MRI indices of functional recovery following intracerebral implantation of a human neural stem cell line in a pre-clinical model of ischaemic stroke

Stem cell therapy for ischaemic stroke is an emerging field in light of an increasing number of patients surviving with permanent disability. Several allogenic and autologous cells types are now in clinical trials with preliminary evidence of safety. Some clinical studies have reported functional improvements in some patients. After initial safety evaluation in a Phase 1 study, the conditionally immortalised human neural stem cell line CTX0E03 is currently in a Phase 2 clinical trial (PISCES-II). Previous pre-clinical studies conducted by ReNeuron Ltd, showed evidence of functional recovery in the Bilateral Asymmetry test up to 6 weeks following transplantation into rodent brain, 4 weeks after middle cerebral artery occlusion. Resting-state fMRI is increasingly used to investigate brain function in health and disease, and may also act as a predictor of recovery due to known network changes in the post-stroke recovery period. Resting-state methods have also been applied to non-human primates and rodents which have been found to have analogous resting-state networks to humans. The sensorimotor resting-state network of rodents is impaired following experimental focal ischaemia of the middle cerebral artery territory. However, the effects of stem cell implantation on brain functional networks has not previously been investigated. Prior studies assessed sensorimotor function following sub-cortical implantation of CTX0E03 cells in the rodent post-stroke brain but with no MRI assessments of functional improvements. This thesis presents research on the effect of sub-cortical implantation of CTX0E03 cells on the resting- state sensorimotor network and sensorimotor deficits in the rat following experimental stroke, using protocols based on previous work with this cell line. The work in this thesis identified functional tests of appropriate sensitivity for long-term dysfunction suitable for this laboratory, and investigated non-invasive monitoring of physiological variables required to optimize BOLD signal stability within a high-field MRI scanner. Following experimental stroke, rats demonstrated expected sensorimotor dysfunction and changes in the resting-state sensorimotor network. CTX0E03 cells did not improve post-stroke functional outcome (compared to previous studies) and with no changes in resting-state sensorimotor network activity. However, in control animals, we observed changes in functional networks due to the stereotaxic procedure. This illustrates the sensitivity of resting-state fMRI to stereotaxic procedures. We hypothesise that the damage caused by cell or vehicle implantation may have prevented functional and network recovery which has not been previously identified due to the application of different functional tests. The findings in this thesis represent one of few pre-clinical studies in resting-state fMRI network changes post-stroke and the only to date applying this technique to evaluate functional outcomes following a clinically applicable human neural stem cell treatment for ischaemic stroke. It was found that injury caused by stereotaxic injection should be taken into account when assessing the effectiveness of treatment.

State-narco networks and the ‘War on Drugs’ in post-transition Bolivia, with special reference to 1989-1993

This thesis examines the development of state-narco networks in post-transition Bolivia. Mainstream discourses of drugs tend to undertheorise such relationships, holding illicit economies, weak states and violence as synergistic phenomena. Such assumptions fail to capture the nuanced relations that emerge between the state and the drug trade in different contexts, their underlying logics and diverse effects. As an understudied case, Bolivia offers novel insights into these dynamics. Bolivian military authoritarian governments (1964-1982), for example, integrated drug rents into clientelistic systems of governance, helping to establish factional coalitions and reinforce regime authority. Following democratic transition in 1982 and the escalation of US counterdrug efforts, these stable modes of exchange between the state and the coca-cocaine economy fragmented. Bolivia, though, continued to experience lower levels of drug-related violence than its Andean neighbours, and sustained democratisation despite being a major drug producer. Focusing on the introduction of the Andean Initiative (1989-1993), I explore state-narco interactions during this period of flux: from authoritarianism to (formal) democracy, and from Cold War to Drug War. As such, the thesis transcends the conventional analyses of the drugs literature and orthodox readings of Latin American narco-violence, providing insights into the relationship between illicit economies and democratic transition, the regional role of the US, and the (unintended) consequences of drug policy interventions. I utilise a mixed methods approach to offer discrete perspectives on the object of study. Drawing on documentary and secondary sources, I argue that state-narco networks were interwoven with Bolivia’s post-transition political settlement. Uneven democratisation ensured pockets of informalism, as clientelistic and authoritarian practices continued. This included police and military autonomy, and tolerance of drug corruption within both institutions. Non-enforcement of democratic norms of accountability and transparency was linked to the maintenance of fragile political equilibrium. Interviews with key US and Bolivian elite actors also revealed differing interpretations of state-narco interactions. These exposed competing agendas, and were folded into alternative paradigms and narratives of the ‘war on drugs’. The extension of US Drug War goals and the targeting of ‘corrupt’ local power structures, clashed with local ambivalence towards the drug trade, opposition to destabilising, ‘Colombianised’ policies and the claimed ‘democratising mission’ of the Bolivian government. In contrasting these US and Bolivian accounts, the thesis shows how real and perceived state-narco webs were understood and navigated by different actors in distinct ways. ‘Drug corruption’ held significance beyond simple economic transaction or institutional failure. Contestation around state-narco interactions was enmeshed in US-Bolivian relations of power and control.

