Limbic white matter microstructure plasticity reflects recovery from depression

BACKGROUND White matter microstructure alterations of limbic and reward pathways have been reported repeatedly for depressive episodes in major depressive disorder (MDD) and bipolar disorder (BD). However, findings during remission are equivocal. It was the aim of this study to investigate if white matter microstructure changes during the time course of clinical remission. METHODS Fifteen depressed patients (11 MDD, 4 BD) underwent diffusion-weighted MRI both during depression, and during remission following successful antidepressive treatment (average time interval between scans=6 months). Fractional anisotropy (FA) was sampled along reconstructions of the supero-lateral medial forebrain bundle (slMFB), the cingulum bundle (CB), the uncinate fasciculus (UF), the parahippocampal cingulum (PHC) and the fornix. Repeated measures ANCOVAs controlling for the effect of age were calculated for each tract. RESULTS There was a significant main effect of time (inter-scan interval) for mean-FA for the right CB and for the left PHC. For both pathways there was a significant time×age interaction. In the right CB, FA increased in younger patients, while FA decreased in older patients. In the left PHC, a reverse pattern was seen. FA changes in the right CB correlated positively with symptom reductions. Mean-FA of UF, slMFB and fornix did not change between the two time points. LIMITATIONS All patients were medicated, sample size, and lack of control group. CONCLUSIONS Right CB and left PHC undergo age-dependent plastic changes during the course of remission and may serve as a state marker in depression. UF, slMFB and FO microstructure remains stable.

Evaluating an e-mental health program (“deprexis”) as adjunctive treatment tool in psychotherapy for depression: design of a pragmatic randomized controlled trial

Background Major depressive disorder (MDD) places a significant disease burden on individuals as well as on societies. Several web-based interventions for MDD have shown to be effective in reducing depressive symptoms. However, it is not known whether web-based interventions, when used as adjunctive treatment tools to regular psychotherapy, have an additional effect compared to regular psychotherapy for depression. Methods/design This study is a currently recruiting pragmatic randomized controlled trial (RCT) that compares regular psychotherapy plus a web-based depression program (¿deprexis¿) with a control condition exclusively receiving regular psychotherapy. Adults with a depressive disorder (N?=?800) will be recruited in routine secondary care from therapists over the course of their initial sessions and will then be randomized within therapists to one of the two conditions. The primary outcome is depressive symptoms measured with the Beck Depression Inventory (BDI-II) at three months post randomization. Secondary outcomes include changes on various indicators such as anxiety, somatic symptoms and quality of life. All outcomes are again assessed at the secondary endpoint six months post randomization. In addition, the working alliance and feasibility/acceptability of the treatment condition will be explored. Discussion This is the first randomized controlled trial to examine the feasibility/acceptability and the effectiveness of a combination of traditional face-to-face psychotherapy and web-based depression program compared to regular psychotherapeutic treatment in depressed outpatients in routine care.

Psychomotor retardation is linked to frontal alpha asymmetry in major depression

BACKGROUND Psychomotor disturbances are a main clinical feature of major depressive disorder (MDD) but little is known about their EEG signature. One of the most replicated EEG findings in MDD is resting frontal asymmetry in the alpha band (FAA), which is thought to be a correlate of withdrawal behavior and reduced approach motivation. The purpose of this study was to assess psychomotor alterations, alpha band power, FAA and investigate the association between them. METHODS 20 MDD patients and 19 healthy subjects were enrolled. Alpha power and FAA scores were calculated from a resting state EEG. Wrist actigraphy was recorded from the non-dominant arm for 24 h and activity level scores (AL) were extrapolated from the wakeful periods. RESULTS MDD patients had a left-lateralized frontal alpha activity and lower AL scores when compared to healthy subjects. A significant correlation was found between mean FAA and AL scores. A negative covariance between power in the lower alpha range and AL scores over the motor cortex bilaterally was detected. LIMITATIONS Relatively small sample size. Patients were pharmacologically treated with antidepressants. CONCLUSIONS This study replicates the finding of left-lateralized FAA and lower AL scores in MDD patients, and establishes the first evidence of significant correlations between alpha power, FAA scores and measures of motor activity, which may be interpreted as an expression of impaired motivational drive in MDD.

