El cerebro está constituido por numerosos elementos que se encuentran interconectados de forma masiva y organizados en módulos que forman redes jerárquicas. Ciertas patologías cerebrales, como la enfermedad de Alzheimer y el trastorno por consumo de alcohol, se consideran el resultado de efectos en cascada que alteran la conectividad cerebral. La presente tesis tiene como objetivo principal la aplicación de las técnicas de análisis de la ciencia de redes para el estudio de las redes estructurales y funcionales en el cerebro, tanto en un estado control como en un estado patológico. Así, en el primer estudio de la presente tesis se examina la relación entre la conectividad estructural y funcional en la corteza cerebral de la rata. Se lleva a cabo un análisis comparativo entre las conexiones estructurales en la corteza cerebral de la rata y los valores de correlación calculados sobre las mismas regiones. La información acerca de la conectividad estructural se ha obtenido a partir de estudios previos, mientras que la conectividad funcional se ha calculado a partir de imágenes de resonancia magnética funcional. Determinadas propiedades topológicas, y extraídas de la conectividad estructural, se relacionan con la organización modular de las redes funcionales en estado de reposo. Los resultados obtenidos en este primer estudio demuestran que la conectividad estructural y funcional cortical están altamente relacionadas entre sí. Estudios recientes sugieren que el origen de la enfermedad de Alzheimer reside en un mecanismo en el cual depósitos de ovillos neurofibrilares y placas de beta-amiloide se acumulan en ciertas regiones cerebrales, y tienen la capacidad de diseminarse por el cerebro actuando como priones. En el segundo estudio de la presente tesis se investiga si las redes estructurales que se generan con la técnica de resonancia magnética ponderada en difusión podrían ser de utilidad para el diagnóstico de la pre-demencia causada por la enfermedad de Alzheimer. Mediante el uso de imágenes procedentes de la base de datos ADNI, se aplican técnicas de aprendizaje máquina con el fin de identificar medidas de centralidad que se encuentran alteradas en la demencia. En la segunda parte del estudio, se utilizan imágenes procedentes de la base de datos NKI para construir un modelo matemático que simule el proceso de envejecimiento normal, así como otro modelo que simule el proceso de desarrollo de la enfermedad. Con este modelado matemático, se pretende estimar la etapa más temprana que está asociada con la demencia. Los resultados obtenidos de las simulaciones sugieren que en etapas tempranas de la enfermedad de Alzheimer se producen alteraciones estructurales relacionados con la demencia. La cuantificación de la relación estadística entre las señales BOLD de diferentes regiones puede informar sobre el estado funcional cerebral característico de enfermedades neurológicas y psiquiátricas. En el tercer estudio de la presente tesis se estudian las alteraciones en la conectividad funcional que tienen lugar en ratas dependientes del consumo de alcohol cuando se encuentran en estado de reposo. Para ello, se ha aplicado el método NBS. El análisis de este modelo de rata revela diferencias estadísticamente significativas en una subred de regiones cerebrales que están implicadas en comportamientos adictivos. Por lo tanto, estas estructuras cerebrales podrían ser el foco de posibles dianas terapéuticas. La tesis aporta tres innovadoras contribuciones para entender la conectividad cerebral bajo la perspectiva de la ciencia de redes, tanto en un estado control como en un estado patológico. Los resultados destacan que los modelos basados en las redes cerebrales permiten esclarecer la relación entre la estructura y la función en el cerebro. Y quizás más importante, esta perspectiva de red tiene aplicaciones que se podrían trasladar a la práctica clínica. / The brain is composed of massively connected elements arranged into modules that form hierarchical networks. Experimental evidence reveals a well-defined connectivity design, characterized by the presence of strategically connected core nodes that critically contribute to resilience and maintain stability in interacting brain networks. Certain brain pathologies, such as Alzheimer's disease and alcohol use disorder, are thought to be a consequence of cascading maladaptive processes that alter normal connectivity. These findings have greatly contributed to the development of network neuroscience to understand the macroscopic organization of the brain. This thesis focuses on the application of network science tools to investigate structural and functional brain networks in health and disease. To accomplish this goal, three specific studies are conducted using human and rodent data recorded with MRI and tracing technologies. In the first study, we examine the relationship between structural and functional connectivity in the rat cortical network. Using a detailed cortical structural matrix obtained from published histological tracing data, we first compare structural connections in the rat cortex with their corresponding spontaneous correlations extracted empirically from fMRI data. We then show the results of this comparison by relating structural properties of brain connectivity to the functional modularity of resting-state networks. Specifically, we study link reciprocity in both intra- and inter-modular connections as well as the structural motif frequency spectrum within functionally defined modules. Overall, our results provide further evidence that structural connectivity is coupled to and shapes functional connectivity in cortical networks. The pathophysiological process of Alzheimer's disease is thought to begin years before clinical decline, with evidence suggesting pahtogenic seeding and subsequent prion-like spreading processes of neurofibrillary tangles and amyloid plaques. In the second study of this thesis, we investigate whether structural brain networks as measured with dMRI could serve as a complementary diagnostic tool in prodromal dementia. Using imaging data from the ADNI database, we first aim to implement machine learning techniques to extract centrality features that are altered in Alzheimer's dementia. We then incorporate data from the NKI database and create dynamical models of normal aging and Alzheimer's disease to estimate the earliest detectable stage associated with dementia in the simulated disease progression. Our model results suggest that changes associated with dementia begin to manifest structurally at early stages. Statistical dependence measures computed between BOLD signals can inform about brain functional states in studies of neurological and psychiatric disorders. Furthermore, its non-invasive nature allows comparable measurements between clinical and animal studies, providing excellent translational capabilities. In the last study, we apply the NBS method to investigate alterations in the resting-state functional connectivity of the rat brain in a PD state, an established animal model of clinical relevant features in alcoholism. The analysis reveal statistically significant differences in a connected subnetwork of structures with known relevance for addictive behaviors, hence suggesting potential targets for therapy. This thesis provides three novel contributions to understand the healthy and pathological brain connectivity under the perspective of network science. The results obtained in this thesis underscore that brain network models offer further insights into the structure-function coupling in the brain. More importantly, this network perspective provides potential applications for the diagnosis and treatment of neurological and psychiatric disorders. / El cervell està constituït per nombrosos elements que es troben interconnectats de forma massiva i organitzats en mòduls que formen xarxes jeràrquiques. Certes patologies cerebrals, com la malaltia d'Alzheimer i el trastorn per consum d'alcohol, es consideren el resultat d'efectes en cascada que alteren la connectivitat cerebral. La present tesi té com a objectiu principal l'aplicació de les tècniques d'anàlisi de la ciència de xarxes per a l'estudi de les xarxes estructurals i funcionals en el cervell, tant en un estat control com en un estat patològic. Així, en el primer estudi de la present tesi s'examina la relació entre la connectivitat estructural i funcional en l'escorça cerebral de la rata. Es du a terme una anàlisi comparativa entre les connexions estructurals en l'escorça cerebral de la rata i els valors de correlació calculats sobre les mateixes regions. La informació sobre la connectivitat estructural s'ha obtingut a partir d'estudis previs, mentre que la connectivitat funcional s'ha calculat a partir d'imatges de ressonància magnètica funcional. Determinades propietats topològiques, i extretes de la connectivitat estructural, es relacionen amb l'organització modular de les xarxes funcionals en estat de repòs. Els resultats obtinguts en este primer estudi demostren que la connectivitat estructural i funcional cortical estan altament relacionades entre si. Estudis recents suggereixen que l'origen de la malaltia d'Alzheimer resideix en un mecanisme en el qual depòsits d'ovulets neurofibrilars i plaques de beta- miloide s'acumulen en certes regions cerebrals, i tenen la capacitat de disseminar-se pel cervell actuant com a prions. En el segon estudi de la present tesi s'investiga si les xarxes estructurals que es generen amb la tècnica de la imatge per ressonància magnètica ponderada en difusió podrien ser d'utilitat per al diagnòstic de la predemència causada per la malaltia