEVAL: THE ANATOMICAL OVERLAP ...............................................................................57 4.1 INTRODUCTION ........................................................................................................................57 4.2 MATERIAL AND METHODS .......................................................................................................60 4.2.1 Subjects...............................................................................................................................60 4.2.2 Stimuli.................................................................................................................................60 4.2.3 Task ....................................................................................................................................61 4.2.4 fMRI Data Acquisition........................................................................................................62 4.2.5 fMRI Data Analysis ............................................................................................................63 4.3 RESULTS ..................................................................................................................................65 4.3.1 Behavioral Data .................................................................................................................65 4.3.2 Imaging Data......................................................................................................................66 4.4 DISCUSSION .............................................................................................................................79 5 NEURAL CORRELATES OF CONTEXTUAL RETRIEVAL AND ITEM RECOGNITION ARE DISSOCIATED WITHIN THE HUMAN MEDIAL TEMPORAL LOBE ........................................85 5.1 INTRODUCTION ........................................................................................................................85 5.2 MATERIAL AND METHODS .......................................................................................................89 5.2.1 Subjects...............................................................................................................................89 5.2.2 Stimuli.................................................................................................................................89 5.2.3 Task ....................................................................................................................................90 5.2.4 fMRI Data Acquisition........................................................................................................92 5.2.5 fMRI Data Analysis ............................................................................................................92 5.3 RESULTS ..................................................................................................................................94 5.3.1 Behavioral Results..............................................................................................................94 5.3.2 Imaging Data......................................................................................................................96 5.4 DISCUSSION ...........................................................................................................................108 6 GENERAL DISCUSSION ....................................................................................................................114 7 REFERENCES.......................................................................................................................................118 8 ACKNOWLEDGEMENTS ..................................................................................................................131 9 CURRICULUM VITAE........................................................................................................................132 10 LIST OF PUBLICATIONS ..................................................................................................................134 4 1 Summary The work presented in this thesis comprises two event-related functional magnetic resonance imaging (fMRI) studies, which aim at dissociating the contributions of different subregions of the human medial temporal lobe (MTL) to declarative memory processes. The first study examines common neural correlates of memory encoding and recognition. Healthy subjects were scanned both while they memorized complex photographs of buildings and landscapes and while they tried to recognize these pictures in a series of new photographs. Confirming earlier findings, declarative memory formation correlated with an activity increase in the MTL and the inferior prefrontal cortex. Further, during recognition, stronger brain responses to correctly identified old items (hits) as compared to correctly identified new items were found in the parietal lobe, the anterior prefrontal cortex, the anterior cingulate and the cerebellum, replicating findings concerning the commonly used old/new effect. As an innovation, a positive and a negative recognition effect were introduced, comparing brain responses to hits and brain responses to misses (old items misclassified as new) during test. This comparison gives a ‘purer’ measure of neural activity associated with explicit recognition than the commonly used old/new effect. Thus, it can be used to identify decreases and increases in brain activity associated with recognition success. The positive recognition effect, stronger responses for hits than misses, identified activations similar to the old/new effect in prefrontal, parietal, and cerebellar areas. The negative recognition effect, weaker brain responses for hits than misses, which is less contaminated by repetition priming than a reversed old/new effect, offers the possibility to study whether recognition success can also be associated with regional brain activity decreases. In line with electrophysiological findings, this effect identified an activity decrease in the anterior MTL related to recognition success.