EEG marker of inhibitory brain activity correlates with resting-state cerebral blood flow in the reward system in major depression

Frontal alpha band asymmetry (FAA) is a marker of altered reward processing in major depressive disorder (MDD), associated with reduced approach behavior and withdrawal. However, its association with brain metabolism remains unclear. The aim of this study is to investigate FAA and its correlation with resting – state cerebral blood flow (rCBF). We hypothesized an association of FAA with regional rCBF in brain regions relevant for reward processing and motivated behavior, such as the striatum. We enrolled 20 patients and 19 healthy subjects. FAA scores and rCBF were quantified with the use of EEG and arterial spin labeling. Correlations of the two were evaluated, as well as the association with FAA and psychometric assessments of motivated behavior and anhedonia. Patients showed a left – lateralized pattern of frontal alpha activity and a correlation of FAA lateralization with subscores of Hamilton Depression Rating Scale linked to motivated behavior. An association of rCBF and FAA scores was found in clusters in the dorsolateral prefrontal cortex bilaterally (patients) and in the left medial frontal gyrus, in the right caudate head and in the right inferior parietal lobule (whole group). No correlations were found in healthy controls. Higher inhibitory right – lateralized alpha power was associated with lower rCBF values in prefrontal and striatal regions, predominantly in the right hemisphere, which are involved in the processing of motivated behavior and reward. Inhibitory brain activity in the reward system may contribute to some of the motivational problems observed in MDD.

Valence and agency influence striatal response to feedback in patients with major depressive disorder

BACKGROUND: Reduced sensitivity to positive feedback is common in patients with major depressive disorder (MDD). However, findings regarding negative feedback are ambiguous, with both exaggerated and blunted responses being reported. The ventral striatum (VS) plays a major role in processing valenced feedback, and previous imaging studies have shown that the locus of controls (self agency v. external agency) over the outcome influences VS response to feedback. We investigated whether attributing the outcome to one's own action or to an external agent influences feedback processing in patients with MDD. We hypothesized that depressed participants would be less sensitive to the feedback attribution reflected by an altered VS response to self-attributed gains and losses. METHODS: Using functional MRI and a motion prediction task, we investigated the neural responses to self-attributed (SA) and externally attributed (EA) monetary gains and losses in unmedicated patients with MDD and healthy controls. RESULTS: We included 21 patients and 25 controls in our study. Consistent with our prediction, healthy controls showed a VS response influenced by feedback valence and attribution, whereas in depressed patients striatal activity was modulated by valence but was insensitive to attribution. This attribution insensitivity led to an altered ventral putamen response for SA - EA losses in patients with MDD compared with healthy controls. LIMITATIONS: Depressed patients with comorbid anxiety disorder were included. CONCLUSION: These results suggest an altered assignment of motivational salience to SA losses in patients with MDD. Altered striatal response to SA negative events may reinforce the belief of not being in control of negative outcomes contributing to a cycle of learned helplessness.

Prefrontal Thinning Affects Functional Connectivity and Regional Homogeneity of the Anterior Cingulate Cortex in Depression

