D format rk2 9xxxxxXXxx - ediss.sub.uni- DOPAMINERGIC AUGMENTATION of HUMAN FEAR EXTINCTION...

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  • Jan Haaker

    DOPAMINERGIC AUGMENTATION of

    HUMAN FEAR EXTINCTION

  • DOPAMINERGIC AUGMENTATION of

    HUMAN FEAR EXTINCTION

    Dissertation zur Erlangung des Doktorgrades

    an der Fakultät für

    Mathematik, Informatik und Naturwissenschaften, Fachbereich Chemie,

    Institut für Pharmazie

    der Universität Hamburg

    vorgelegt von Jan Haaker Hamburg, 2012

  • Gutachter: Frau JProf. Dr. Dorothee Dartsch Herr Prof. Dr. Christian Büchel Tag der Disputation: 03.August 2012 Bild auf der Umschlagseite: Wikipedia Commons, keine Verwertungsbechränkung, da gemeinfrei veröffentlicht.

  • Table of contents

    1

    Table of contents

    Abbreviations.............................................................................................................. 6

    1. Introduction .......................................................................................................... 8

    1.1 General Introduction ...................................................................................... 8

    1.2 Conditioning ................................................................................................... 9

    1.3 Extinction ...................................................................................................... 10

    1.4 Neural systems mediating fear extinction ................................................. 11

    1.4.1 Amygdala................................................................................................. 11

    1.4.2 Medial Prefrontal Cortex .......................................................................... 14

    1.4.3 Hippocampus........................................................................................... 16

    1.5 Anxiety related disorders ............................................................................ 17

    1.5.1 General .................................................................................................... 17

    1.5.2 Associative learning in acquisition of anxiety related disorders............... 19

    1.5.3 Treatment of anxiety related disorders .................................................... 21

    1.5.3.1 Cognitive-behavioural therapy (CBT) and extinction learning .......................21

    1.5.3.2 Neuroimaging of CBT and extinction.............................................................22

    1.5.3.3 Pharmacological therapy of anxiety disorders...............................................23

    1.6 Memory consolidation ................................................................................. 26

    1.6.1 LTP .......................................................................................................... 26

    1.6.2 Cellular steps in extinction memory consolidation ................................... 27

  • Table of contents

    2

    1.7 Dopamine ......................................................................................................28

    1.7.1 Dopamine in the human body and brain ..................................................28

    1.7.2 Dopamine in appetitive conditioning and motivational control .................29

    1.7.3 Dopamine in fear conditioning and fear memory consolidation ...............30

    1.7.4 Dopamine in extinction and extinction memory consolidation..................33

    2. Study design .......................................................................................................36

    3. Methods...............................................................................................................38

    3.1 SCR ................................................................................................................38

    3.2 fMRI ................................................................................................................40

    3.2.1 fMRI and BOLD........................................................................................40

    3.2.2 fMRI data analysis....................................................................................41

    3.2.2.1 Pre-processing...............................................................................................41

    3.2.2.2 Single-subject analysis ..................................................................................42

    3.2.2.3 Group statistics ..............................................................................................43

    3.2.2.4 Caveats of fMRI analysis ...............................................................................43

    3.3 Methods Study A ..........................................................................................44

    3.3.1.1 Subjects .........................................................................................................44

    3.3.1.2 Randomization...............................................................................................45

    3.3.1.3 Experimental design ......................................................................................46

    3.3.1.3.1 Day 1 (Conditioning) ...............................................................................46

    3.3.1.3.2 Day 2 (Extinction) ...................................................................................48

    3.3.1.3.3 Day 8 (Test) ............................................................................................48

  • Table of contents

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    3.3.2 Ratings..................................................................................................... 48

    3.3.3 SCR ......................................................................................................... 49

    3.3.4 Statistical analysis of behavioural data.................................................... 49

    3.3.5 fMRI (day 8) ............................................................................................. 50

    3.4 Methods Study B .......................................................................................... 54

    3.4.1 Subjects ................................................................................................... 54

    3.4.2 Randomization......................................................................................... 55

    3.4.3 Experimental design ................................................................................ 55

    3.4.3.1 Day 1 (Conditioning + Extinction) ..................................................................55

    3.4.3.2 Day 2 (Test) ...................................................................................................57

    3.4.4 Ratings..................................................................................................... 57

    3.4.5 SCR ......................................................................................................... 58

    3.4.6 Statistical analysis of behavioural data.................................................... 58

    3.4.7 fMRI (day 2) ............................................................................................. 59

    4. Results ................................................................................................................ 61

    4.1 Results Study A............................................................................................ 61

    4.1.1 Day 1 ....................................................................................................... 61

    4.1.1.1 SCR ...............................................................................................................61

    4.1.1.2 Rating of fear/distress....................................................................................64

    4.1.1.3 Summary .......................................................................................................66

    4.1.2 Day 2 ....................................................................................................... 66

    4.1.2.1 SCR ...............................................................................................................67

  • Table of contents

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    4.1.2.2 Ratings of fear/distress ..................................................................................69

    4.1.2.3 Summary .......................................................................................................72

    4.1.3 Day 8 ........................................................................................................73

    4.1.3.1 Spontaneous Recovery .................................................................................74

    4.1.3.1.1 SCR ........................................................................................................74

    4.1.3.1.2 Ratings of fear/distress ...........................................................................76

    4.1.3.1.3 Summary ................................................................................................78

    4.1.3.2 Post-reinstatement.........................................................................................78

    4.1.3.2.1 SCR ........................................................................................................78

    4.1.3.2.2 Ratings of fear/distress ...........................................................................79