d'Alzheimer. Per mitjà de l'ús d'imatges procedents de la base de dades ADNI, s'apliquen tècniques d'aprenentatge màquina a fi d'identificar mesures de centralitat que es troben alterades en la demència. En la segona part de l'estudi, s'utilitzen imatges procedents de la base de dades NKI per a construir un model matemàtic que simule el procés d'envelliment normal, així com un altre model que simule el procés de desenrotllament de la malaltia. Amb este modelatge matemàtic, es pretén estimar l'etapa més primerenca que està associada amb la demència. Els resultats obtinguts de les simulacions suggereixen que en etapes primerenques de la malaltia d'Alzheimer es produeixen alteracions estructurals relacionats amb la demència. La quantificació de la relació estadística entre els senyals BOLD de diferents regions pot informar sobre l'estat funcional cerebral característic de malalties neurològiques i psiquiàtriques. A més, a causa de la seua naturalesa no invasiva, és possible comparar els resultats obtinguts entre estudis clínics i estudis amb animals d'experimentació. En el tercer estudi de la present tesi s'estudien les alteracions en la connectivitat funcional que tenen lloc en rates dependents del consum d'alcohol quan es troben en estat de repòs. Per a realitzar-ho, s'ha aplicat el mètode NBS. L'anàlisi d'aquest model de rata revela diferències estadísticament significatives en una subxarxa de regions cerebrals que estan implicades en comportaments addictius. Per tant, estes estructures cerebrals podrien ser el focus de possibles dianes terapèutiques. La tesi aporta tres innovadores contribucions per a entendre la connectivitat cerebral davall la perspectiva de la ciència de xarxes, tant en un estat control com en un estat patològic. Els resultats destaquen que els models basats en les xarxes cerebrals permeten aclarir la relació entre l'estructura i la funció en el cervell. I potser més important, esta perspectiva de xarxa té aplicacions que es podrien traslladar a la pràcti / Díaz Parra, A. (2018). A network science approach of the macroscopic organization of the brain: analysis of structural and functional brain networks in health and disease [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/106966 / TESIS

El balance del cerebro se altera a nivel estructural y funcional por el consumo de alcohol y puede causar trastornos por consumo de alcohol (TCA). El objetivo de esta Tesis Doctoral fue investigar los efectos del consumo crónico y excesivo de alcohol en el cerebro desde una perspectiva funcional y estructural, mediante análisis de imágenes multimodales de resonancia magnética (RM). Realizamos tres estudios con objetivos específicos: i) Para entender cómo las neuroadaptaciones desencadenadas por el consumo de alcohol se ven reflejadas en la conectividad cerebral funcional entre redes cerebrales, así como en la actividad cerebral, realizamos estudios en ratas msP en condiciones de control y tras un mes con acceso a alcohol. Para cada sujeto se obtuvieron las señales específicas de sus redes cerebrales tras aplicar análisis probabilístico de componentes independientes y regresión espacial a las imágenes funcionales de RM en estado de reposo (RMf-er). Después, estimamos la conectividad cerebral en estado de reposo mediante correlación parcial regularizada. Para una lectura de la actividad neuronal realizamos un experimento con imágenes de RM realzadas con manganeso. En la condición de alcohol encontramos hipoconectividades entre la red visual y las redes estriatal y sensorial; todas con incrementos en actividad. Por el contrario, hubo hiperconectividades entre tres pares de redes cerebrales: 1) red prefrontal cingulada media y red estriatal, 2) red sensorial y red parietal de asociación y 3) red motora-retroesplenial y red sensorial, siendo la red parietal de asociación la única red sin incremento de actividad. Estos resultados indican que las redes cerebrales ya se alteran desde una fase temprana de consumo continuo y prolongado de alcohol, disminuyendo el control ejecutivo y la flexibilidad comportamental. ii) Para comparar el volumen de materia gris (MG) cortical entre 34 controles sanos y 35 pacientes con dependencia al alcohol, desintoxicados y en abstinencia de 1 a 5 semanas, realizamos un análisis de morfometría basado en vóxel. Las principales estructuras cuyo volumen de MG disminuyó en los sujetos en abstinencia fueron el giro precentral (GPreC), el giro postcentral (GPostC), la corteza motora suplementaria (CMS), el giro frontal medio (GFM), el precúneo (PCUN) y el lóbulo parietal superior (LPS). Disminuciones de MG en el volumen de esas áreas pueden dar lugar a cambios en el control de los movimientos (GPreC y CMS), en el procesamiento de información táctil y propioceptiva (GPostC), personalidad, previsión (GFM), reconocimiento sensorial, entendimiento del lenguaje, orientación (PCUN) y reconocimiento de objetos a través de su forma (LPS). iii) Caracterizar estados cerebrales dinámicos en señales de RMf mediante una metodología basada en un modelo oculto de Markov (HMM en inglés)-Gaussiano en un paradigma con diseño de bloques, junto con distintas señales temporales de múltiples redes: componentes independientes y modos funcionales probabilísticos (PFMs en inglés) en 14 sujetos sanos. Cuatro condiciones experimentales formaron el paradigma de bloques: reposo, visual, motora y visual-motora. Mediante la aplicación de HMM-Gaussiano a los PFMs pudimos caracterizar cuatro estados cerebrales a partir de la actividad media de cada PFM. Los cuatro mapas espaciales obtenidos fueron llamados HMM-reposo, HMM-visual, HMM-motor y HMM-RND (red neuronal por defecto). HMM-RND apareció una vez el estado de tarea se había estabilizado. En un futuro cercano se espera obtener estados cerebrales en nuestros datos de RMf-er en ratas, para comparar dinámicamente el comportamiento de las redes cerebrales como un biomarcador de TCA. En conclusión, las técnicas de neuroimagen aplicadas en imagen de RM multimodal para estimar la conectividad cerebral en estado de reposo, la actividad cerebral y el volumen de materia gris han permitido avanzar en el entendimiento de los mecanismos homeostático / La ingesta d'alcohol altera el balanç del cervell a nivell estructural i funcional i pot causar trastorns per consum d' alcohol (TCA). L'objectiu d'aquesta Tesi Doctoral fou estudiar els efectes en el cervell del consum crònic i excessiu d'alcohol, des d'un punt de vista funcional i estructural i per mitjà d'anàlisi d'imatges de ressonància magnètica (RM). Vam realitzar tres anàlisis amb objectius específics: i) Per a entendre com les neuroadaptacions desencadenades pel consum d'alcohol es veuen reflectides en la connectivitat cerebral funcional entre xarxes cerebrals, així com en l'activitat cerebral, vam realitzar estudis en rates msP en les condicions de control i després d'un mes amb accés a alcohol. Per a cada subjecte vam obtindre els senyals de les xarxes cerebrals tras aplicar a les imatges funcionals de RM en estat de repòs una anàlisi probabilística de components independents i regressió espacial. Després, estimàrem la connectivitat cerebral en estat de repòs per mitjà de correlació parcial regularitzada. Per a una lectura de l'activitat cerebral vam adquirir imatges de RM realçades amb manganés. En la condició d'alcohol vam trobar hipoconnectivitats entre la xarxa visual i les xarxes estriatal i sensorial, totes amb increments en activitat. Al contrari, va haver-hi hiperconnectivitats entre tres parells de xarxes cerebrals: 1) xarxa prefrontal cingulada mitja i xarxa estriatal, 2) xarxa sensorial i xarxa parietal d'associació i 3) xarxa motora-retroesplenial i xarxa sensorial, sent la xarxa parietal d'associació l'única xarxa sense increment d'activitat. Aquests resultats indiquen que les xarxes cerebrals ja s'alteren des d'una fase primerenca caracteritzada per consum continu i prolongat d'alcohol, disminuint el control executiu i la flexibilitat comportamental. ii) Per a comparar el volum de MG cortical entre 34 controls sans i 35 pacients amb dependència a l'alcohol, desintoxicats i en abstinència de 1 a 5 setmanes vam emprar anàlisi de morfometria basada en vòxel. Les principals estructures on el volum de MG va disminuir en els subjectes en abstinència van ser el gir precentral (GPreC), el gir postcentral (GPostC), la corteça motora suplementària (CMS), el gir frontal mig (GFM), el precuni (PCUN) i el lòbul parietal superior (LPS). Les disminucions de MG en eixes àrees poden donar lloc a canvis en el control dels moviments (GPreC i CMS), en el processament d'informació tàctil i propioceptiva (GPostC), personalitat, previsió (GFM), reconeixement sensorial, enteniment del llenguatge, orientació (PCUN) i reconeixement d'objectes a través de la seua forma (LPS). iii) Caracterització de les dinàmiques temporals del cervell com a diferents estats cerebrals, en senyals de RMf mitjançant una metodologia basada en un model ocult de Markov (HMM en anglès)-Gaussià en imatges de RMf, junt amb dos tipus de senyals temporals de múltiples xarxes cerebrals: components independents i modes funcionals probabilístics (PFMs en anglès) en 14 subjectes sans. Quatre condicions experimentals van formar el paradigma de blocs: repòs, visual, motora i visual-motora. HMM-Gaussià aplicat als PFMs (senyals de RM funcional de xarxes cerebrals) va permetre la millor caracterització dels quatre estats cerebrals a partir de l'activitat mitjana de cada PFM. Els quatre mapes espacials obtinguts van ser anomenats HMM-repòs, HMM-visual, HMM-motor i HMM-XND (xarxa neuronal per defecte). HMM-XND va aparèixer una vegada una tasca estava estabilitzada. En un