Pseudoneglect and visual attention networks

Pseudoneglect represents the tendency for healthy individuals to show a slight but consistent bias in favour of stimuli appearing in the left visual field. The bias is often measured using variants of the line bisection task. An accurate model of the functional architecture of the visuospatial attention system must account for this widely observed phenomenon, as well as for modulation of the direction and magnitude of the bias within individuals by a variety of factors relating to the state of the participant and/or stimulus characteristics. To date, the neural correlates of pseudoneglect remain relatively unmapped. In the current thesis, I employed a combination of psychophysical measurements, electroencephalography (EEG) recording and transcranial direct current stimulation (tDCS) in an attempt to probe the neural generator(s) of pseudoneglect. In particular, I wished to utilise and investigate some of the factors known to modulate the bias (including age, time-on-task and the length of the to-be-bisected line) in order to identify neural processes and activity that are necessary and sufficient for the lateralized bias to arise. Across four experiments utilising a computerized version of a perceptual line bisection task, pseudoneglect was consistently observed at baseline in healthy young participants. However, decreased line length (experiments 1, 2 and 3), time-on-task (experiment 1) and healthy aging (experiment 3) were all found to modulate the bias. Specifically, all three modulations induced a rightward shift in subjective midpoint estimation. Additionally, the line length and time-on-task effects (experiment 1) and the line length and aging effects (experiment 3) were found to have additive relationships. In experiment 2, EEG measurements revealed the line length effect to be reflected in neural activity 100 – 200ms post-stimulus onset over source estimated posterior regions of the right hemisphere (RH: temporo-parietal junction (TPJ)). Long lines induced a hemispheric asymmetry in processing (in favour of the RH) during this period that was absent in short lines. In experiment 4, bi-parietal tDCS (Left Anodal/Right Cathodal) induced a polarity-specific rightward shift in bias, highlighting the crucial role played by parietal cortex in the genesis of pseudoneglect. The opposite polarity (Left Cathodal/Right Anodal) did not induce a change in bias. The combined results from the four experiments of the current thesis provide converging evidence as to the crucial role played by the RH in the genesis of pseudoneglect and in the processing of visual input more generally. The reduction in pseudoneglect with decreased line length, increased time-on-task and healthy aging may be explained by a reduction in RH function, and hence contribution to task processing, induced by each of these modulations. I discuss how behavioural and neuroimaging studies of pseudoneglect (and its various modulators) can provide empirical data upon which accurate formal models of visuospatial attention networks may be based and further tested.

