Neurocognitive networks for social cognition: Insights from diffusion weighted imaging and frontotemporal dementia

Empathy is a complex and multicomponent social cognitive function. It is underpinned by large-scale neurocognitive networks, the precise cognitive and neural structure of which remains debated. Despite this, relatively little work has considered the cognitive or neural components of empathy at the network-level. Here I present work using diffusion weighted magnetic resonance imaging (DWI) in healthy adults, and cognitive and behavioural assessment in a relatively rare form of dementia, the behavioural variant of frontotemporal dementia (bvFTD). Using these methods I explore: (a) the relationship between the microstructural properties of white matter tracts that mediate connectivity between distinct neurocognitive networks and separable cognitive components of empathic cognition (b) the cognitive and behavioural consequences of perturbation to neurocognitive networks in dementia. BvFTD is of interest here as it appears to preferentially target neural networks that support socioemotional processing. In chapters 2 and 3, evidence regarding the white matter structures that are affected by bvFTD guides investigations of the relationship between the microstructural properties of specific white matter tracts and social cognitive functioning in the healthy adult brain. In these chapters, I show that, in young healthy adults, two white matter pathways, sensitive to early changes in bvFTD, the Uncinate fasciculus (UF) and the cingulum bundle (CB), are related to individual differences in two components of empathic functioning, respectively: facial emotion decoding and mentalising. In chapter 4 I show the dissociation of performance on tasks assessing these cognitive functions in an individual with early bvFTD. I highlight the sensitivity and potential clinical utility of tasks assessing literary fiction-based mentalising. In Chapter 5 I present a detailed qualitative description of social cognitive change in frontotemporal dementia (FTD), from the perspective of family members. I consider what such detailed descriptions of everyday behaviour may tell us about the cognitive underpinnings of complex social behaviour. The findings of this thesis further our understanding of the dissociable neurocognitive networks that support empathic functioning, including their structural underpinnings and the behavioural consequences of their perturbation. In the general discussion, I consider the implications of this work for our understanding of social cognitive functioning and bvFTD

Structural connections support emotional connections: uncinate fasciculus microstructure is related to the ability to decode facial emotion expressions

The Uncinate Fasciculus (UF) is an association fibre tract connecting regions in the frontal and anterior temporal lobes. UF disruption is seen in several disorders associated with impaired social behaviour, but its functional role is unclear. Here we set out to test the hypothesis that the UF is important for facial expression processing, an ability fundamental to adaptive social behaviour. In two separate experiments in healthy adults, we used high-angular resolution diffusion-weighted imaging (HARDI) and constrained spherical deconvolution (CSD) tractography to virtually dissect the UF, plus a control tract (the corticospinal tract (CST)), and quantify, via tissue fractional anisotropy (FAT), individual differences in tract microstructure. In Experiment 1, participants completed the Reading the Mind in the Eyes Task (RMET), a well-validated assay of facial expression decoding. In Experiment 2, a different set of participants completed the RMET, plus an odd-emotion-out task of facial emotion discrimination. In both experiments, participants also completed a control odd-identity-out facial identity discrimination task. In Experiment 1, FAT of the right-, but not the left-hemisphere, UF was significantly correlated with performance on the RMET task, specifically for emotional, but not neutral expressions. UF FAT was not significantly correlated with facial identity discrimination performance. In Experiment 2, FA of the right-, but not left-hemisphere, UF was again significantly correlated with performance on emotional items from the RMET, together with performance on the facial emotion discrimination task. Again, no significant association was found between UF FAT and facial identity discrimination performance. Our findings highlight the contribution of right-hemisphere UF microstructure to inter-individual variability in the ability to decode facial emotion expressions, and may explain why disruption of this pathway affects social behaviour

Precommissural and postcommissural fornix microstructure in healthy aging and cognition

The fornix is a key tract of the hippocampal formation, whose status is presumed to contribute to age-related cognitive decline. The precommissural and postcommissural fornix subdivisions form respective basal forebrain/frontal and diencephalic networks that may differentially affect aging and cognition. We employed multi-parametric magnetic resonance imaging (MRI) including neurite orientation density and dispersion imaging, quantitative magnetization transfer (qMT), and T1-relaxometry MRI to investigate the microstructural properties of these fornix subdivisions and their relationship with aging and cognition in 149 asymptomatic participants (38–71 years). Aging was associated with increased free water signal and reductions in myelin-sensitive R1 and qMT indices but no apparent axon density differences in both precommissural and postcommissural fibers. Precommissural relative to postcommissural fibers showed a distinct microstructural pattern characterised by larger free water signal and axon orientation dispersion, with lower apparent myelin and axon density. Furthermore, differences in postcommissural microstructure were related to performance differences in object-location paired-associate learning. These results provide novel in vivo neuroimaging evidence for distinct microstructural properties of precommissural and postcommissural fibers that are consistent with their anatomy as found in axonal tracer studies, as well as for a contribution of postcommissural fibers to the learning of spatial configurations

