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The copyright of this thesis vests in the author. No quotation from it or information derived from it is to be published without full acknowledgement of the source. The thesis is to be used for private study or non- commercial research purposes only. Published by the University of Cape Town (UCT) in terms of the non-exclusive license granted to UCT by the author. University of Cape Town The relationship between impulsivity, affect and a history of psychological adversity: A cognitive-affective neuroscience approach Jonathan C. Ipser Supervisor: Prof. Dan J. Stein Thesis presented for the degree of DOCTORATE OF PHILOSOPHY in the Department of Psychiatry n ow Faculty of Health Science UNIVERSITY OF CAPE TOWN June 2011 ape T y of C Universit DECLARATION I, Jonathan Ipser, hereby declare that the work on which this dissertation is based is my original work (except where acknowledgements indicate otherwise) and that neither the whole work nor any part of it has been, is being, or is to be submitted for another degree in this or any other university. I empower the university to reproduce for the purpose of research either the whole or any portion of the contents in any manner whatsoever. n Signature: ow Date: 23 June, 2011 ape T y of C Universit ABSTRACT Background: There is increasing evidence that trauma exposure is associated with impulsive behaviour and difficulties regulating affect. The findings of recent studies implicate the disruption of neurobiological mechanisms, particularly those involving the neurotransmitter serotonin, in both impulsivity and affect regulation. Method: This thesis interrogated the link between maladaptive responses to childhood trauma, affect-regulation and impulsivity, using a four-pronged approach. Firstly, a systematic meta-analysis of pharmacotherapy for disorders associated with npoor impulse control and aggression in children and adolescents provided a basisow for the argument that developmental disruptions of the serotonergic system are common to both. The extent to which serotonin is involved in difficulties regulating emotion in traumatised adults was subsequently investigated via a meta-analysis of the efficacyape of selective T serotonin-reuptake inhibitors (SSRIs) in treating posttraumatic stress disorder (PTSD). The neural circuitry underlying behavioural impulsivity and affect regulation was identified by conducting an Activation Likelihood Estimation meta-analysisy of of fMRI C data from 51 studies employing the Go/NoGo paradigm. Finally, an empirical investigation of the hypothesis that the relationship between childhood trauma exposure and subsequent difficulties in emotion regulation and impulsivity might be mediated by impaired opioid neurotransmission was conducted by comparing performanceUniversit on an emotion recognition paradigm in 40 trauma-exposed and healthy students from the University of Cape Town who participated in a placebo-controlled study of the partial mu-opioid agonist buprenorphine. Results: This thesis observed evidence that (a) the reduction of aggression symptoms in disruptive behaviour disorders might be mediated by serotonergic pathways, (b) that the SSRIs are effective in treating PTSD, (c), that the GNG paradigm reliability elicits neural activation associated with inhibition and emotion regulation, and (d), that adults with a history of childhood trauma demonstrate impairments in affect regulation, including the avoidance of angry faces, and that buprenorphine was effective in normalising trauma-associated deficits in the recognition of fearful faces. Conclusion: Collectively, the results obtained through a combination of multiple methodologies, including the analysis of data from a pharmacological challenge study as well as that collected through meta-analysis, point to possible clinical and research implications for the serotonergic manipulation of childhood-trauma associated impairments in impulsivity and affect regulation. Moreover, the GNG paradigm appears to ben a suitable candidate measure for the effect of serotonergic agents on affective formsow of impulsive behaviour. ape T y of C Universit ACKNOWLEDGEMENTS I owe a large debt of gratitude to my supervisor, Prof. Dan Stein, who provided encouragement and support during the entire process of writing the thesis. In addition, my family and friends, and in particular Ines Meyer, Floretta Boonzaier & Loraine Townsend, were supportive throughout. I have listed chapter-specific acknowledgements below. Chapter 3 of this thesis, entitled "Systematic review of pharmacotherapy of disruptive behaviour disorders in children and adolescents" was published as a review article in the peer-reviewed journal, Psychopharmacology (impact factor: 4.103). The fulln citation of the article is: Ipser J, Stein DJ. (2007). Systematic review of pharmacotherapyow of disruptive behavior disorders in children and adolescents. Psychopharmacology (Berl). 