Major depressive disorder (MDD) is associated with structural and functional alterations in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC). Enhanced ACC activity at rest (measured using various imaging methodologies) is found in treatment-responsive patients and is hypothesized to bolster treatment response by fostering adaptive rumination. However, whether structural changes influence functional coupling between fronto-cingulate regions and ACC regional homogeneity (ReHo) and whether these functional changes are related to levels of adaptive rumination and treatment response is still unclear. Cortical thickness and ReHo maps were calculated in 21 unmedicated depressed patients and 35 healthy controls. Regions with reduced cortical thickness defined the seeds for the subsequent functional connectivity (FC) analyses. Patients completed the Response Style Questionnaire, which provided a measure of adaptive rumination associated with better response to psychotherapy. Compared with controls, depressed patients showed thinning of the right anterior PFC, increased prefrontal connectivity with the supragenual ACC (suACC), and higher ReHo in the suACC. The suACC clusters of increased ReHo and FC spatially overlapped. In depressed patients, suACC ReHo scores positively correlated with PFC thickness and with FC strength. Moreover, stronger fronto-cingulate connectivity was related to higher levels of adaptive rumination. Greater suACC ReHo and connectivity with the right anterior PFC seem to foster adaptive forms of self-referential processing associated with better response to psychotherapy, whereas prefrontal thinning impairs the ability of depressed patients to engage the suACC during a major depressive episode. Bolstering the function of the suACC may represent a potential target for treatment.

Olfactory bulb volume predicts therapeutic outcome in major depression disorder

The volume of the olfactory bulb (OB) is strongly reduced in patients with major depressive disorder (MDD) and this group exhibits markedly decreased olfactory function. It has been suggested that olfactory input is important for maintaining balance in limbic neurocircuits. The aim of our study was to investigate whether reduced OB volume is associated with response to therapy in MDD. Twenty-four inpatients (all women, age 21-49 years, mean 38 ± 10 years SD) with MDD and 36 healthy controls (all women, age 20-52 years, mean 36 ± 10 years SD) underwent structural MRI. OB volume was compared between responders (N = 13) and non-responders (N = 11) to psychotherapy. Retest of OB volume was performed about 6 months after the end of therapy in nine of the patients. Therapy responders exhibited no significant difference in OB volume compared to healthy controls. However, average OB volume of non-responders was 23 % smaller compared to responders (p = .0011). Furthermore, OB volume was correlated with the change of depression severity (r = .46, p = .024). Volume of the OB did not change in the course of therapy. OB volume may be a biological vulnerability factor for the occurrence and/or maintenance of depression, at least in women.

Evaluation of association between childhood obesity and depression: A systematic literature review

Obesity has become a major public health concern throughout the world. Both developing as well as developed countries have been facing the consequences of obesity. [1, 2] According to World Health Organization, worldwide prevalence of overweight among adults was 1.6 billion and that of obesity was 400 million by the end of year 2005. At the same time, around 20 million children of less than 5 years of age were overweight worldwide. [3] ^ From amongst the obese children, around 15% of children manifest symptoms of depression before 18 years of age as compared to non-obese children of the same age group. Approximately 3-5% of these obese individuals develop major depressive disorders (MDD). [4, 5] The incidence of depression increases markedly as the child reaches puberty. The risk of persistent depression in childhood as well as in adulthood is two to four times higher if the child is obese as compared to those depressed adult individuals who are not obese in their childhood. [6, 7] ^ This paper will review the scientific literature concerning the association between childhood obesity and depression. ^

Validity of using item response theory to analyze data from the Work Limitations Questionnaire

