Attention and Inference in Melancholic Depression Matthew Paul Hyett BSc (Psych); PGDipPsych A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy in Psychiatry at the University of New South Wales SCHOOL OF PSYCHIATRY FACULTY OF MEDICINE January 2015 PLEASE TYPE THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet Surname or Family name: Hyett First name: Matthew Other name/s: Paul Abbreviation for degree as given in the University calendar: PhD School: Psychiatry Faculty: Medicine Title: Attention and Inference in Melancholic Depression Abstract 350 words maximum: (PLEASE TYPE) Melancholia has long been positioned as a quintessentially biological depressive condition. Impairments in attention are prominent, particularly in shifting attention away from internal states, but a detailed neurocognitive understanding of these deficits is lacking. This thesis hence sought to clarify the cognitive and neurobiological mechanisms of attention deficits in melancholia. Analytic methods spanning cognitive and brain network modelling were employed to explore the biases and inflexibility of attention in melancholia, compared to non-melancholic depressed and healthy individuals. The first study (Chapter 2) investigates disrupted attentional inference to emotional stimuli across sub-types of depression and healthy participants. I hypothesised that both depressed groups would show impaired discriminability of emotional signals, and that melancholia would be characterised by decreased sensitivity to emotional stimuli. Signal detection data .from an attentional control task were modelled using hierarchical (Bayesian) statistics. Melancholia was associated with disrupted sensitivity of emotional signals, and poorer discriminability of neutral signals, hence likely reflecting distorted attentional inference. The second study (Chapter 3) explores resting state functional brain network effective connectivity across melancholic, non-melancholic and control groups. Interactions between cortical systems corresponding to attention, executive control and interoception - derived from independent component analysis (ICA) - were modelled using dynamic causal modelling (DCM). Analyses supported the hypothesis that relationships amongst networks subserving attention and interoception would be disrupted in melancholia. This study revealed a specific 'dysconnectivity' between brain regions underpinning attention and interoception in melancholia. In the third study (Chapter 4), I advanced an in-scanner naturalistic film viewing paradigm to quantify brain networks underling the shifting of attention from rest to dynamic processing of exogenous emotional stimuli, employing the same groups as Chapter 3. I hypothesised that cortical systems would remain in an "at-rest" state in melancholia, reflecting impaired attentional shifting to exogenous stimuli. Surprisingly, neuronal activity in systems supporting attention and interoception were increased in melancholia compared to controls during negative film viewing. I speculate that these findings reflect ineffective neuronal adaptation during attentional resource allocation to emotional material in melancholia. Preliminary analyses (presented in Chapter 5) highlight that impaired attentional set-shifting performance is associated with disruptions to these neuronal systems, hence pointing to a disorder-specific behavioural analogue of the neurobiological findings. The studies comprising this thesis offer a unique cognitive and neurobiological explanation for attentional deficits in melancholia, and act to explain aspects of its clinical presentation in terms of impaired redirection of attention away from persistent and dysphoric internal states. Declaration relating to disposition of project thesis/dissertation I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or in part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all property rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. 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FOR OFFICE USE ONLY Date of completion of requirements for Award: THIS SHEET IS TO BE GLUED TO THE INSIDE FRONT COVER OF THE THESIS Originality Statement I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project’s design and conception or in style, presentation and linguistic expression is acknowledged. Matthew Paul Hyett 5 January 2015 Page | II Copyright Statement I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or part in the University libraries in all forms of media, now or hereafter known, subject to the provisions of the Copyright Act 1968. I retain all proprietary rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the abstract of my thesis in Dissertations Abstract International (this is applicable to doctoral theses only). I have either used no substantial portions of copyright material in my thesis or I have obtained permission to use copyright material where permission has not been granted. I have applied/will apply for a partial restriction of the digital copy of my thesis or dissertation. Note: Copyright has been obtained from each journal for inclusion of the published material in this thesis. Matthew Paul Hyett 5 January 2015 Page | III Authenticity Statement I certify that the Library deposit digital copy is a direct equivalent of the final officially approved version of my thesis. No emendation of content has occurred and if there are any minor variations in formatting, they are the result of the conversion to digital format. Matthew Paul Hyett 5 January 2015 Page | IV Table of Contents Chapter 1: General Introduction.............................................................................. 1 1.1 Background ..................................................................................................... 1 1.2 Depression: Epidemiology and Classification ................................................ 4 1.2.1 The Burden of Depression ............................................................................................4 1.2.2 Classifying Depression – From Phenomenology to the Laboratory ................................5 1.3 Theories of Attention ....................................................................................... 8 1.3.1 Parsing Attention into Distinct Behavioural Components ..............................................9 1.3.2 Automatic and Controlled Attention............................................................................ 10 1.3.3 Neuropsychological Models of Attention .................................................................... 10 1.3.4 Cognitive and Computational Modelling of Attentional Processes ............................... 12 1.4 Functional Neuroimaging: Background and Analysis Methods .................. 14 1.4.1 Dynamics of Brain Organisation ................................................................................. 16 1.5 Neuroimaging Studies of Attention ............................................................... 18 1.5.1 Segregation of Attentional Brain Networks ................................................................. 19 1.6 Cognitive Deficits and Attentional Disturbances in Melancholia ................ 21 1.6.1 Relationships between Psychomotor Disturbance and Attention Deficits ..................... 22 1.6.2 Selective Attention: Set-Shifting and Inhibition .......................................................... 23 1.6.3 Controlled/Effortful and Automatic Attentional Processing ......................................... 24 1.6.4 Summary of the Neuropsychology of Attention in Depression .................................... 25 1.7 Functional Imaging Studies of Depression ................................................... 25 1.7.1 Emotional Circuitry and Depressive Disorders ...........................................................