Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Social Sciences 140 The Amygdala, Fear and Reconsolidation Neural and Behavioral Effects of Retrieval-Extinction in Fear Conditioning and Spider Phobia JOHANNES BJÖRKSTRAND ACTA UNIVERSITATIS UPSALIENSIS ISSN 1652-9030 ISBN 978-91-554-9863-4 UPPSALA urn:nbn:se:uu:diva-317866 2017 Dissertation presented at Uppsala University to be publicly examined in Gunnar Johansson salen, Blåsenhus, von Kraemers allé 1A, Uppsala, Friday, 12 May 2017 at 13:00 for the degree of Doctor of Philosophy. The examination will be conducted in English. Faculty examiner: Emily Holmes (Karolinska institutet, Institutionen för klinisk neurovetenskap; University of Oxford, Department of Psychiatry). Abstract Björkstrand, J. 2017. The Amygdala, Fear and Reconsolidation. Neural and Behavioral Effects of Retrieval-Extinction in Fear Conditioning and Spider Phobia. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Social Sciences 140. 72 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-9863-4. The amygdala is crucially involved in the acquisition and retention of fear memories. Experimental research on fear conditioning has shown that memory retrieval shortly followed by pharmacological manipulations or extinction, thereby interfering with memory reconsolidation, decreases later fear expression. Fear memory reconsolidation depends on synaptic plasticity in the amygdala, which has been demonstrated in rodents using both pharmacological manipulations and retrieval-extinction procedures. The retrieval-extinction procedure decreases fear expression also in humans, but the underlying neural mechanism have not been studied. Interfering with reconsolidation is held to alter the original fear memory representation, resulting in long-term reductions in fear responses, and might therefore be used in the treatment of anxiety disorders, but few studies have directly investigated this question. The aim of this thesis was to examine the effects of the retrieval-extinction procedure on amygdala activity and behavioral fear expression in humans. The work presented here also investigated whether findings from studies on recent fear memories, established through fear conditioning, extends to naturally occurring long-term phobic fears. Study I, combining fear conditioning and a retrieval-extinction procedure with functional magnetic resonance imaging (fMRI), demonstrated that memory retrieval shortly followed by extinction reduces later amygdala activity and fear expression in healthy subjects. In Study II, these subjects were re-tested 18 months later. The results showed that the effects on fear expression were still present and that initial amygdala activity predicted long-term fear expression. Using an adapted version of the retrieval-extinction procedure, Study III showed that memory retrieval shortly followed by exposure to spider pictures, attenuates subsequent amygdala activity and increases approach behavior in subjects with life-long fear of spiders. In Study IV, these subjects were re-tested 6 months later, and the results showed that effects on amygdala activity as well as approach behavior were maintained. In summation, retrieval-extinction leads to long-lasting reductions in amygdala activity and fear expression. These findings are consistent with the hypothesis that retrieval-extinction alters an amygdala dependent fear memory. Retrieval-extinction can also attenuate long-term phobic fears, indicating that this manipulation could be used to enhance exposure-based treatments for anxiety disorders. Keywords: Fear conditioning, phobia, memory reconsolidation, retrieval-extinction, exposure therapy, amygdala, fMRI Johannes Björkstrand, Department of Psychology, Box 1225, Uppsala University, SE-75142 Uppsala, Sweden. © Johannes Björkstrand 2017 ISSN 1652-9030 ISBN 978-91-554-9863-4 urn:nbn:se:uu:diva-317866 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-317866) To Frida, Arvid and Nora List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Agren, T., Engman, J., Frick, A., Björkstrand, J., Larsson, E. M., Furmark, T., Fredrikson, M. (2012) Disruption of reconsolida- tion erases a fear memory trace in the human amygdala. Science, 337(6101),1550-1552 II Björkstrand, J., Agren, T., Frick, A., Engman, J., Larsson, E. M., Furmark, T., Fredrikson, M. (2015) Disruption of memory recon- solidation erases a fear memory trace in the human amygdala: an 18-month follow-up. PLoS ONE, 10(7), e0129393 III Björkstrand, J., Agren, T., Åhs, F., Frick, A., Larsson, E. M., Hjorth, O., Furmark, T., Fredrikson, M. (2016) Disrupting recon- solidation attenuates long-term fear memory in the human amyg- dala and facilitates approach behavior. Current Biology, 26(19), 2690-2695. IV Björkstrand, J., Agren, T., Åhs, F., Frick, A., Larsson, E. M., Hjorth, O., Furmark, T., Fredrikson, M. (2016) Think twice, it’s alright: Long lasting effects of disrupted reconsolidation on brain and behavior in human long-term fear. Behavioural Brain Re- search, 324, 125-129. Reprints were made with permission from the respective publishers. Contents Introduction ............................................................................................... 11 Learning and memory .......................................................................... 11 Consolidation and reconsolidation ....................................................... 13 Fear conditioning .................................................................................. 14 Neural substrates of fear conditioning ............................................. 15 Fear extinction ...................................................................................... 17 Neural substrates of fear extinction ................................................. 18 Fear conditioning, extinction and anxiety disorders ............................ 20 Disrupting the reconsolidation of fear memories ................................. 23 Age and strength of fear memories .................................................. 23 Length of memory activation .......................................................... 25 Neural substrates of fear reconsolidation ............................................. 26 Pharmacological reconsolidation disruption in humans ....................... 28 Updating fear memories using retrieval-extinction .............................. 29 Translating retrieval-extinction to humans .......................................... 30 Disrupting reconsolidation in anxiety disorders ................................... 33 PTSD ............................................................................................... 34 Spider phobia ................................................................................... 35 Aims .......................................................................................................... 39 Methods..................................................................................................... 40 Skin conductance responses ................................................................. 40 fMRI ..................................................................................................... 40 Summary of studies ................................................................................... 42 Study I .................................................................................................. 42 Background and aim ........................................................................ 42 Methods ........................................................................................... 42 Results ............................................................................................. 44 Discussion ........................................................................................ 44 Study II ................................................................................................. 45 Background and aim ........................................................................ 45 Method ............................................................................................. 45 Results ............................................................................................. 45 Discussion ........................................................................................ 46 Study III ................................................................................................ 48 Background and aim ........................................................................ 48 Methods ........................................................................................... 48 Results ............................................................................................. 49 Discussion ........................................................................................ 52 Study IV ............................................................................................... 53 Background and aim ........................................................................ 53 Methods ........................................................................................... 53 Results ............................................................................................. 53 Discussion ........................................................................................ 55 General discussion ...................................................................................