The Work Limitations Questionnaire (WLQ) is used to determine the amount of work loss and productivity which stem from certain health conditions, including rheumatoid arthritis and cancer. The questionnaire is currently scored using methodology from Classical Test Theory. Item Response Theory, on the other hand, is a theory based on analyzing item responses. This study wanted to determine the validity of using Item Response Theory (IRT), to analyze data from the WLQ. Item responses from 572 employed adults with dysthymia, major depressive disorder (MDD), double depressive disorder (both dysthymia and MDD), rheumatoid arthritis and healthy individuals were used to determine the validity of IRT (Adler et al., 2006).^ PARSCALE, which is IRT software from Scientific Software International, Inc., was used to calculate estimates of the work limitations based on item responses from the WLQ. These estimates, also known as ability estimates, were then correlated with the raw score estimates calculated from the sum of all the items responses. Concurrent validity, which claims a measurement is valid if the correlation between the new measurement and the valid measurement is greater or equal to .90, was used to determine the validity of IRT methodology for the WLQ. Ability estimates from IRT were found to be somewhat highly correlated with the raw scores from the WLQ (above .80). However, the only subscale which had a high enough correlation for IRT to be considered valid was the time management subscale (r = .90). All other subscales, mental/interpersonal, physical, and output, did not produce valid IRT ability estimates.^ An explanation for these lower than expected correlations can be explained by the outliers found in the sample. Also, acquiescent responding (AR) bias, which is caused by the tendency for people to respond the same way to every question on a questionnaire, and the multidimensionality of the questionnaire (the WLQ is composed of four dimensions and thus four different latent variables) probably had a major impact on the IRT estimates. Furthermore, it is possible that the mental/interpersonal dimension violated the monotonocity assumption of IRT causing PARSCALE to fail to run for these estimates. The monotonicity assumption needs to be checked for the mental/interpersonal dimension. Furthermore, the use of multidimensional IRT methods would most likely remove the AR bias and increase the validity of using IRT to analyze data from the WLQ.^