futur pròxim s'espera obtindre estats cerebrals en les nostres dades de RMf-er en rates, per a comparar dinàmicament el comportament de les xarxes cerebrals com a biomarcador de TCA. En conclusió, s'han aplicat tècniques de neuroimatge per a estimar la connectivitat cerebral en estat de repòs, l'activitat cerebral i el volum de MG, aplicades a imatges multimodals de RM i s'han obtés resultats que han permés avançar en l'enteniment dels m / Alcohol intake alters brain balance, affecting its structure and function, and it may cause Alcohol Use Disorders (AUDs). We aimed to study the effects of chronic, excessive alcohol consumption on the brain from a functional and structural point of view, via analysis of multimodal magnetic resonance (MR) images. We conducted three studies with specific aims: i) To understand how the neuroadaptations triggered by alcohol intake are reflected in between-network resting-state functional connectivity (rs-FC) and brain activity in the onset of alcohol dependence, we performed studies in msP rats in control and alcohol conditions. Group probabilistic independent component analysis (group-PICA) and spatial regression were applied to resting-state functional magnetic resonance imaging (rs-fMRI) images to obtain subject-specific time courses of seven resting-state networks (RSNs). Then, we estimated rs-FC via L2-regularized partial correlation. We performed a manganese-enhanced (MEMRI) experiment as a readout of neuronal activity. In alcohol condition, we found hypoconnectivities between the visual network (VN), and striatal (StrN) and sensory-cortex (SCN) networks, all with increased brain activity. On the contrary, hyperconnectivities were found between three pairs of RSNs: 1) medial prefrontal-cingulate (mPRN) and StrN, 2) SCN and parietal association (PAN) and 3) motor-retrosplenial (MRN) and SCN networks, being PAN the only network without brain activity rise. Interestingly, the hypoconnectivities could be explained as control to alcohol transitions from direct to indirect connectivity, whereas the hyperconnectivities reflected an indirect to an even more indirect connection. These findings indicate that RSNs are early altered by prolonged and moderate alcohol exposure, diminishing the executive control and behavioral flexibility. ii) To compare cortical gray matter (GM) volume between 34 healthy controls and 35 alcohol-dependent patients who were detoxified and remained abstinent for 1-5 weeks before MRI acquisition, we performed a voxel-based morphometry analysis. The main structures whose GM volume decreased in abstinent subjects compared to controls were precentral gyrus (PreCG), postcentral gyrus (PostCG), supplementary motor cortex (SMC), middle frontal gyrus (MFG), precuneus (PCUN) and superior parietal lobule (SPL). Decreases in GM volume in these areas may lead to changes in control of movement (PreCG and SMC), in processing tactile and proprioceptive information (PostCG), personality, insight, prevision (MFG), sensory appreciation, language understanding, orientation (PCUN) and the recognition of objects by touch and shapes (SPL). iii) To characterize dynamic brain states in functional MRI (fMRI) signals by means of an approach based on the Hidden Markov model (HMM). Several parameter configurations of HMM-Gaussian in a block-design paradigm were considered, together with different time series: independent components (ICs) and probabilistic functional modes (PFMs) on 14 healthy subjects. The block-design fMRI paradigm consisted of four experimental conditions: rest, visual, motor and visual-motor. Characterizing brain states' dynamics in fMRI data was possible applying the HMM-Gaussian approach to PFMs, with mean activity driving the states. The four spatial maps obtained were named HMM-rest, HMM-visual, HMM-motor and HMM-DMN (default mode network). HMM-DMN appeared once a task state had stabilized. The ultimate goal will be to obtain brain states in our rs-fMRI rat data, to dynamically compare the behavior of brain RSNs as a biomarker of AUD. In conclusion, neuroimaging techniques to estimate rs-FC, brain activity and GM volume can be successfully applied to multimodal MRI in the advance of the understanding of brain homeostasis in AUDs. These functional and structural alterations are a biomarker of chronic alcoholism to explain impairments in executive control, reward evaluation and visuospatial processing. / Pérez Ramírez, MÚ. (2018). Characterizing functional and structural brain alterations driven by chronic alcohol drinking: a resting-state fMRI connectivity and voxel-based morphometry analysis [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/113164 / TESIS

Alcohol use disorder (AUD) is a widespread mental disease denoted by chronic alcohol use despite significant negative consequences for a person’s life. It affected more than 14 million persons in Europe alone and accounted for more than 5% of deaths worldwide in 2011-2012. Understanding the psychological and neurobiological mechanisms driving the development and maintenance of pathological alcohol use is key to conceptualizing new programs for prevention and therapy of AUD. There has been a variety of etiological models trying to describe and relate these mechanisms. Lately, the view of AUD as a disorder of learning and decision making has received much support proposing dual systems to be at work in AUD – one system being deliberate, forward-planning, and goal-directed and the other one reflexive, automatic, and habitual. Both systems supposedly work in parallel in a framework of value-based decision making and their balance can be flexibly adjusted in healthy agents, while a progressive imbalance favoring habitual over goal-directed choice strategies is assumed in AUD. This imbalance has been theoretically associated to neural adaptations to chronic alcohol use in corticostriatal pathways involved in reward processing, especially in ventral striatum. However, these theoretical models are grounded strongly on animal research while empirical research in the human domain remains rather sparse and inconclusive. Furthermore, alterations in value-based decision-making processes and their neural implementation might not only result from prolonged alcohol misuse but may also represent premorbid interindividual differences posing a risk factor for the development of AUD. Therefore, I here present three studies investigating the relation of alcohol use with the balance between goal-directed and habitual decision systems and with parameters modulating option valuation processes of these systems, namely delay, risk, and valence of option outcomes. To separate the investigation of these decision processes as predisposing risk for or consequence of alcohol use, two samples were examined: one sample of 201 eighteen-year-old men being neither abstinent from nor dependent on alcohol as well as one sample of 114 AUD patients in detoxification treatment and 98 control participants matched for age, sex, educational background, and smoking status. Both samples had a baseline assessment of several behavioral tasks, questionnaires, and neuropsychological testing and were followed-up over one year to examine drinking trajectories in the sample of young men and relapse in detoxified patients. The behavioral tasks included a sequential choice task using model-free and model-based reinforcement learning as operationalization of habitual and goal-directed decision making, respectively, during functional magnetic resonance imaging and four tasks probing participants’ delay discounting, probability discounting for gains and losses, and loss aversion. Study 1 presents the cross-sectional analysis of the sequential choice task in relation to baseline drinking behavior of the young-adult sample. These analyses did not reveal an association between non-pathological alcohol use and habitual and goal-directed control on neither a behavioral nor neural level except for one exploratory finding of increased BOLD responses to model-free habitual learning signals in participants with earlier onset of drinking. Study 2 examined the same task in AUD patients compared to control participants showing no difference in behavioral control or neural correlates between those groups. However, prospectively relapsing AUD patients showed lower BOLD responses associated to model-based goal-directed control than abstaining patients and control participants. Additionally, the interaction of goal-directed control and positive expectancies of alcohol effects discriminated subsequently relapsing and abstaining patients revealing an increased risk of relapse for those patients who showed higher levels of goal-directed control and low alcohol expectancies or low levels of goal-directedness and high expectancies. Study 3 examined modulating features of goal-directed and habitual option valuation – delay, risk, and valence of options – in association to alcohol use in the young-adult sample and AUD status in the sample of patients and matched control participants on a cross-sectional as well as longitudinal level. This study revealed no relation of delay, risk, and loss aversion with current alcohol use and consumption one year later in the young men. In contrast, AUD patients showed systematically more impulsive choice behavior than control participants in all four tasks: a higher preference for immediate rewards, more risky choices when facing gains and less when facing losses, and lower loss aversion. Furthermore, a general tendency to overestimate the probability of uncertain losses could predict relapse risk over the following year in AUD patients. Taken