Concurrent and prospective associations between negative social-evaluative beliefs, safety behaviours, and symptoms during and following cognitive behavioural group therapy for social anxiety disorder

Background: Improving the delivery of cognitive-behavioural therapy (CBT) for social anxiety disorder (SAD) requires an in-depth understanding of which cognitive and behavioural mechanisms drive change in social anxiety symptoms (i.e., social interaction anxiety) during and after treatment. The current study explores the dynamic temporal associations between theory-driven cognitive and behavioural mechanisms of symptom change both during and following group CBT. Methods: A randomized controlled trial of imagery-enhanced CBT (n = 51) versus traditional verbal CBT (n = 54) for social anxiety was completed in a community mental health clinic setting. This study included data collected from 12-weekly sessions and a 1-month follow-up session. Mixed models were used to assess magnitude of change over the course of treatment. Cross-lagged panel models were fit to the data to examine temporal relationships between mechanisms (social evaluative beliefs, safety behaviours) and social interaction anxiety symptoms. Results: Participants in both CBT groups experienced significant improvements across all cognitive, behavioural, and symptom measures, with no significant differences in the magnitude of changes between treatments. During treatment, greater social-evaluative beliefs (fear of negative evaluation, negative self-portrayals) at one time point (T) were predictive of more severe SAD symptoms and safety behaviours at T+1. Social-evaluative beliefs (fear of negative evaluation, probability and cost of social failure) and safety behaviours measured at post-treatment were positively associated with SAD symptoms at the 1-month follow-up. Conclusions: The current study identifies social-evaluative beliefs that may be important targets for symptom and avoidance reduction during and following CBT. Assessment of these social-evaluative beliefs throughout treatment may be useful for predicting future SAD symptoms and avoidance, and for adapting treatment to promote optimal change for patients

HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer

BACKGROUND: Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks’ presurgical AI treatment in ER+/HER2+ BCs. METHODS: All available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki672wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. FINDINGS: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki672wk (p<0.0001) than non-HER2-E BCs. High expression of ERBB2 expression, homologous recombination deficiency (HRD) and TP53 mutational score were associated with poor response and immune-related signatures with High Ki672wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14–5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. INTERPRETATION: Our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse

OPTIMIZATIONS OF CHOP: AN EXTENDED MEATAXE ALGORITHM IN GAP

The Meataxe algorithm is a popular algorithm to test modules for irreducibility. I review the theory and particular cases of the Meataxe algorithm and the analogies that can be drawn from normal forms of matrices. I describe my implementation of an algorithm already implemented in GAP (Groups, Algorithms, Programming) to compute the simple composition factors of a module, and implement changes that should in theory speed up computations with large modules. I then test and evaluate predictions

Attention and Inference in Melancholic Depression

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

An Approach for Automatically Measuring Facial Activity in Depressed Subjects

This paper is motivated by Ellgring's work in non-verbal communication in depression to measure and compare the levels of facial activity, before and after treatment, of endogenous and neurotic depressives. Similar to that work, we loosely associate the measurements with Action Units (AU) groups from the Facial Action Coding System (FACS). However, we use the neologism Region Units (RU) to describe regions of the face that encapsulate AUs. In contrast to Ellgring's approach, we automatically generate the measurements and provide both prototypical expression recognition and RU-specific activity measurements. Latency between expressions is also measured and the system is conducive to comparison across groups and individual subjects. By using Active Appearance Models (AAM) to locate the fiduciary facial points, and MultiBoost to classify prototypical expressions and the RUs, we can provide a simple, objective, flexible and cost-effective means of automatically measuring facial activity

White matter alterations in the internal capsule and psychomotor impairment in melancholic depression.

Emerging evidence suggests that structural brain abnormalities may play a role in the pathophysiology of melancholic depression. We set out to test whether diffusion-derived estimates of white matter structure were disrupted in melancholia in regions underpinning psychomotor function. We hypothesized that those with melancholia (and evidencing impaired psychomotor function) would show disrupted white matter organization in internal capsule subdivisions. Diffusion magnetic resonance imaging (dMRI) data were acquired from 22 melancholic depressed, 23 non-melancholic depressed, and 29 healthy control participants. Voxel-wise fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) values were derived for anterior, posterior, and retrolenticular limbs of the internal capsule and compared between groups. Neuropsychological (reaction time) and psychomotor functioning were assessed and correlated against FA. Fractional anisotropy was distinctly increased, whilst RD was decreased, in the right anterior internal capsule in those with melancholia, compared to controls. The right anterior limb of the internal capsule correlated with clinical ratings of psychomotor disturbance, and reduced psychomotor speed was associated with increased FA values in the right retrolenticular limb in those with melancholia. Our findings highlight a distinct disturbance in the local white matter arrangement in specific regions of the internal capsule in melancholia, which in turn is associated with psychomotor dysfunction. This study clarifies the contribution of structural brain integrity to the phenomenology of melancholia, and may assist future efforts seeking to integrate neurobiological markers into depression subtyping

Photocatalytic, structural and optical properties of mixed anion solid solutions Ba3Sc2-xInxO5Cu2S2 and Ba3In2O5Cu2S2-ySey

Nine members of two contiguous solid solutions, Ba3Sc2−xInxO5Cu2S2 and Ba3In2O5Cu2S2−ySey (x, y = 0, 0.5, 1, 1.5 and 2), were synthesised at temperatures between 800 °C and 900 °C by stoichiometric combination of binary precursors. Their structures were determined by Rietveld refinement of X-ray powder diffraction data and found to adopt the SmNi3Ge3 structure with I4/mmm symmetry. Approximate Vegard law relationships were found within each solution between the lattice parameters and composition, with an observed cell volume of 466.4 Å3 for Ba3Sc2O5Cu2S2 increasing to 481.0 Å3 for Ba3In2O5Cu2S2 and finally to 499.0 Å3 for Ba3In2O5Cu2Se2. In the first solid solution, this volume increase is driven by the replacement of scandium by the larger indium ion, generating increased strain in the copper chalcogenide layer. In the second solution the substitution into the structure of the larger selenium drives further volume expansion, while relieving the strain in the copper chalcogenide layer. Band gaps were estimated from reflectance spectroscopy and these were determined to be 3.3 eV, 1.8 eV, and 1.3 eV for the three end members Ba3Sc2O5Cu2S2, Ba3In2O5Cu2S2, and Ba3Sc2In2O5Cu2Se2, respectively. For the intermediate compositions a linear relationship between band gap size and composition was observed, driven in the first solution by the introduction of the more electronegative indium lowering the conduction band minimum and in the second solution by the substitution of the electropositive selenium raising the valance band maximum. Photocatalytic activity was observed in all samples under solar simulated light, based on a dye degradation test, with the exception of Ba3In2O5Cu2Se1.5S0.5. The most active sample was found to be Ba3Sc2O5Cu2S2, the material with the largest band gap

Demographic, clinical and neuropsychological comparisons across melancholic, non-melancholic and control groups.

<p>Demographic, clinical and neuropsychological comparisons across melancholic, non-melancholic and control groups.</p