Semantic Service Discovery Techniques for the composable web

This PhD thesis contributes to the problem of resource and service discovery in the context of the composable web. In the current web, mashup technologies allow developers reusing services and contents to build new web applications. However, developers face a problem of information flood when searching for appropriate services or resources for their combination. To contribute to overcoming this problem, a framework is defined for the discovery of services and resources. In this framework, three levels are defined for performing discovery at content, discovery and agente levels. The content level involves the information available in web resources. The web follows the Representational Stateless Transfer (REST) architectural style, in which resources are returned as representations from servers to clients. These representations usually employ the HyperText Markup Language (HTML), which, along with Content Style Sheets (CSS), describes the markup employed to render representations in a web browser. Although the use of SemanticWeb standards such as Resource Description Framework (RDF) make this architecture suitable for automatic processes to use the information present in web resources, these standards are too often not employed, so automation must rely on processing HTML. This process, often referred as Screen Scraping in the literature, is the content discovery according to the proposed framework. At this level, discovery rules indicate how the different pieces of data in resources’ representations are mapped onto semantic entities. By processing discovery rules on web resources, semantically described contents can be obtained out of them. The service level involves the operations that can be performed on the web. The current web allows users to perform different tasks such as search, blogging, e-commerce, or social networking. To describe the possible services in RESTful architectures, a high-level feature-oriented service methodology is proposed at this level. This lightweight description framework allows defining service discovery rules to identify operations in interactions with REST resources. The discovery is thus performed by applying discovery rules to contents discovered in REST interactions, in a novel process called service probing. Also, service discovery can be performed by modelling services as contents, i.e., by retrieving Application Programming Interface (API) documentation and API listings in service registries such as ProgrammableWeb. For this, a unified model for composable components in Mashup-Driven Development (MDD) has been defined after the analysis of service repositories from the web. The agent level involves the orchestration of the discovery of services and contents. At this level, agent rules allow to specify behaviours for crawling and executing services, which results in the fulfilment of a high-level goal. Agent rules are plans that allow introspecting the discovered data and services from the web and the knowledge present in service and content discovery rules to anticipate the contents and services to be found on specific resources from the web. By the definition of plans, an agent can be configured to target specific resources. The discovery framework has been evaluated on different scenarios, each one covering different levels of the framework. Contenidos a la Carta project deals with the mashing-up of news from electronic newspapers, and the framework was used for the discovery and extraction of pieces of news from the web. Similarly, in Resulta and VulneraNET projects the discovery of ideas and security knowledge in the web is covered, respectively. The service level is covered in the OMELETTE project, where mashup components such as services and widgets are discovered from component repositories from the web. The agent level is applied to the crawling of services and news in these scenarios, highlighting how the semantic description of rules and extracted data can provide complex behaviours and orchestrations of tasks in the web. The main contributions of the thesis are the unified framework for discovery, which allows configuring agents to perform automated tasks. Also, a scraping ontology has been defined for the construction of mappings for scraping web resources. A novel first-order logic rule induction algorithm is defined for the automated construction and maintenance of these mappings out of the visual information in web resources. Additionally, a common unified model for the discovery of services is defined, which allows sharing service descriptions. Future work comprises the further extension of service probing, resource ranking, the extension of the Scraping Ontology, extensions of the agent model, and contructing a base of discovery rules. Resumen La presente tesis doctoral contribuye al problema de descubrimiento de servicios y recursos en el contexto de la web combinable. En la web actual, las tecnologías de combinación de aplicaciones permiten a los desarrolladores reutilizar servicios y contenidos para construir nuevas aplicaciones web. Pese a todo, los desarrolladores afrontan un problema de saturación de información a la hora de buscar servicios o recursos apropiados para su combinación. Para contribuir a la solución de este problema, se propone un marco de trabajo para el descubrimiento de servicios y recursos. En este marco, se definen tres capas sobre las que se realiza descubrimiento a nivel de contenido, servicio y agente. El nivel de contenido involucra a la información disponible en recursos web. La web sigue el estilo arquitectónico Representational Stateless Transfer (REST), en el que los recursos son devueltos como representaciones por parte de los servidores a los clientes. Estas representaciones normalmente emplean el lenguaje de marcado HyperText Markup Language (HTML), que, unido al estándar Content Style Sheets (CSS), describe el marcado empleado para mostrar representaciones en un navegador web. Aunque el uso de estándares de la web semántica como Resource Description Framework (RDF) hace apta esta arquitectura para su uso por procesos automatizados, estos estándares no son empleados en muchas ocasiones, por lo que cualquier automatización debe basarse en el procesado del marcado HTML. Este proceso, normalmente conocido como Screen Scraping en la literatura, es el descubrimiento de contenidos en el marco de trabajo propuesto. En este nivel, un conjunto de reglas de descubrimiento indican cómo los diferentes datos en las representaciones de recursos se corresponden con entidades semánticas. Al procesar estas reglas sobre recursos web, pueden obtenerse contenidos descritos semánticamente. El nivel de servicio involucra las operaciones que pueden ser llevadas a cabo en la web. Actualmente, los usuarios de la web pueden realizar diversas tareas como búsqueda, blogging, comercio electrónico o redes sociales. Para describir los posibles servicios en arquitecturas REST, se propone en este nivel una metodología de alto nivel para descubrimiento de servicios orientada a funcionalidades. Este marco de descubrimiento ligero permite definir reglas de descubrimiento de servicios para identificar operaciones en interacciones con recursos REST. Este descubrimiento es por tanto llevado a cabo al aplicar las reglas de descubrimiento sobre contenidos descubiertos en interacciones REST, en un nuevo procedimiento llamado sondeo de servicios. Además, el descubrimiento de servicios puede ser llevado a cabo mediante el modelado de servicios como contenidos. Es decir, mediante la recuperación de documentación de Application Programming Interfaces (APIs) y listas de APIs en registros de servicios como ProgrammableWeb. Para ello, se ha definido un modelo unificado de componentes combinables para Mashup-Driven Development (MDD) tras el análisis de repositorios de servicios de la web. El nivel de agente involucra la orquestación del descubrimiento de servicios y contenidos. En este nivel, las reglas de nivel de agente permiten especificar comportamientos para el rastreo y ejecución de servicios, lo que permite la consecución de metas de mayor nivel. Las reglas de los agentes son planes que permiten la introspección sobre los datos y servicios descubiertos, así como sobre el conocimiento presente en las reglas de descubrimiento de servicios y contenidos para anticipar contenidos y servicios por encontrar en recursos específicos de la web. Mediante la definición de planes, un agente puede ser configurado para descubrir recursos específicos. El marco de descubrimiento ha sido evaluado sobre diferentes escenarios, cada uno cubriendo distintos niveles del marco. El proyecto Contenidos a la Carta trata de la combinación de noticias de periódicos digitales, y en él el framework se ha empleado para el descubrimiento y extracción de noticias de la web. De manera análoga, en los proyectos Resulta y VulneraNET se ha llevado a cabo un descubrimiento de ideas y de conocimientos de seguridad, respectivamente. El nivel de servicio se cubre en el proyecto OMELETTE, en el que componentes combinables como servicios y widgets se descubren en repositorios de componentes de la web. El nivel de agente se aplica al rastreo de servicios y noticias en estos escenarios, mostrando cómo la descripción semántica de reglas y datos extraídos permiten proporcionar comportamientos complejos y orquestaciones de tareas en la web. Las principales contribuciones de la tesis son el marco de trabajo unificado para descubrimiento, que permite configurar agentes para realizar tareas automatizadas. Además, una ontología de extracción ha sido definida para la construcción de correspondencias y extraer información de recursos web. Asimismo, un algoritmo para la inducción de reglas de lógica de primer orden se ha definido para la construcción y el mantenimiento de estas correspondencias a partir de la información visual de recursos web. Adicionalmente, se ha definido un modelo común y unificado para el descubrimiento de servicios que permite la compartición de descripciones de servicios. Como trabajos futuros se considera la extensión del sondeo de servicios, clasificación de recursos, extensión de la ontología de extracción y la construcción de una base de reglas de descubrimiento.