together, these results do not support the hypothesis that mechanisms of value-based decision making might be predisposing risk factors for alcohol consumption. The findings for patients already suffering from AUD are mixed: while choice biases regarding delays, risks, and valence of option outcomes seem to be altered systematically in AUD, there was no indication of an imbalance of habitual and goal-directed control. These findings challenge the assumption of a generalized outcome-unspecific shift of behavioral control from goal-directed to habitual strategies during the development of AUD and point towards several possible future avenues of research to modify or extend the theoretical model.:Table of Contents List of Figures List of Tables List of Abbreviations Abstract Chapter 1. Perspectives on alcohol use disorder 1.1 The size of alcohol use disorder 1.1.1 Terminology of alcohol-use related disorders 1.1.2 Size and burden of alcohol consumption and alcohol use disorders 1.2 Cognitive psychological perspectives on alcohol use disorder 1.2.1 A unified framework for addiction 1.2.2 Value-based decision making 1.2.3 Goal-directed and habitual systems 1.3 Neurobiological perspectives on alcohol use disorders 1.3.1 Neural underpinnings of the reward circuit 1.3.2 Neural underpinning of goal-directed and habitual decision making 1.3.3 Striatal adaptations associated with chronic alcohol consumption 1.4 Synopsis and research questions Chapter 2. Study 1 2.1 Abstract 2.2 Introduction 2.3 Material and methods 2.3.1 Participants and procedure 2.3.2 Measures of goal-directed and habitual behavioral control 2.3.3 Measure of alcohol consumption 2.3.4 Behavioral statistical analyses 2.3.5 Functional magnetic resonance imaging data acquisition and analysis 2.4 Results 2.4.1 Sample characteristics 2.4.2 Behavioral results 2.4.3 Functional magnetic resonance imaging results 2.5 Discussion Chapter 3. Study 2 3.1 Abstract 3.2 Introduction 3.3 Methods and materials 3.3.1 Participants 3.3.2 Procedure 3.3.3 Alcohol Expectancy Questionnaire 3.3.4 Task 3.3.5 Magnetic Resonance Imaging 3.3.6 Follow-up procedure 3.3.7 Data analysis 3.3.8 fMRI analysis 3.4 Results 3.4.1 Sample characteristics 3.4.2 Task-related group differences 3.4.3 Interaction between alcohol expectancies and model-based control 3.4.4 fMRI results 3.5 Discussion Chapter 4. Study 3 4.1 Abstract 4.2 Introduction 4.3 Study 3.1 4.3.1 Material and methods 4.3.2 Results 4.4 Study 3.2 4.4.1 Material and methods 4.4.2 Results 4.5 Discussion Chapter 5. General discussion 5.1 Summary of findings and discussion 5.1.1 Goal-directed and habitual decision making and alcohol use (disorder) 5.1.2 Neuroimaging correlates of goal-directed and habitual control 5.1.3 Modulators of the valuation systems and alcohol use (disorders) 5.1.4 Integration of findings 5.2 Limitations 5.2.1 Methodological critique of the Two-Step task 5.3 Outlook for future studies 5.3.1 Tentative framework for future studies 5.4 Conclusions References Appendix A Supplementary Information of Study 1 A.1 Supplementary Methods 1 - behavioral A.2 Supplementary Methods 2 - fMRI A.3 Supplementary Results - behavioral A.4 Supplementary results - fMRI B Supplementary Information of Study 2 B.1 Computational fits B.2 Preprocessing of the functional imaging data B.3 Exclusion criteria for different analyses B.4 First level analysis of the functional imaging analysis B.5 Voxel-based morphometry B.6 Drinking Motives Questionnaire B.7 Model-free comparisons B.8 Association with time to relapse B.9 Number of detoxifications and model-based control: behavioral and neuroimaging analyses C Supplementary Information of Study 3 C.1 Differences between VBDM version used in this study compared to the VBDM version reported in Pooseh et al. (under review) C.2 Additional correlational analyses D Supplementary Information for additional analyses

Zusammenfassung Hintergrund Der Konsum von Alkohol ist unter Jugendlichen weitverbreitet und stellt in Europa noch vor Nikotin die am häufigsten konsumierte abhängigkeitserzeugende Substanz dar. Die individuellen und gesellschaftlichen Konsequenzen jugendlichen Alkoholgebrauchs sind weitreichend, so gilt dieser als wichtigster Risikofaktor für Morbidität und Mortalität bei jungen Menschen in der westlichen Welt (Rehm et al., 2006). Vor diesem Hintergrund hat in Deutschland und anderen europäischen Ländern seit Beginn der 2000er Jahre der besorgniserregende Trend steigender Zahlen stationär behandelter jugendlicher Alkohol-intoxikationen Aufmerksamkeit erhalten. Unbehandelt stellt eine Alkoholintoxikation mit sehr hoher Blutalkoholkonzentration eine lebensbedrohliche Situation dar. Die entsprechenden Behandlungszahlen für Minderjährige haben sich im Zeitraum von 2000 bis 2012 mehr als verdreifacht. Verglichen mit anderen Altersgruppen stellte die Gruppe der 15- bis 20-Jährigen im genannten Zeitraum die mit Abstand größte Altersgruppe dar, gemessen an der Zahl der Behandlungsfälle pro 100 000 Gleichaltriger. Für diese junge Patientenpopulation liegen jedoch noch keine aussagekräftigen Daten darüber vor, welche Faktoren mit problematischem habituellen Alkoholkonsum assoziiert sind und in welchem Ausmaß bereits Alkoholgebrauchsstörungen bestehen. Ebenso wenig existieren Informationen über längerfristige Entwicklungsverläufe der betroffenen Kinder und Jugendlichen, was jedoch ausschlaggebend für die Identifizierung besonders gefährdeter Patienten ist. Fragestellungen Auf der Grundlage der aktuellen Literatur ergeben sich für die vorliegende Arbeit folgende Fragen: - Welche biopsychosozialen Faktoren sind mit problematischem habituellen Alkoholkonsum bei Fällen jugendlicher Alkoholintoxikationen assoziiert? - Sind betroffene Jugendliche im Vergleich zu Peers aus der Allgemeinbevölkerung gefährdeter hinsichtlich Alkoholgebrauchsstörungen und Substanzgebrauch? - Haben Kinder und Jugendliche, die aufgrund einer Alkoholintoxikation stationär behandelt wurden, ein erhöhtes Risiko, im jungen Erwachsenenalter eine Alkoholgebrauchsstörung und andere psychosoziale Probleme zu entwickeln, verglichen mit minderjährigen Patienten, die aus nicht-alkoholassoziierten Gründen behandelt wurden? - Welche Faktoren, die zum Zeitpunkt der stationär behandelten Alkoholintoxikation im Kindes- bzw. Jugendalter bekannt sind, sagen psychosoziale Outcome-Variablen im jungen Erwachsenenalter voraus? Die genannten Fragen sollen mit drei Studien beantwortet werden. Material und Methode Studie 1: In dieser naturalistischen Querschnittsuntersuchung wurden 65 Kinder und Jugendliche (Durchschnittsalter: MW (SD) 15,2 (1,6) Jahre), die stationär aufgrund von Alkoholintoxikation in den beiden Dresdner Kinderkliniken behandelt wurden, am Tag nach der Aufnahme am Krankenbett mündlich und schriftlich befragt. Die Datenerhebung erfolgte zwischen Mai 2009 und September 2010. Neben der Prävalenz des Substanzkonsums und von Alkoholgebrauchsstörungen, wurden auch bekannte Risikofaktoren für problematischen Alkoholgebrauch erhoben, wie das wahrgenommene elterliche Erziehungsverhalten, die Familienanamnese für Alkoholprobleme, deviante Verhaltensweisen der Freunde, Alkoholtoleranz und Alter des Alkoholerstkonsums. Studie 2 und Studie 3: Beide Studien entstanden im Rahmen des RiScA-Projekts (Risiko- und Schutzfaktoren bei Alkoholvergiftungen im Kindes- und Jugendalter) und beziehen sich auf dieselbe Stichprobe. In diesem Projekt wurden die Krankenakten von 1603 Fällen von jugendlichen Alkoholintoxikationen, die im Zeitraum von 2000 bis 2007 in einem von fünf Kinderkliniken (Universitätsklinikum Carl Gustav Carus, Städtisches Klinikum Dresden-Neustadt, HELIOS Klinikum Pirna, Universitätsmedizin Rostock, Münchner Klinikum Schwabing) stationär behandelt wurden, analysiert (Intoxikationsgruppe). Die Akten wurden systematisch hinsichtlich geeigneter Prädiktorvariablen, die die psychosoziale Langzeitentwicklung nach der Krankenhausbehandlung vorhersagen sollen, ausgewertet. Die Langzeitkatamnese wurde realisiert, indem die ehemaligen Patienten zur Teilnahme an einem standardisierten Telefoninterview eingeladen wurden. Zusätzlich wurde eine hinsichtlich Alter, Geschlecht und geographischer Region gematchte Kontrollgruppe telefonisch interviewt, die im selben Untersuchungszeitraum und in den selben Kinderkliniken stationär behandelt wurde aufgrund anderer, nicht-alkoholassoziierter Gründe. In der Intoxikationsgruppe nahmen 277 (Durchschnittsalter: MW (SD) 24,3 (2,3) Jahre) und in der Kontrollgruppe 116 junge Erwachsene (MW (SD) 23,9 (2,1) Jahre) am Telefoninterview teil (Beobachtungszeitraum seit der Krankenhausbehandlung: 5–13 Jahre (MW (SD) 8,3 (2,3) Jahre)). Folgende Outcome-Variablen des Langzeitverlaufs wurden erhoben: Konsum von Alkohol, Tabak und illegalen Substanzen, Vorliegen von Alkoholgebrauchsstörungen, allgemeine Lebenszufriedenheit, Delinquenz und Inanspruchnahme psychiatrischer/psychotherapeutischer Behandlungen. Ergebnisse Studie 1: Es zeigten sich erhöhte Prävalenzwerte für Alkoholabhängigkeit und -missbrauch, Rauschtrinken, regelmäßiges Rauchen und Gebrauch illegaler Drogen im Vergleich zu Daten aus der Allgemeinbevölkerung. Kein Unterschied wurde jedoch in Bezug auf die Häufigkeit des Alkoholkonsums, verglichen mit der Allgemeinbevölkerung, gefunden. Weiterhin zeigte sich, dass Patienten, die problematischen habituellen Alkoholkonsum betrieben – verglichen mit Patienten, auf die dies nicht zutraf – signifikant häufiger deviante Verhaltensweisen bei ihrem Freundeskreis, eine signifikant höhere Anzahl von Familienmitgliedern, die ein Alkoholproblem haben, berichteten, eine höhere Alkoholtoleranz, gemessen durch den Self-Rating of the Effects