2024-03-29T13:12:42Zhttps://www.tdx.cat/oai/requestoai:www.tdx.cat:10803/4405302017-10-23T13:12:44Zcom_10803_183col_10803_202
nam a 5i 4500
Contributions to the development and validation of fMRI-based biomarkers for drug discovery in social anxiety disorder
[Barcelona] :
Universitat Politècnica de Catalunya,
2017
Accés lliure
http://hdl.handle.net/10803/440530
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Ortiz València, Héctor,
autor
1 recurs en línia (224 pàgines)
Tesi
Doctorat
Universitat Politècnica de Catalunya. Departament d'Enginyeria de Sistemes, Automàtica i Informàtica Industrial
2016
Universitat Politècnica de Catalunya. Departament d'Enginyeria de Sistemes, Automàtica i Informàtica Industrial
Tesis i dissertacions electròniques
Rosell Ferrer, Javier,
supervisor acadèmic
Pujol Nuez, Jesús,
supervisor acadèmic
TDX
This document presents the theoretical background and experimental work made to develop and validate a set of experiments based on functional magnetic resonance imaging (fMRI). These experiments are aimed to demonstrate that fMRI can be a valuable tool to objectivize drug treatment response in Social Anxiety Disorder (SAD) patients.
Functional MRI is a non-invasive imaging technique which provides localized indicators of brain activity. The analysis of fMRI data has recently facilitated neuroscience to make a leap forward in the understanding of the human brain.
Psychiatric clinical research, however, hasn’t fully embraced yet the potential of fMRI. In parallel, the societal costs of new psychiatric drug discovery are reaching unbearable limits. It has been hypothesized that the addition of fMRI in clinical trials of pharmacologic treatments of SAD can provide new biomarkers of treatment response which, in the future, shall reduce the temporal and economic burden of drug discovery. Five studies are presented in this dissertation in an evolving path towards the validation of the hypothesis.
In study 1, a widely validated state-of-the-art emotional face processing paradigm was piloted in a non-clinical sample. Task related activations were in line with the findings previously reported in the literature. However, the results of experiment did not show a correlation with symptom severity. An additional exploratory psychophysiological interaction analysis revealed that the relationship between two emotion-processing areas had a significant correlation with SAD symptom severity. This emphasized the potential value of studies based on functional connectivity for our objectives.
Study 2 explored the reproducibility of connectivity analysis of fMRI data. To do so, a brain network was selected and explored with Independent Component Analysis (ICA) on data collected from three categorically differentiated paradigms: A resting task, a moral dilemma task and in a cognitive-challenging Stroop task. The selected network was systematically identified in the three cases, exemplifying the robustness of the technique in three extreme cases.
Study 3 explores the sensitivity of ICA by analyzing resting-state data acquired before and after an experimental induction of sad mood. Multiple regions reflected changes in their intranetwork connectivity after sad mood induction. Results were validated using a split-half re-analysis and confirmatory seed-based functional connectivity measurements. These results support the idea that spatial ICA of fMRI is not only reliable, but also a sensitive paradigm.
Study 4 presents a novel SAD symptom-provoking paradigm that was validated on SAD patients and controls. The analysis of this pilot revealed a striking non-linear relationship between task activation and social anxiety scores. This non-linear relationship is compatible with some of the divergences found in literature regarding the alteration of emotional regulation brain areas in SAD.
Study 5 presents the results of a small placebo-controlled clinical trial using a common treatment for SAD (paroxetine) in SAD patients. Subjects underwent the emotional face processing, the symptom-provoking and resting state tasks that were administered and analyzed following the experience obtained in studies 1 to 4. The selected fMRI paradigms and analysis methods showed significant sensitivity to the effects of paroxetine treatment on SAD. Treatment effects were identified in areas related to the processing of fear stress and anxiety, which are known to be altered in SAD. Remarkably, ICA revealed sensitivity to pharmacologically-induced clinical improvement in the same areas and direction than the symptom-provocation task.
Along with the evidences reported in the literature review, the methods and results obtained throughout this dissertation provide a proof of concept on the usage of fMRI as a biomarker for SAD pharmacologic research.
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