From the Cell to the Brain –Fear and Anxiety Across the Levels of Neuroscience

From the Cell to the Brain –Fear and Anxiety across the Levels of Neuroscience Cumulus zur Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) dem Fachbereich Psychologie der Philipps-Universität Marburg vorgelegt von Erik M. Mueller aus Offenbach am Main Marburg, 2011 II When you suffer an attack of nerves you're being attacked by the nervous system. What chance has a man got against a system? ~Russell Hoban III Acknowledgements I would like to express my gratitude to a number of people who have provided invaluable support throughout the course of my research and without whom I would not have been able to compose this thesis. First of all, my „Doktorvater“ Jan Wacker, for being a terrific mentor in all respects. The degrees of freedom you provided on the one hand and the support you gave whenever I asked for it on the other lead to a really pleasant and productive work atmosphere. Gerhard Stemmler, my „Doktorgrossvater“, for being a highly inspirational work group leader and for providing a lot of substantial support for the herein presented studies (including the laboratory and the scientific expertise on psychophysiological measurements). I would like to express particular thanks to Prof. Dr. Nater (Biological Cinical Psycho- logy, Marburg University) who agreed to evaluate this thesis together with Jan Wacker. I am thankful that you take this time although you certainly have a plethora of far ranging other duties and commitments. In this context I further like to thank Prof. Dr. Gollwitzer (Statistical Methods, Marburg University) and Prof. Dr. Schubö (Cognitive Psychophysiology, Marburg University) for taking their time to be part of my dissertation committee. The work presented herein would not have been possible without a variety of collaborators and supervisors overseas. First of all I would like to thank Tom Borkovec (Pennsylva- nia State University), a pioneer in the field of experimental research on Generalized Anxiety Disorder, for helping with Study 3 but even more for his very authentic expression of respect for each and everyone that keeps inspiring me today. Without the help of Stefan Hofmann, who is an expert on Social Phobia at Boston University, and the trust he put into me, neither my diploma thesis nor Study 4 would have been feasible and I am very looking forward to future collaborations. Thank you very much, Stefan! I further have to express my gratitude to Scott Makeig (University of California, San Diego) who is among the leading experts in com- putational EEG research, and who kindly invited me to visit his laboratory for the spring and IV summer of 2010 where the foundations for Study 2 were laid. The work atmosphere you provided was so inspirational that I ended up being in San Diego for several months and only went surfing once! In this context, I obviously have to thank the Society for Psychophysiolo- gical Research for funding my stay at Scott’s laboratory with the 2009 SPR Research Fel- lowship Award. With regard to collaborators and helpers from abroad I would also like to mention Arnaud Delorme and Tim Mullen (UCSD), William Ray and Jennifer Nguyen (PSU), James Cherry (BU), Diane Santesso (Brock University), and Diego Pizzagalli (Har- vard University) who played a substantial role in the studies I have conducted on my way to the PhD. When I started my work as a PhD student my office mate Mira Chavanon welcomed me with a small plant. Although I occasionally forget to water it, this plant is still alive and reminds me of the beginnings. Throughout all the time Mira provided terrific support with whatever questions there were. Particularly at the end she had a close look at this thesis and helped me with some great remarks. Leslie, you did the same and proof-read the thesis as a native speaker, which was a great help! Sebastian and Frank: thank you so much for also ha- ving a closer look at the thesis and pointing out some important aspects. I wish to thank my friends and my family for providing the social support that made my PhD years a time with very precious memories. My father, my mother and my brother, my very close friends Annika, Sebastian, Stefan, Eva and her son Leo. Thank you for being there! Last but not least and most importantly of all I thank you, Verena, for being so encouraging when it comes to my work and for many more things that are far beyond the scope of this thesis... V Content Introduction 1 Methodological Considerations 12 Summaries of Empirical Studies Study I 15 Study II 21 Study III 32 Study IV 38 Integration and Conclusion 46 References 55 Empirical Studies Study I 70 Study II 81 Study III 110 Study IV 118 Appendix 127 Summary in German A-2 Additional Remarks to Study 2 A-9 Matlab scripts A-14 Curriculum Vitae A-19 Relative Contributions to empirical studies A-20 Erklärung A-22 VI List of Abbreviations AMC Anterior Midcingulate Cortex BIS Behavioral Inhibition System BOLD Blood Oxygen Level Dependent cAMP Cyclic Adenosine Monophosphate CECT Cardio-Electroencephalographic