of Alcohol (SRE) - Fragebogen, erreichten und häufiger elterliche Erziehungsverhaltensweisen berichteten, die durch weniger Aufsicht gekennzeichnet waren. Studie 2: Die Probanden der Intoxikationsgruppe betrieben signifikant häufiger problematischen habituellen Alkoholkonsum, berichteten häufiger delinquente Verhaltensweisen und den Gebrauch illegaler Drogen und erfüllten häufiger die DSM-5-Kriterien einer schweren Alkoholgebrauchsstörung verglichen mit der Kontrollgruppe. Die Mehrheit der Probanden berichtete jedoch keine psychosozialen Belastungen. Keine signifikanten Unterschiede zwischen beiden Gruppen zeigten sich beim Bildungsgrad, regelmäßigen Rauchen, der allgemeinen Lebenszufriedenheit und der Inanspruchnahme von psychiatrischer oder psychotherapeutischer Behandlungen. Studie 3: 277 junge Erwachsene (Rücklaufquote: 22,7%) konnten nach durchschnittlich 8 Jahren nach der Klinikbehandlung befragt werden. Es zeigte sich mittels logistischer und linearer Regressionsmodelle, dass vor allem die Variablen männliches Geschlecht, Gebrauch illegaler Drogen und deviante Verhaltensweisen im Jugendalter, wie mehrmaliges Schulschwänzen oder Weglaufen von Zuhause, psychosoziale Outcome-Maße im jungen Erwachsenenalter, wie Rauschtrinken, Alkoholabhängigkeit, den Gebrauch illegaler Drogen und eine geringe allgemeine Lebenszufriedenheit signifikant vorhersagten. Die durch die Regressionsmodelle erklärte Varianz der im jungen Erwachsenenalter erhobenen psychosozialen Outcome-Variablen lag jedoch nur bei 13 bis 24%. Schlussfolgerungen Für Kinder und Jugendliche, die mit einer Alkoholintoxikation stationär behandelt wurden, besteht ein erhöhtes Risiko, bis zum jungen Erwachsenenalter eine schwere Alkoholgebrauchsstörung oder andere psychosoziale Probleme entwickelt zu haben. Allerdings war die Mehrheit der Probanden sowohl im Kindes- und Jugendalter (Studie 1) als auch im jungen Erwachsenenalter (Studie 2 und 3) nicht von Alkoholgebrauchs-störungen oder anderen negativen Entwicklungsaspekten betroffen. Der überwiegende Teil der betroffenen Kinder und Jugendlichen war scheinbar unerfahren im Gebrauch von Alkohol und/oder besaß eine geringe Alkoholtoleranz. Es kann jedoch nicht ausgeschlossen werden, dass eine besonders belastete Subgruppe existiert, die bereits Suchterkrankungen und/oder andere Verhaltensprobleme aufweisen, wobei das exzessive Trinkverhalten, das der stationären Behandlung vorausging, möglicherweise auf zugrundeliegende Entwicklungsgefährdungen hinweist. Interventionen sollten daher das problematische Trinkverhalten nicht losgelöst vom sozialen Umfeld, wie beispielsweise den Eltern, betrachten. Um besonders gefährdete Kinder und Jugendliche besser identifizieren zu können, sollten vor allem die Verlaufsprädiktoren männliches Geschlecht, Gebrauch illegaler Drogen und Verhaltensauffälligkeiten wie Schulschwänzen und Weglaufen von zu Hause (Studie 3) z. B. in Präventions- und Interventions-maßnahmen Beachtung finden. / Summary Background Alcohol use by young people is widespread and alcohol is the most frequently used psychoactive substance in Europe still before nicotine. Individual and societal consequences of adolescent alcohol use are far reaching, as it is considered to be the most important risk factor for morbidity and mortality among young people in the Western world (Rehm et al., 2006). Against this background, the worrying trend of increasing numbers of adolescents admitted to inpatient treatment with alcohol intoxication (AIA) since the 2000s has gained attention in Germany and other European countries. Alcohol intoxication with a high level of blood alcohol concentration can be life-threatening if untreated. The number of AIA more than tripled in the period from 2000 to 2012 and compared with all other age groups, 15- to 20-year-olds were the largest group measured in terms of the number of treated individuals per 100 000 peers. However, meaningful empirical data concerning the prevalence of alcohol use disorders (AUD) in AIA and which factors are associated with problematic habitual alcohol use in this patient population are lacking. Moreover, the long-term psychosocial development of AIA is still unknown, while this information is crucial for identifying high-risk patients. Research questions The present thesis addresses the following research questions: Study 1: Which biopsychosocial factors are associated with problematic habitual alcohol use in cases of AIA? Are the prevalences of substance use and AUDs in AIA elevated compared to adolescents from the general population? Study 2: Do AIA have an increased risk to develop AUD and other adverse psychosocial outcomes in young adulthood compared to their peers? Study 3: Which variables at the time of hospital admission in adolescence predict psychosocial outcomes in young adulthood in cases of AIA? Methods Study 1: In this cross-sectional naturalistic study 65 AIA (M and SD age 15.2 ± 1.6 yr) completed questionnaires and were interviewed the morning after admission. The study was conducted between May 2009 and September 2010 in both pediatric hospitals in the City of Dresden, Germany, i.e., the University Hospital Carl Gustav Carus and the Municipal Hospital Dresden-Neustadt. Assessment included substance use, alcohol use disorders and known risk factors for problematic alcohol use such as perceived parental monitoring, family history of alcohol problems, deviant peer affiliations, alcohol tolerance, and age of first drink. Study2: Study 2 and study 3 originated from the RiScA project (Risk and Protective Factors in the Context of Acute Alcohol Intoxication in Childhood and Adolescence; German: Risiko- und Schutzfaktoren nach Alkoholvergiftungen im Kindes- und Jugendalter). In this study, 277 young adults (mean age 24.3 years (SD 2.3)) who had been hospitalized due to alcohol intoxication in one of five pediatric departments (University Hospital Carl Gustav Carus, Municipal Hospital Dresden-Neustadt, HELIOS Hospital Pirna, Municipal Hospital Schwabing, University Medicine Rostock) 5 – 13 years ago (mean 8.3 years (SD 2.3)) between 2000 and 2007 participated in a standardized telephone interview. The interview was also conducted with a control group consisting of 116 former patients (mean age 23.9 years (SD 2.1)) matched in terms of age, sex and geographic region who were admitted to the same hospitals in the same period due to conditions other than alcohol intoxication in adolescence. Long-term outcome measures included current DSM-5 AUD, drinking patterns, illicit substance use, regular smoking, general life satisfaction, use of mental health treatment, and delinquency. Study 3: 1603 cases of AIA who had been hospitalized in the same period and in the same hospitals as in Study 2 were identified. These former patients were invited to participate in a standardized telephone interview in young adulthood collecting the following long-term psychosocial outcomes: binge-drinking, alcohol abuse and alcohol dependence (according to DSM-IV), illicit substance use, general life satisfaction, delinquency, and use of psychiatric or psychotherapeutic treatment. Medical records of AIA were retrospectively analyzed extracting potential variables predicting psychosocial long-term outcomes in young adulthood. Results Study 1: Elevated prevalence rates were found for alcohol abuse, alcohol dependence, binge drinking, regular smoking, and illicit substance in AIA compared to adolescents from the general population. No difference was found with respect to frequency of alcohol use compared with the general population. Exploratory analyses revealed that deviant peer affiliations, a positive family history of alcoholism, an elevated alcohol tolerance, and a parenting style characterized by less supervision and strictness were associated with problematic habitual alcohol use. Study 2: AIA had a significantly elevated risk to engage in problematic habitual alcohol use, to exhibit delinquent behaviors, and to use illicit substances in young adulthood compared to the control group. Severe AUD also occurred considerably more often in the AIA than the control group. However, the majority of participants did not report adverse psychosocial outcomes. No significant differences between the study groups were found regarding level of education, regular smoking, general life satisfaction and use of psychiatric or psychotherapeutic treatment. Study 3: 277 young adults (response rate: 22.7%) could be interviewed 5–13 (mean 8.3 (SD 2.3)) years after hospital treatment. Logistic and linear regression models revealed that being male, using illicit substances and truancy or runaway behavior in adolescence predicted binge drinking, alcohol dependence, use of illicit substances and poor general life satisfaction in young adulthood, explaining between 13 and 24% of the variance for the different outcome variables. Conclusions AIA are at an elevated risk to develop severe AUD or other psychosocial problems in young adulthood. However, the majority of participants both in childhood and adolescence (Study 1) and young adulthood (Study 2 and 3) was not affected by AUD or other developmental hazards. It seems that the greater part of AIA were inexperienced drinkers and / or had a low alcohol tolerance. However, it cannot be ruled out that a particularly vulnerable subgroup exist which already developed AUD and / or other behavioral problems. To better identify high-risk AIA, the predictor variables being male, illicit substance use and behavioral problems such as truancy or runaway behavior in adolescence (Study 3) should be practically included in prevention programs and brief interventions.

