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University of Southampton Research Repository University of Southampton Research Repository Copyright © and Moral Rights for this thesis and, where applicable, any accompanying data are retained by the author and/or other copyright owners. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This thesis and the accompanying data cannot be reproduced or quoted extensively from without first obtaining permission in writing from the copyright holder/s. The content of the thesis and accompanying research data (where applicable) must not be changed in any way or sold commercially in any format or medium without the formal permission of the copyright holder/s. When referring to this thesis and any accompanying data, full bibliographic details must be given, e.g. Thesis: Author (Year of Submission) "Full thesis title", University of Southampton, name of the University Faculty or School or Department, PhD Thesis, pagination. Data: Author (Year) Title. URI [dataset] UNIVERSITY OF SOUTHAMPTON FACULTY OF FACULTY OF SOCIAL, MATHEMATICAL, AND HUMAN SCIENCES Psychology INVESTIGATING THE FRONTO-LIMBIC AND HYPOTHALAMIC-PITUITARY-ADRENAL AXIS SYSTEMS IN CONDUCT DISORDER by Karen Denise González-Madruga Thesis for the degree of Doctor of Philosophy March 2018 UNIVERSITY OF SOUTHAMPTON ABSTRACT FACULTY OF SOCIAL, MATHEMATICAL, AND HUMAN SCIENCES Psychology Thesis for the degree of Doctor of Philosophy INVESTIGATING THE FRONTO-LIMBIC AND HYPOTHALAMIC-PITUITARY-ADRENAL AXIS SYSTEMS IN CONDUCT DISORDER Karen Denise González-Madruga In this thesis, I report studies investigating the neurobiology of conduct disorder (CD) – a disorder diagnosed in children and adolescents who display a persistent pattern of disruptive and aggressive behaviour. My particular focus is on the role of frontal, limbic and hypothalamic-pituitary-adrenal (HPA) axis systems, and especially whether CD-related alterations in these systems differ between males and females. A range of different imaging techniques were applied to data from the Neurobiological and Treatment of Adolescent Female Conduct Disorder study (Fem-NAT-CD). In study 1 (Chapter 4), we employed surface-based morphometry techniques to assess frontal and limbic (cortical and subcortical) brain structures. Similar patterns of CD-related related reductions in cortical volume, thickness, and surface area in the superior frontal gyrus were seen in both sexes. The second study (Chapter 5) assessed the shape of subcortical limbic structures. Youths with CD exhibited shape deformations (i.e., inward) in the shell of the nucleus accumbens compared to controls, independent of sex. The third study (Chapter 6) used spherical deconvolution based- tractography and virtually dissected key fronto-limbic white matter tracts, namely: the uncinate fasciculus, fornix, and the subgenual, retrosplenial and parahippocampal bundles of the cingulum. We observed reduced fractional anisotropy in the retrosplenial cingulum in the CD group relative to healthy controls. However, this result was moderated by sex: males with CD showed reduced, while females with CD showed increased fractional anisotropy compared to sex-matched healthy controls. Finally, we investigated sex differences in HPA axis function (Chapter 7) by measuring cortisol response during the Trier Social Stress Test for Children. Both males and females with CD showed blunted cortisol response to stress, and such effects were not explained by low levels of self-rated fear or anxiety. In a small, proof of concept analysis we observed a positive correlation between cortical volume of the superior frontal gyrus and cortisol reactivity. I conclude that the neurobiological basis of CD is relatively similar in males and females. Thus, previous findings in males with CD may also apply for females with CD. Suggestions for future research are presented and clinical implications are discussed. Table of Contents Table of Contents Table of Contents .................................................................................................................. i Table of Tables .................................................................................................................... xi Table of Figures ................................................................................................................. xiii Academic Thesis: Declaration Of Authorship .............................................................. xvii Acknowledgements ........................................................................................................... xix Definitions and Abbreviations ......................................................................................... xxi Chapter 1 An Introduction to Conduct Disorder ......................................................... 1 1.1 Delimiting the characteristics of Antisocial Behaviour ........................................... 1 1.2 Disruptive behaviour disorders ................................................................................ 2 1.2.1 Oppositional Defiant Disorder ........................................................................ 2 1.2.2 Conduct Disorder ............................................................................................ 3 1.3 Characteristics and prevalence of Conduct Disorder ............................................... 4 1.3.1 Diagnostic Criteria .......................................................................................... 4 1.3.2 Criticisms of the Conduct Disorder Diagnostic Criteria ................................. 5 1.3.3 Prevalence ....................................................................................................... 5 1.3.3.1 Sex Differences in Conduct Disorder ..................................................... 5 1.3.3.2 Possible causes of sex differences in CD ................................................ 7 1.3.3.3 Implications of sex differences ............................................................... 7 1.3.4 Subtypes of CD ............................................................................................... 7 1.3.4.1 Aggressive and non-aggressive forms of CD .......................................... 8 1.3.4.2 Reactive, instrumental and relational aggression .................................... 8 1.3.4.3 Childhood-Onset versus Adolescent-Onset CD ...................................... 9 1.3.4.4 Callous-Unemotional Traits .................................................................... 9 1.4 Conclusion ............................................................................................................. 10 Chapter 2 Biological correlates of Conduct Disorder ................................................ 13 2.1 Risk Factors for Conduct Disorder ........................................................................ 13 2.1.1 Sex differences in risk factors ....................................................................... 15 2.2 The Hypothalamic-Pituitary-Adrenal Axis ............................................................ 16 2.2.1 Associations between the HPA axis and antisocial behaviour ...................... 18 i Table of Contents 2.3 An Introduction to the Limbic System .................................................................. 18 2.4 The neuroanatomy and functions of the fronto-limbic system .............................. 20 2.4.1 Cortical Brain Structures ............................................................................... 20 2.4.1.1 Insular cortex ......................................................................................... 20 2.4.1.2 Orbitofrontal cortex ............................................................................... 20 2.4.1.3 Dorsolateral and medial prefrontal cortex ............................................. 20 2.4.1.4 Anterior and posterior cingulate cortex and parahippocampal gyrus ... 20 2.4.2 Subcortical Brain Structures .......................................................................... 21 2.4.2.1 Hippocampus ......................................................................................... 21 2.4.2.2 Amygdala .............................................................................................. 21 2.4.2.3 Thalamus and Hypothalamus ................................................................ 22 2.4.2.4 Striatum ................................................................................................. 22 2.5 The Associations between the Fronto-Limbic and HPA axis Systems ................. 23 2.6 The Effects of Stress on Fronto-Limbic Structures and the HPA Axis ................. 24 2.7 Prefrontal and Limbic Brain Areas implicated in Conduct Disorder .................... 27 2.7.1 Cortical Brain Structures ............................................................................... 27 2.7.1.1 Insula cortex .......................................................................................... 27 2.7.1.2 Prefrontal cortex .................................................................................... 28 2.7.1.3 Anterior and posterior cingulate cortex and parahippocampal gyrus ... 29 2.7.2 Subcortical Brain Structures .......................................................................... 29 2.7.2.1 Hippocampus ......................................................................................... 29 2.7.2.2 Amygdala .............................................................................................. 30 2.7.2.3 Thalamus and Hypothalamus ...............................................................
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