Characterising population variability in brain structure through models of whole-brain structural connectivity

Models of whole-brain connectivity are valuable for understanding neurological function. This thesis seeks to develop an optimal framework for extracting models of whole-brain connectivity from clinically acquired diffusion data. We propose new approaches for studying these models. The aim is to develop techniques which can take models of brain connectivity and use them to identify biomarkers or phenotypes of disease. The models of connectivity are extracted using a standard probabilistic tractography algorithm, modified to assess the structural integrity of tracts, through estimates of white matter anisotropy. Connections are traced between 77 regions of interest, automatically extracted by label propagation from multiple brain atlases followed by classifier fusion. The estimates of tissue integrity for each tract are input as indices in 77x77 ”connectivity” matrices, extracted for large populations of clinical data. These are compared in subsequent studies. To date, most whole-brain connectivity studies have characterised population differences using graph theory techniques. However these can be limited in their ability to pinpoint the locations of differences in the underlying neural anatomy. Therefore, this thesis proposes new techniques. These include a spectral clustering approach for comparing population differences in the clustering properties of weighted brain networks. In addition, machine learning approaches are suggested for the first time. These are particularly advantageous as they allow classification of subjects and extraction of features which best represent the differences between groups. One limitation of the proposed approach is that errors propagate from segmentation and registration steps prior to tractography. This can cumulate in the assignment of false positive connections, where the contribution of these factors may vary across populations, causing the appearance of population differences where there are none. The final contribution of this thesis is therefore to develop a common co-ordinate space approach. This combines probabilistic models of voxel-wise diffusion for each subject into a single probabilistic model of diffusion for the population. This allows tractography to be performed only once, ensuring that there is one model of connectivity. Cross-subject differences can then be identified by mapping individual subjects’ anisotropy data to this model. The approach is used to compare populations separated by age and gender

Diffusion Modelling Reveals the Decision Making Processes Underlying Negative Judgement Bias in Rats:Modelling Decision Making during Negative Affect

Human decision making is modified by emotional state. Rodents exhibit similar biases during interpretation of ambiguous cues that can be altered by affective state manipulations. In this study, the impact of negative affective state on judgement bias in rats was measured using an ambiguous-cue interpretation task. Acute treatment with an anxiogenic drug (FG7142), and chronic restraint stress and social isolation both induced a bias towards more negative interpretation of the ambiguous cue. The diffusion model was fit to behavioural data to allow further analysis of the underlying decision making processes. To uncover the way in which parameters vary together in relation to affective state manipulations, independent component analysis was conducted on rate of information accumulation and distances to decision threshold parameters for control data. Results from this analysis were applied to parameters from negative affective state manipulations. These projected components were compared to control components to reveal the changes in decision making processes that are due to affective state manipulations. Negative affective bias in rodents induced by either FG7142 or chronic stress is due to a combination of more negative interpretation of the ambiguous cue, reduced anticipation of the high reward and increased anticipation of the low reward

Translating a rodent measure of negative bias into humans:the impact of induced anxiety and unmedicated mood and anxiety disorders

BACKGROUND: Mood and anxiety disorders are ubiquitous but current treatment options are ineffective for many sufferers. Moreover, a number of promising pre-clinical interventions have failed to translate into clinical efficacy in humans. Improved treatments are unlikely without better animal-human translational pipelines. Here, we translate a rodent measure of negative affective bias into humans, exploring its relationship with (1) pathological mood and anxiety symptoms and (2) transient induced anxiety. METHODS: Adult participants (age = 29 ± 11) who met criteria for mood or anxiety disorder symptomatology according to a face-to-face neuropsychiatric interview were included in the symptomatic group. Study 1 included N = 77 (47 = asymptomatic [female = 21]; 30 = symptomatic [female = 25]), study 2 included N = 47 asymptomatic participants (25 = female). Outcome measures were choice ratios, reaction times and parameters recovered from a computational model of reaction time - the drift diffusion model (DDM) - from a two-alternative-forced-choice task in which ambiguous and unambiguous auditory stimuli were paired with high and low rewards. RESULTS: Both groups showed over 93% accuracy on unambiguous tones indicating intact discrimination, but symptomatic individuals demonstrated increased negative affective bias on ambiguous tones [proportion high reward = 0.42 (s.d. = 0.14)] relative to asymptomatic individuals [0.53 (s.d. = 0.17)] as well as a significantly reduced DDM drift rate. No significant effects were observed for the within-subjects anxiety-induction. CONCLUSIONS: Humans with pathological anxiety symptoms directly mimic rodents undergoing anxiogenic manipulation. The lack of sensitivity to transient anxiety suggests the paradigm might be more sensitive to clinically relevant symptoms. Our results establish a direct translational pipeline (and candidate therapeutics screen) from negative affective bias in rodents to pathological mood and anxiety symptoms in humans