Background; Alcohol use disorder is a global problem that cause harm to the individual’s health and can also lead to death. Patients with alcohol use disorder often comes in contact with the somatic care due to physical harm and sickness. Therefore, nurses often meet these patients and their attitudes and skills affect the further care. Aim; The aim of this study is to investigate nurses’ experiences of caring for patients with alcohol use disorder in the somatic care. Method; A literature-based review based on analysis of qualitative and quantitative studies according to Friberg’s three step model. Four were qualitative, four quantitative and one mixed method. Result; The result of this literature review was shaped by three categories, lack of motivation, lack of treatment and attitudes and lack of knowledge. Throughout all the categories lack of knowledge was a repetitive problem that led to stigmatization of the patients with alcohol use disorder. Conclusion; In conclusion the nurse needs more knowledge to provide equal care and not risk the patient a deteriorated course of care. / Populärvetenskaplig sammanfattning Skadligt bruk av alkohol är ett folkhälsoproblem världen över och varje år omkommer omkring tre miljoner människor till följd av alkoholen. Förutom dödsfall orsakar alkohol skador och olyckor samt leder till relaterade sjukdomar. Detta orsakar stort lidande för patienten och dess närstående men också kostnader för samhället i stort. Ett skadligt bruk av alkohol kallas för alkoholbrukssyndrom och personer med alkoholbrukssyndrom som har en annan samtida diagnos riskerar att få ett sämre förlopp i sjukvården då samsjukligheten gör att de hamnar mellan olika specialistområden och instanser. Syftet med denna litteraturöversikt var att undersöka sjuksköterskors erfarenheter av att vårda patienter med alkoholbrukssyndrom inom den somatiska vården. I denna litteraturöversikt beskrivs alkoholbrukssyndrom som en diagnos som innefattar ett problematiskt bruk av alkohol som orsakar klinisk utmärkande funktionsnedsättning eller lidande. Personer med alkoholbrukssyndrom anses vara en komplex patientgrupp vilket gör att sjuksköterskan behöver ha bred kunskap och helhetsperspektivet är av stor vikt. Att arbeta personcentrerat ingår i sjuksköterskans roll och ansvarsområde och bör tillämpas för att fånga helhetsperspektivet. Hälso- och sjukvården bör enligt lag bedrivas på ett sådant sätt att den värnar om alla människors lika värde. Trotts detta upplever patienter med alkoholbrukssyndrom att de blir stigmatiserade i vården. Metoden som användes var en litteraturöversikt där både kvalitativa och kvantitativa artiklar inkluderats. Totalt inkluderades nio artiklar. De analyserades enligt Fribergs trestegsmodell där tre huvudkategorier identifierades med två underkategorier till respektive huvudkategori i resultatet. I resultatet framkommer det att sjuksköterskorna upplever att de saknar kunskap om alkoholbrukssyndrom. I kombination med detta saknar de även stöd från organisationen, kollegor och specialister inom beroendevården vilket bidrar till ytterligare svårigheter vid omhändertagandet av denna patientgrupp. Sjuksköterskorna saknar motivation att vårda personer med alkoholbrukssyndrom då de upplever frustration över att patienterna ofta återkommer till vården med samma problem. Det beskrivs även en misstro riktat till patientens egen förmåga, likaså misstro till sjuksköterskans egen förmåga att vårda, men också misstro till organisationen och vårdens möjligheter till att hjälpa patienten. Fortsatt beskrives att patienter som är förgiftade av alkohol kan vara aggressiva och sjuksköterskorna beskriver en rädsla för att göra fel och göra någon upprörd. Sammanfattningsvis är sjuksköterskorna i behov av ökade kunskaper om alkoholbrukssyndrom för att minska stigmatiseringen av denna patientgrupp och därmed risken för ett sämre vårdförlopp.

Background and Aims: In India, alcohol per capita consumption (APC) has substantially increased over the past 2 decades. Although consumption does vary across the country, consistent state-level data are lacking. We aimed to identify all state-level alcohol exposure estimates since 2000 to (i) model consistent current drinking (CD) (12 months) prevalence estimates for all 36 states/union territories (UT) in 2019 and (ii) compare state-level CD trends with national-level APC trends. Design: A systematic review for studies on the Indian state-level prevalence of CD, lifetime abstinence (LA), alcohol use disorders (AUD) or the quantity of alcohol consumed among current drinkers (QU) was conducted. Subsequently, statistical modelling was applied. Setting: Data were collected and modelled for all Indian states/UTs. Participants: Studies since 2000 referring to the general adult population (≥15 years) of at least one Indian state/UT were eligible. The total sample size covered was 29 600 000 (males: females, 1:1.6). Measurements: Results on LA, AUD and QU were summarized descriptively. For (i) the state-, sex- and age-specific CD prevalence was estimated using random intercept fractional response models. For (ii) random intercept and slope models were performed. Findings: Of 2870 studies identified, 30 were retained for data extraction. LA, AUD and QU data were available for 31, 36 and 12 states/UTs, respectively. CD model estimates ranged from 6.4% (95% CI = 2.1%–18.1%; males) in Lakshadweep and 1.3% (95% CI = 0.7%–2.6%; females) in Delhi to 76.1% (95% CI = 68.1%–82.6%; males) and 63.7% (95% CI = 49.4%–75.7%; females) in Arunachal Pradesh. Over time, CD decreased in most states/UTs in the observed data, contradicting increasing national-level APC trends. Conclusions: Alcohol use (measured as consistent current drinking) in India has large regional variations, with alcohol consumption being most prevalent in the North-East, Chhattisgarh, Telangana, Himachal Pradesh, Punjab and Jharkhand.

Alcohol use disorder (AUD) is a relapsing–remitting condition characterized by excessive and/or continued alcohol consumption despite harmful consequences. New adjuvant tools, such as noninvasive brain stimulation techniques, might be helpful additions to conventional treatment approaches or even provide an alternative option for patients who fail to respond adequately to other treatment options. Here, we discuss the potential use of auricular transcutaneous vagus nerve stimulation (atVNS) as an ADD-ON intervention in AUD. Compared with other techniques, atVNS has the advantage of directly stimulating nuclei that synthesize GABA and catecholamines, both of which are functionally altered by alcohol intake in AUD patients. Pharmacological options targeting those neurotransmitters are widely available, but have relatively limited beneficial effects on cognition, even though restoring normal cognitive functioning, especially cognitive control, is key to maintaining abstinence. Against this background, atVNS could be a particularly useful add-on because there is substantial meta-analytic evidence based on studies in healthy individuals that atVNS can enhance cognitive control processes that are crucial to regaining control over drug intake. We discuss essential future research on using atVNS as an ADD-ON intervention in AUD to enhance clinical and cognitive outcomes by providing a translational application. Given that this novel technique can be worn like an earpiece and can be employed without medical supervision/outside the clinical settings, atVNS could be well integratable into the daily life of the patients, where the task of regaining control over drug intake is most challenging.