Covariance-Trace CNS Central Nervous System CR Conditioned Response CREB cAMP-Responsive Element Binding Protein CS Conditioned Stimulus COMT Catechol-O-Methyltransferase DA Dopamine DSM – IV Diagnostic Statistical Manual of Mental Disorders, IV EEG Electroencephalography ERN Error-Related Negativity FPS Fear Potentiated Startle FRN Feedback Related Negativity GAD Generalized Anxiety Disorder HA Harm Avoidance ICA Independent Component Analysis IGT Iowa Gambling Task PDE-4 Type IV Phosphodiesterase PES Post-Error Slowing PFC Prefrontal Cortex PKA Protein Kinase A PNS Peripheral Nervous System SS Sensation Seeking US Unconditioned Stimulus 1 Introduction Fear and anxiety from genes to behavior – a dynamic multilevel perspective From the perspective of a genome, danger is something bad. Danger means that the probability of primary or secondary needs of an organism being violated is larger than zero (and smaller than one). Eventually, such violations may have negative consequences for the survival and/or reproduction of an organism and its genes. To reduce danger, evolution may have equipped us with fear and anxiety, which are considered two general strategies in the present work. It is assumed that while fear has evolved to get us out of dangerous situations, for example by making us fight, flee or freeze (reactive danger reduction), anxiety helps us to not even get into a dangerous situation in the first place or at least reduce danger of an upco- ming situation (proactive danger reduction). To be able to implement these strategies, fear and anxiety have access to a rich array of “tools”. For example, they can facilitate shifting our attention to potential signs of threat (Eysenck, 1992; E. M. Mueller et al., 2008), increase our awareness for errors (Hajcak, McDonald, & Simons, 2003a; Pailing & Segalowitz, 2004), potentiate our reflexes (M. Davis, 2001; E. M. Mueller, Hofmann, & Cherry, 2010), influence our peripheral nervous system (Stemmler, 2004; Wager, van Ast et al., 2009), make us menta- lize about potential negative futures (i.e. worry; Borkovec, 2002; Borkovec, Robinson, Pru- zinsky, & DePree, 1983) and affect how we make decisions (E. M. Mueller, Nguyen, Ray, & Borkovec, 2010). Most importantly, fear and anxiety are associated with an aversive experience, which biases us to behave in a way that reduces fear and anxiety (Mowrer, 1947). From the perspective of a genome then, it would make sense to establish a selection of genes that provide their carrier with those toolboxes associated with fear and anxiety. For a genome however, wrapped up and packed into hundred billions of cell nuclei, it must be in- credibly difficult to influence the complex physiology, cognition and experience of an organ- 2 ism about a million times larger. How can that be achieved? In the present work this question is addressed from a multilevel perspective inspired from cognitive neuroscience (Churchland & Sejnowski, 1988), where ”level” stands for levels of organization within the central nervous system. Due to gene expression (Molecules Level), neurotransmitters and receptors are built and transported to the synapse (Synapses Level) and thus affect the neurons they connect (Neurons Level). The interconnection of neurons leads to complex networks (Networks Level), which are in turn organized into increasingly higher levels of organization such as anatomical structures (Structures Level), systems of interconnected structures (Systems Level), and the central and peripheral nervous systems (CNS/PNS Level), which eventually compose a human being with feelings of fear or anxiety, physiological symptoms such as increased heart rate and complex behaviors that serve to reduce present or future threats. This path is not unidirectional – in fact, behavior influences activity at anatomical structures and networks, influences synapse formation, and even indirectly influences the expression of genes (Philibert et al., 2010). Another important aspect of the herein presented view on fear and anxiety is that the abovementioned toolbox for fear and anxiety are considered dynamic. Which tools are used in a given instance of fear or anxiety (e.g., increased worrying vs. increased error monitoring), depends not only on genetic contributions, but also on factors such as individual learning experiences (e.g., whether worrying has helped before, or whether errors have led to dangerous situations before), situational demands (e.g., if anticipated danger will lead to subsequent problems that must be solved, and whether the individual is performing at the moment), as well as their interactions. Both learning experiences and situational characteristics are also represented across levels of neuroscience, and thereby modulate fear and anxiety in complex ways. There is good support for attempts to discriminate fear and anxiety at multiple levels of neuroscience. For example, substances that modulate fear (i.e., panicolytics) are different 3 from those that modulate anxiety (i.e.

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