Management accounting and supply chains: actions, concerns, and networks

What does this thesis do? This thesis uses Actor-Network Theory (ANT) to examine how a UK retailer’s organization and strategy, and, in turn, its form of management accounting was shaped by its supply chain. The thesis does this by reporting on four related themes in the form of four inter-connected essays. The first essay undertakes a state-of-the-art review of the literature. It examines how accounting issues within supply chains permeate ‘matters of concern’. In accordance with this idea of ANT, the essay illustrates how issues emerged, controversies developed, and matters evolved through an actor-network of accounting researchers within the supply chain domain. This leads on to the second essay, which exemplifies the nature of the UK’s retailing industry within which the supply chain case organization emerged and developed. The purposes of the essay are twofold: to introduce the contextual ramifications of the case organization; and to illustrate the emergence of a new market logic, which led to the creation of a global supply chain and a new form of management accounting therein. The third essay reports on a qualitative case study. It analyses the dualistic relation between ostensive and performative aspects of supply chain strategy, reveals how accounting numbers act as an obligatory passage point within this dualism, and makes a contribution to the ANT debate around the issue of whether and how a dualism between ostensive and performative aspects exists. The final essay reports on another case analysis of institutionalizing a heterarchical form of management accounting: a distributed form of intelligence that penetrates through lateral accountable relations. The analysis reveals a new form of management accounting characterised by ambiguity; it emphasizes the possibilities of compromises and negotiations, and it thus contributes to knowledge by combining an aspect of ANT with heterarchical tendencies in the world of contemporary organizations. Finally, the thesis concludes that it is the supply chain that organises today’s neoliberal capitalism; and it is management accounting that unites both human and non-human actors within such supply chains, despite that form of management accounting being ambiguous. The thesis comprises the introduction, these four essays, and the conclusion.

Query routing in cooperative semi-structured peer-to-peer information retrieval networks

Conventional web search engines are centralised in that a single entity crawls and indexes the documents selected for future retrieval, and the relevance models used to determine which documents are relevant to a given user query. As a result, these search engines suffer from several technical drawbacks such as handling scale, timeliness and reliability, in addition to ethical concerns such as commercial manipulation and information censorship. Alleviating the need to rely entirely on a single entity, Peer-to-Peer (P2P) Information Retrieval (IR) has been proposed as a solution, as it distributes the functional components of a web search engine – from crawling and indexing documents, to query processing – across the network of users (or, peers) who use the search engine. This strategy for constructing an IR system poses several efficiency and effectiveness challenges which have been identified in past work. Accordingly, this thesis makes several contributions towards advancing the state of the art in P2P-IR effectiveness by improving the query processing and relevance scoring aspects of a P2P web search. Federated search systems are a form of distributed information retrieval model that route the user’s information need, formulated as a query, to distributed resources and merge the retrieved result lists into a final list. P2P-IR networks are one form of federated search in routing queries and merging result among participating peers. The query is propagated through disseminated nodes to hit the peers that are most likely to contain relevant documents, then the retrieved result lists are merged at different points along the path from the relevant peers to the query initializer (or namely, customer). However, query routing in P2P-IR networks is considered as one of the major challenges and critical part in P2P-IR networks; as the relevant peers might be lost in low-quality peer selection while executing the query routing, and inevitably lead to less effective retrieval results. This motivates this thesis to study and propose query routing techniques to improve retrieval quality in such networks. Cluster-based semi-structured P2P-IR networks exploit the cluster hypothesis to organise the peers into similar semantic clusters where each such semantic cluster is managed by super-peers. In this thesis, I construct three semi-structured P2P-IR models and examine their retrieval effectiveness. I also leverage the cluster centroids at the super-peer level as content representations gathered from cooperative peers to propose a query routing approach called Inverted PeerCluster Index (IPI) that simulates the conventional inverted index of the centralised corpus to organise the statistics of peers’ terms. The results show a competitive retrieval quality in comparison to baseline approaches. Furthermore, I study the applicability of using the conventional Information Retrieval models as peer selection approaches where each peer can be considered as a big document of documents. The experimental evaluation shows comparative and significant results and explains that document retrieval methods are very effective for peer selection that brings back the analogy between documents and peers. Additionally, Learning to Rank (LtR) algorithms are exploited to build a learned classifier for peer ranking at the super-peer level. The experiments show significant results with state-of-the-art resource selection methods and competitive results to corresponding classification-based approaches. Finally, I propose reputation-based query routing approaches that exploit the idea of providing feedback on a specific item in the social community networks and manage it for future decision-making. The system monitors users’ behaviours when they click or download documents from the final ranked list as implicit feedback and mines the given information to build a reputation-based data structure. The data structure is used to score peers and then rank them for query routing. I conduct a set of experiments to cover various scenarios including noisy feedback information (i.e, providing positive feedback on non-relevant documents) to examine the robustness of reputation-based approaches. The empirical evaluation shows significant results in almost all measurement metrics with approximate improvement more than 56% compared to baseline approaches. Thus, based on the results, if one were to choose one technique, reputation-based approaches are clearly the natural choices which also can be deployed on any P2P network.