Les dérèglements émotionnels ont été largement avancés dans le développement et le maintien des conduites addictives. Ces perturbations des processus émotionnels sont associées à l’utilisation privilégiée de stratégies compensatoires mal adaptées qui vont à leur tour entériner les conduites addictives et entraver une consolidation de l’abstinence. Ce travail vise une meilleure compréhension des facteurs de vulnérabilité de la rechute à l’alcool par l’étude de l’évolution des compétences émotionnelles avec l’abstinence à travers trois volets expérimentaux. Pour cela, nous étudierons spécifiquement les mécanismes de régulation émotionnelle considérés comme centraux dans la problématique addictive. Nous utiliserons des outils particuliers pour étudier ces mécanismes que sont des indicateurs physiologiques du système nerveux autonome.Dans un premier volet, nous avons étudié les réponses du système sympathique par la mesure du diamètre pupillaire en réponse à la présentation d’images neutres etémotionnelles (positives et négatives). Nous avons démontré qu’en situation d’induction émotionnelle les patients abstinents à court terme présentent une activation plus forte du système d’alerte sympathique que les abstinents à long terme et les participants contrôles. Le niveau intermédiaire de la réponse pupillaire observé chez les abstinents à long terme suggère une amélioration partielle dans l’activation sympathique à la présentation d’une information émotionnelle (étude 1). La variabilité de la fréquence cardiaque (VFC) est un indicateur du système parasympathique, est reconnue comme marqueur de la régulation émotionnelle. L’étude de la VFC avant pendant et après une situation d’induction émotionnelle a montré une normalisation de la VFC en réponse aux stimuli émotionnels avec une abstinence à long terme. Cependant, les résultats pour les stimuli à valence négative ne sont pas différents entre les groupes abstinents à court et à long terme. Ce pattern de réponse appuie l’hypothèse d’un maintien de vulnérabilité aux émotions négatives en dépit d’une abstinence prolongée. De plus, une corrélation négative a été observée pour les deux groupes de patients entre les scores de craving et une augmentation de la VFC (étude 2). Enfin, dans un dernier volet expérimental, nous avons investigué les compétences et difficultés de régulation émotionnelle par des autoquestionnaires(CERQ et DERS) auprès de patients abstinents de quelques semaines à plusieurs années. Les résultats supportent l’hypothèse d’une limite de récupération capacités après deux ans d’abstinence (étude 3). L’étude de l’étendue des récupérations des compétences émotionnelles est une piste majeure dans la consolidation de l’abstinence. Ces trois études confirment la récupération des compétences émotionnelles avec l’abstinence mais surtout la persistance d’une vulnérabilité dans les processus émotionnels. Le caractère partiel des récupérations de ces mécanismes suppose non seulement le maintien d’une vulnérabilité en dépit d’une abstinence prolongée et met également en évidence la nécessité d’un travail d’accompagnement dans la remédiation de ces compétences à long terme. Un ensemble de perspectives de recherches et d’applications cliniques s’ouvrent au regard de ces résultats, et seront ici discutées. / Emotional disorders are recognized as a major factor of development andcontinuity of addictive behavior. These perturbations of the emotional processes areassociated with the preference given to ill-suited compensatory strategies which will inturn perpetuate addictive behaviors and interfere with the consolidation of abstinence.This study aimed to give a better understanding of the vulnerability factors of alcoholrelapse by studying the evolution of emotional competence with abstinence over threeexperimental chapters. For this purpose, we looked more closely at the mechanisms ofemotional regulation, which are considered as crucial in the addiction problem. In orderto study these mechanisms we used specific tools like the physiological cues of theautonomic nervous system.In a first chapter, we studied sympathetic system response by measuringpupillary diameter after exposure to neutral and emotional pictures (positive andnegative). We showed that when exposed to emotional induction, short-term abstinentpatients showed a stronger activation of the sympathetic nervous system than long-termabstinent patients as well as the control group. The intermediary level of pupillaryresponse found among long-term abstinent patients suggests a partial improvement ofsympathetic activation when exposed to emotional information (study 1). Heart RateVariability (HRV) is an indicator of the parasympathetic system and is viewed as amarker of emotional regulation. The study of HRV before, during and after a situation ofemotional induction showed a normalization of HRV in response to emotional stimuliwith long-term abstinence. However, results for stimuli with negative valence are notdifferent between the long-term and short-term abstinence groups. This responsepattern supports the hypothesis that there is still a vulnerability to negative emotionsdespite the prolonged abstinence. Moreover, a negative correlation between cravingscores and increase of HRV has been observed for the two patient groups (study 2).Finally, in a last experimental chapter, emotional competence and emotional regulationdifficulties were assessed by presenting the Difficulties in Emotion Regulation Scale(DERS) and the Cognitive Emotion Regulation Questionnaire (CERQ) to few weeks tofew years abstinent patients. Results support the hypothesis of a recovery shift of twoyears of abstinence for these abilities (study 3).The study of the extent of the recoveries of emotional competence is a major leadfor the consolidation of abstinence. Those three studies confirm the retrieval ofemotional competence with abstinence but they particularly show the persistence of avulnerability in the emotional processes. The fact that there is a recovery shift for thosemechanisms not only involves the continuity of a vulnerability despite a prolongedabstinence, but also underlines the need of a work of support for the remediation ofemotional competence in the long term. These results can lead to several researchprospects and clinical applications that will be discussed here.

Contexte : L'évolution des pratiques en alcoologie, suivant le modèle des soins centrés sur la patient, permet de revisiter le concept de rémission pour une meilleure prise en compte du point de vue du patient, participant de façon prépondérante dans la définition de ses objectifs thérapeutiques et dans leur évaluation. Pourtant, peu de ces critères subjectifs de l’évaluation du devenir des patients ont véritablement inclus le patient dans leur développement. Jusqu'à récemment, les instruments mesurant la qualité de vie les plus utilisés en alcoologie étaient génériques, constitués d'items générés par les experts et s'appuyant sur la littérature existante, mais n'ayant pas impliqué de patient dans leur développement, c’est-à-dire dans la génération des items. Méthodes : nous avons réalisé une revue systématique de la littérature recensant les essais thérapeutiques randomisés testant une intervention chez les patients alcoolodépendants, et mesurant son efficacité sur la qualité de vie. Nous avons répertorié les dimensions explorées dans les instruments existants. Il a été montré que ces instruments n'exploraient pas de façon optimale l’impact de l’alcoolodépendance sur la qualité de vie. Sur ce constat, nous avons développé conformément aux recommandations de la Food and Drug Administration (FDA) sur le développement des « Patients-Reported Outcomes » une échelle spécifique au trouble d'usage d'alcool, à partir du vécu rapporté par les patients. Nous avons utilisé la méthode des groupes focus, réalisés en parallèle en France et en Grande-Bretagne auprès de 38 patients présentant un trouble d’usage d’alcool. Ces groupes ont pu générer un pool d’items, testés secondairement par des entretiens cognitifs individuels auprès de 31 patients, aboutissant à l’échelle finale « Alcohol Quality of life Scale » (AQoLS). Nous avons ensuite validé l’échelle AQoLS sur un échantillon de 285 patients français présentant un trouble d’usage d’alcool, recrutés dans des centres sélectionnés de façon aléatoire en France. Résultats : L’échelle développée comporte 34 items, répartis selon 7 dimensions : les relations sociales, les activités, les conditions de vie, s’occuper de soi, les émotions négatives, le sommeil et la perte de contrôle. L’analyse de l’échelle a pu confirmer 6 de ces sept dimensions, avec une répartition légèrement différente des items. La dimension « s’occuper de soi » a disparu au profit d’une nouvelle dimension, l’estime de soi. Les dimensions de contrôle et d’estime de soi sont novatrices dans un instrument de qualité de vie liée à la santé, chez l’adulte. L’échelle a montré de bonnes propriétés psychométriques, avec une bonne consistance interne (Cronbach = 0.96), et une corrélation modérée mais significative avec certains sous-scores de la SF-36 et l’EQ-5D. Un travail complémentaire qualitatif a pu illustrer les liens entre les différents domaines impactés, et notamment la proximité de perception dans les propos des patients, entre l’estime de soi, la perte de contrôle et les troubles cognitifs. Conclusion : L’évolution vers un modèle des soins centrés sur le patient permet d’envisager une conception différente de la rémission et de construire et valider une mesure de la qualité de vie se rapprochant des préoccupations des patients, l’échelle AQoLS. Deux dimensions novatrices ont été rattachées à ce concept : la perte de contrôle du point de vue du patient, et l’estime de soi. / Context : The evolution of practices in alcohol use disorder field, following the model of patient-centered care, lets revisit the concept of remission for a better consideration of the patient's point of view, participating predominantly in the definition of therapeutic objectives and in their assessment. Yet few of these subjective criteria of the evaluation of patient outcomes have actually included the patient in their development. Until recently, quality of life instruments the most used among patients with alcohol use disorder were generic ones, and their development and particularly generation of items did not involve patients, but rather experts and were based on existing literature. Methods : we conducted a systematic literature review identifying randomized clinical trials testing an intervention in alcohol-dependent patients, and measuring its effectiveness on quality of life. We have listed the dimensions explored in the existing instruments. It has been shown that these instruments did not optimally explore the impact of alcohol dependence on quality of life in this population. On this, we have developed a scale specific for patients with alcohol use disorder, following the recommendations of the Food and Drug Administration (FDA) on the development of "Patient-Reported Outcomes", namely involving patients extensively. We used the method of focus groups conducted in parallel in France and Great Britain with 38 patients with alcohol use disorder. These groups allowed the generation of a pool of items, secondarily tested by individual cognitive interviews with 31 patients, resulting in the final scale "Alcohol Quality of Life Scale" (AQoLS). We then validated the AQoLS scale on a sample of 285 French patients with alcoho use disorder, recruited from randomly selected centers in France. Results: The scale has 34 items developed, distributed in seven dimensions: social relationships, activities, living conditions, looking after self, negative emotions, sleep and loss of control. The validation study confirmed six of the seven dimensions, with a slightly different distribution of the items. The "looking after self" dimension disappeared in favor of a new dimension of self-esteem. Control and self-esteem dimensions are innovative in a health-related quality of life instrument in adults. The scale showed good psychometric properties, with good internal consistency (Cronbach = 0.96), and a moderate correlation with sub-scores of the SF-36 and EQ-5D. A qualitative complementary work could illustrate the links between the different affected areas, including the proximity in patients’ perception between self-esteem, loss of control and cognitive impairment. Conclusion : The move towards a model of patient-centered care allows considering a different approach of remission and to build and validate a measure of health-related quality of life close to the concerns of patients with a alcohol use disorder, AQoLS scale. Two innovative dimensions were attached to this concept: loss of control from the patient's perspective, and self-esteem.