Apolipoprotein ε4 modifies obesity-related atrophy in the hippocampal formation of cognitively healthy adults

Characterizing age- and risk-related hippocampal vulnerabilities may inform about the neural underpinnings of cognitive decline. We studied the impact of three risk-factors, Apolipoprotein (APOE)-ε4, a family history of dementia, and central obesity, on the CA1, CA2/3, dentate gyrus and subiculum of 158 cognitively healthy adults (38-71 years). Subfields were labelled with the Automatic Segmentation of Hippocampal Subfields and FreeSurfer (version 6) protocols. Volumetric and microstructural measurements from quantitative magnetization transfer and Neurite Orientation Density and Dispersion Imaging were extracted for each subfield and reduced to three principal components capturing apparent myelin/neurite packing, size/complexity, and metabolism. Aging was associated with an inverse U-shaped curve on myelin/neurite packing and affected all subfields. Obesity led to reductions in myelin/neurite packing and size/complexity regardless of APOE and family history of dementia status. However, amongst individuals with a healthy Waist-Hip-Ratio, APOE ε4 carriers showed lower size/complexity than non-carriers. Segmentation protocol type did not affect this risk pattern. These findings reveal interactive effects between APOE and central obesity on the hippocampal formation of cognitively healthy adults

Apolipoprotein ε4 modifies obesity-related atrophy in the hippocampal formation of cognitively healthy adults

Characterizing age- and risk-related hippocampal vulnerabilities may inform about the neural underpinnings of cognitive decline. We studied the impact of three risk-factors, Apolipoprotein (APOE)-ε4, a family history of dementia, and central obesity, on CA1, CA2/3, dentate gyrus (DG) and subiculum in 158 cognitively healthy adults (38-71 years). Subfields were labelled with the Automatic Segmentation of Hippocampal Subfields (ASHS) and FreeSurfer (version 6) protocols. Volumetric and microstructural measurements from quantitative magnetization transfer and Neurite Orientation Density and Dispersion Imaging were extracted for each subfield and reduced to three principal components capturing apparent myelin/neurite packing, size/complexity, and metabolism. Aging was associated with an inverse U-shaped curve on myelin/neurite packing and affected all subfields. Obesity led to reductions in myelin/neurite packing and size/complexity regardless of APOE and FH status. However, amongst individuals with a healthy Waist-Hip-Ratio, APOE ε4 carriers showed lower size/complexity than non-carriers. Protocol type did not affect this risk pattern. These findings provide novel evidence for interactive effects between APOE and central obesity on the hippocampal formation of cognitively healthy adults

‘A good decision is the one that feels right for me’: codesign with patients to inform theoretical underpinning of a decision aid website

Introduction: patient decision aids (PtDA) complement shared decision-making with healthcare professionals and improve decision quality. However, PtDA often lack theoretical underpinning. We are codesigning a PtDA to help people with increased genetic cancer risks manage choices. The aim of an innovative workshop described here was to engage with the people who will use the PtDA regarding the theoretical underpinning and logic model outlining our hypothesis of how the PtDA would lead to more informed decision-making. Methods: short presentations about psychological and behavioural theories by an expert were interspersed with facilitated, small-group discussions led by patients. Patients were asked what is important to them when they make health decisions, what theoretical constructs are most meaningful and how this should be applied to codesign of a PtDA. An artist created a visual summary. Notes from patient discussions and the artwork were analysed using reflexive thematic analysis. Results: the overarching theme was: It's personal. Contextual factors important for decision-making were varied and changed over time. There was no one ‘best fit’ theory to target support needs in a PtDA, suggesting an inductive, flexible framework approach to programme theory would be most effective. The PtDA logic model was revised based on patient feedback. Conclusion: meaningful codesign of PtDA including discussions about the theoretical mechanisms through which they support decision-making has the potential to lead to improved patient care through understanding the intricately personal nature of health decisions, and tailoring content and format for holistic care. Patient Contribution: Patients with lived experience were involved in codesign and coproduction of this workshop and analysis as partners and coauthors. Patient discussions were the primary data source. Facilitators provided a semi-structured guide, but they did not influence the patient discussions or provide clinical advice. The premise of this workshop was to prioritise the importance of patient lived experience: to listen, learn, then reflect together to understand and propose ideas to improve patient care through codesign of a PtDA.</p