Commissioning care for people with dementia at the end of life: a mixed methods study.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ The version of record, Zoe M Gotts, Nicole Baur, Emma McLellan, Claire Goodman, Louise Robinson and Richard P Lee, ‘Commissioning care for people with dementia at the end of life: a mixed methods study’, BMJ Open, 2016,; 6: e013554, is available online at doi: 10.1136/ bmjopen-2016-013554Objectives To understand how end of life care for people with dementia is currently commissioned (.e contracted)and organised, with a view to informing the development of commissioning guidance for good quality community-based end of life care in dementia. Design Mixed-methods study; narrative review and qualitative interviews. Setting 8 NHS clinical commissioning groups and 5 Adult Services across England. Methods Narrative review of evidence; 20 semi structured interviews (telephone and face-to-face) with professionals involved in commissioning end of life care for people with dementia. Main outcome measures Summary of the existing evidence base for commissioning, commissioners’ approaches to the commissioning process for end of life care for people with dementia in England. Results In the context of commissioning end of life care for people with dementia, the literature review generated three key themes; (1) importance of joint commissioning; (2) lack of clarity for the process; and (3) factors influencing commissioning. In exploring health professionals’ perceptions of the commissioning process, ‘uncertainty’ was elicited as an overarching theme across the CCGs interviewed. Organisation of the process, lack of expertise, issues surrounding integration and the art of specification were considered important factors that contribute to the uncertainty surrounding the commissioning process. Conclusions The current evidence base for commissioning end of life care is limited with considerable uncertainty as how clinical commissioners in England undertake the process to ensure future services are evidence-based. Strengths and limitations of this study • The use of a multimethod approach (narrative review, qualitative interviews) allowed for triangulation of our findings. • The evidence indentified in the review may be limited given that ‘commissioning’ is a relatively new term in England. • The review presented is a narrative review; the manuscripts were not subject to a quality assessment process. • Generalisability of findings might be affected by the small number of published studies, their heterogeneity in methodologies, and small sample sizes. • The study highlights that information on commissioning specifically for health and social care in England is limited; this is mirrored in commissioners’ accounts.Peer reviewe

Correlation of Nav1.8 and Nav1.9 sodium channel expression with neuropathic pain in human subjects with lingual nerve neuromas

Background: Voltage-gated sodium channels Nav1.8 and Nav1.9 are expressed preferentially in small diameter sensory neurons, and are thought to play a role in the generation of ectopic activity in neuronal cell bodies and/or their axons following peripheral nerve injury. The expression of Nav1.8 and Nav1.9 has been quantified in human lingual nerves that have been previously injured inadvertently during lower third molar removal, and any correlation between the expression of these ion channels and the presence or absence of dysaesthesia investigated. Results: Immunohistochemical processing and quantitative image analysis revealed that Nav1.8 and Nav1.9 were expressed in human lingual nerve neuromas from patients with or without symptoms of dysaesthesia. The level of Nav1.8 expression was significantly higher in patients reporting pain compared with no pain, and a significant positive correlation was observed between levels of Nav1.8 expression and VAS scores for the symptom of tingling. No significant differences were recorded in the level of expression of Nav1.9 between patients with or without pain. Conclusions: These results demonstrate that Nav1.8 and Nav1.9 are present in human lingual nerve neuromas, with significant correlations between the level of expression of Nav1.8 and symptoms of pain. These data provide further evidence that changes in expression of Nav1.8 are important in the development and/or maintenance of nerve injury-induced pain, and suggest that Nav1.8 may be a potential therapeutic target