Introdução: A ocorrência de episódios depressivos e abuso ou dependência de álcool após um evento agudo de insuficiência coronariana pode representar um marcador independente de mau prognóstico. Portanto, investigamos a presença de sintomas depressivos, transtorno depressivo maior (TDM) e abuso ou dependência de álcool em uma subamostra de uma coorte prospectiva de Síndrome Coronariana Aguda (SCA), Estratégia de Registro de Insuficiência Coronariana Aguda (ERICO) em andamento no pronto-socorro do Hospital Universitário. Métodos: Foi realizado um estudo observacional em 146 participantes do estudo ERICO. A gravidade dos sintomas depressivos foi avaliada em três momentos: 1ª) na admissão hospitalar pelo Patient Health Questionnaire (PHQ-9 itens); 2º) 30 dias pós-SCA pelo PHQ-9, Inventário de Depressão de Beck (BDI) e Escala de Depressão de Hamilton (HDRS-21 itens); e 3º) 180 dias pós-SCA pelo PHQ-9 e BDI. O abuso e uso nocivo de álcool foram avaliados pelo AUDIT e CAGE em 30 e 180 dias pós-SCA. Resultados: Ao longo do estudo as frequências de sintomas depressivos variaram entre 40% e 60% e de TDM entre 28% e 33%. Na admissão hospitalar houve maior predominância de sintomas depressivos entre os homens (58%; p=0,03) e sedentários (72,1%; p=0,02), entretanto, TDM foi mais frequente na população feminina (55,1%; p < 0,001) com uma razão de chances [(RC) 4,5; intervalo de confiança IC 95% 1,85-10,98]. Após 30 dias do evento agudo constatou-se um maior risco de sintomas depressivos entre os tabagistas (RC 5,8; IC 95% 1,81-18,72) e diabéticos (RC 3,6; IC 95% 1,40-9,60). Os diabéticos também apresentaram (RC 3,5; IC 95% 1,39-8,71) para desenvolver TDM. No seguimento de 180 dias verificou-se que indivíduos com angina instável (AI) (RC 4, 46; IC 95% 1,39-14,32) e infarto agudo do miocárdio com supradesnivelamento do segmento ST (IAMCST) (RC 3,40; IC 95% 1,30-8,87) apresentaram maior probabilidade de desenvolverem sintomas depressivos em relação aos indivíduos que apresentaram IAMSST. Os únicos fatores de risco que se mantiveram associados a um maior risco de sintomas depressivos após 180 dias foi o sexo feminino (RC 3,9; IC 95% 1,54-9,73) e o tabagismo (RC 5,34; IC 95% 1,64-17,44). Em relação à TDM, encontramos uma RC de 14 (IC 95% 2,94-67,51) para associação com tabagismo. Quanto ao abuso e uso nocivo de álcool as frequências variaram ao longo do estudo pelo AUDIT e CAGE entre 18,3% e 33,6%. Verificamos na populacão masculina uma frequência de 88,2% (p=0,001) e entre os tabagistas de 55,9% (p=0,003) e foi encontrada uma RC de 51,64 para população mais jovem (35-44 anos) e uma RC de 42,95 para tabagistas. Finalmente, não foi encontrada nenhuma associação entre abuso de álcool e depressão de acordo com os subtipos de SCA nos períodos analisados. Conclusão: A frequência de depressão variou entre 40% e 60% da admissão até 180 dias pós-SCA. Indivíduos que desenvolveram AI ou IAMCST, além de mulheres e tabagistas apresentaram maiores chances de desenvolver depressão ao longo do seguimento de 180 dias e indivíduos entre 35 e 44 anos e tabagistas apresentaram maior possibilidade de abusar do álcool / Introduction: The occurrence of depression and alcohol abuse or dependence after an acute coronary insufficiency may represent an independent marker of poor prognosis. Therefore, we investigated the presence of depressive symptoms, major depressive disorder (MDD) and alcohol abuse or dependence in a subsample of a prospective cohort of Acute Coronary Syndrome (ACS), Strategy of Registry of Acute Coronary Syndrome Study (ERICO study), which is still ongoing in the emergency room of the Hospital Universitário. Methods: We conducted an observational study in 146 participants of the ERICO study. The severity of depressive symptoms was evaluated in 3 moments: 1st) at the hospital admission using The Patient Health Questionnaire (PHQ-9 items); 2nd) 30 days post-ACS using the PHQ-9, the Beck Depression Inventory (BDI) and the Hamilton Depression Rating Scale (HDRS -21 items), and 3rd) 180 days post -ACS through PHQ-9 and BDI. The abuse and harmful alcohol consumption were assessed by the AUDIT and the CAGE 30 and 180 days post-ACS. Results: Along the study, the frequencies of depressive symptoms ranged from 40% to 60% and MDD from 28% to 33%. At the hospital admission there was a higher prevalence of depressive symptoms among men (58%, p= 0.03) and sedentary patients (72.1%, p= 0.02), however, MDD was higher among women (55.1%, p < 0.001) with an increased risk of [odds ratio [(OR) 4.5; confidence interval CI 95% 1.85-10.98]. After 30 days of the acute event, we observed an increased risk of depressive symptoms among smokers (OR 5.8; CI 95%, 1.81-18.72) and among diabetics (OR 3.6; CI 95%, 1.40-9.60) the diabetics were also more likely to develop MDD (OR 3.5; IC 95% 1,39-8,71). At 180 days follow-up, individuals with unstable angina (UA) (OR 4.46; CI 95% 1.39-14.32) and ST elevation myocardial infarction (STEMI) (OR 3.40; CI 95% 1.30-8.87) were more likely to develop depressive symptoms compared with patients who had NSTEMI. The only two factors that remained associated with a higher risk of depressive symptoms after 180 days were female gender (OR 3.9; CI 95% 1.54-9.73) and smokers (OR 5.34; CI 95% 1.64-17.44). Regarding MDD we found an OR of 14 (CI 95% 2.9-67.51) for smokers. In relation to abuse and hazardous consumption of alcohol, the frequencies for CAGE and AUDIT ranged from 18.3% to 33.6% along the study. We found among the male population a frequency of 88.2% (p=0.001) and smokers 55.9% (p=0.003). We also found OR of 51.64 among younger (aged 35-44 years) and OR of 42.95 for smokers. Finally, no association between alcohol abuse and depression according to ACS subtypes was observed. Conclusion: The prevalence of depression post-ACS ranged from 40% to 60% during the follow-up (admission hospital to 180 days). Individuals who developed UA or STEMI, besides women and smokers were more likely to develop depression during follow-up of 180 days and individual aged between 35-44 years and smokers were more likely to abuse of alcohol