2007 Mar;191(1):127-40. ape T Chapter 4 of this thesis, entitled "Evidence-based pharmacotherapy of posttraumatic stress disorder" is currently in press with the peer-reviewedy of C International Journal of Neuropsychopharmacology (Impact factor: 4.874). I would like to thank my co-author, Dan Stein, as well as Carli Sager and Nicole Phillips, who assisted with trial selection and data extraction for the meta-analysis included as part of this chapter. Sarah Dawson, the trial search coordinator of the Cochrane Collaboration Depression, Anxiety and Neurosis (CCDAN) review group,Universit kindly assisted with database search queries. I am also grateful to the PIs of the randomised controlled trials who responded to requests for information required to determine the eligibility of trials for inclusion in the review. Drs Mark Hamner, Mark Pollack, Gina Manguno-Mire, and Jonathan Davidson were particularly helpful in this regard. Finally, Dr Michael Hertzberg kindly responded to queries concerning trial methodology. Chapter 5 of this thesis, entitled "Imaging meta-analysis of response inhibition and the Go/NoGo paradigm", and co-authored by Jonathan Ipser and Dan Stein, has been submitted as a manuscript for publication in the peer-reviewed journal, Human Brain Mapping (Impact Factor: 6.25). We would like to thank the anonymous reviewers for their helpful feedback on the review. We are indebted to the authors of the imaging articles who responded to requests for additional information. Particular thanks must go to Hugh Garavan, Robert Hester, Kristin Laurens, Todd Hare and Katya Rubia for their timely feedback. Prof Angela Laird also provided assistance with regards to methodological aspects of the ALE analysis. Finally, we are grateful to Nicole Phillips for assistingn with data entry. ow Finally, a number of people were involved in the placebo-controlled study of buprenorphine, reported in chapter 6 under the heading of "Early psychologicalape trauma T influences later emo- tion recognition: Understanding the role of the opioid system". I would like to thank Prof. Dan Stein as P.I. of the study for allowing me to use this data as part of my thesis. Supriya Syal's assistance with regards to providingy input of in C writing the paper is much appreciated. As co-investigators on the study, Jack van Honk, Ernesta Meintjes, Kevin Thomas, Mark Solms, Susan Malcolm-Smith and Jaak Panksepp were integrally involved in its conception. I am also grateful to Prof. Jack van Honk at Utrecht University for providing the emotion recogni- tion task, and ProfUniversit Martin Kidd in the Faculty of Health Sciences at Stellenbosch University for conducting the GEE and REML analyses reported in this chapter. Nicole Philips assisted with the administration of the study and testing of subjects, with the assistance of Marc Dey, Chris du Plooy and Bjorn Christ. Finally, I am indebted to the students who participated in this study, without whom this research would not have been possible. CONTENTS 1. INTRODUCTION ........................................................................................................... 1 1.1 Characterising the relationship between emotion regulation and impulsivity ............... 3 1.2 The neurobiology of emotion regulation and trauma exposure .................................... 7 1.3 Involvement of neurotransmitters in the relationship between trauma and affect dysregulation ..................................................................................................................... 9 1.4 The behavioural measurement of impulsivity and affect regulation ........................... 12 2. OBJECTIVES .............................................................................................................. 15 3. SYSTEMATIC REVIEW OF PHARMACOTHERAPY OF DISRUPTIVE BEHAVIOURn DISORDERS IN CHILDREN AND ADOLESCENTS............................................................ 18 3.1 Preface......................................................................................................................ow 18 3.2 Introduction............................................................................................................... 19 3.2.1 Treatment ..............................................................................................................ape T 22 3.3 Method ...................................................................................................................... 23 3.4 Results ..................................................................................................................... 27 3.4.1 Meta-analysis.....................................................................................................y