Including functional usability features in a Model-Driven Development Method

The Software Engineering (SE) community has historically focused on working with models to represent functionality and persistence, pushing interaction modelling into the background, which has been covered by the Human Computer Interaction (HCI) community. Recently, adequately modelling interaction, and specifically usability, is being considered as a key factor for success in user acceptance, making the integration of the SE and HCI communities more necessary. If we focus on the Model-Driven Development (MDD) paradigm, we notice that there is a lack of proposals to deal with usability features from the very first steps of software development process. In general, usability features are manually implemented once the code has been generated from models. This contradicts the MDD paradigm, which claims that all the analysts? effort must be focused on building models, and the code generation is relegated to model to code transformations. Moreover, usability features related to functionality may involve important changes in the system architecture if they are not considered from the early steps. We state that these usability features related to functionality can be represented abstractly in a conceptual model, and their implementation can be carried out automatically.

PRISMA: Model-driven development of aspect-oriented software architectures

This summary presents a methodology for supporting the development of AOSAs following the MDD paradigm. This new methodology is called PRISMA and allows the code generation from models which specify functional and non-functional requirements.

A framework to identify primitives that represent usability within model-driven development methods

Nowadays, there are sound methods and tools which implement the Model-Driven Development approach (MDD) satisfactorily. However, MDD approaches focus on representing and generating code that represents functionality, behaviour and persistence, putting the interaction, and more specifically the usability, in a second place. If we aim to include usability features in a system developed with a MDD tool, we need to extend manually the generated code

Glial reduction in the subgenual prefrontal cortex in mood disorders

Mood disorders are among the most common neuropsychiatric illnesses, yet little is known about their neurobiology. Recent neuroimaging studies have found that the volume of the subgenual part of Brodmann’s area 24 (sg24) is reduced in familial forms of major depressive disorder (MDD) and bipolar disorder (BD). In this histological study, we used unbiased stereological techniques to examine the cellular composition of area sg24 in two different sets of brains. There was no change in the number or size of neurons in area sg24 in mood disorders. In contrast, the numbers of glia were reduced markedly in both MDD and BD. The reduction in glial number was most prominent in subgroups of subjects with familial MDD (24%, P = 0.01) or BD (41%, P = 0.01). The glial reduction in subjects without a clear family history was lower in magnitude and not statistically significant. Consistent with neuroimaging findings, cortical volume was reduced in area sg24 in subjects with familial mood disorders. Schizophrenic brains studied as psychiatric controls had normal neuronal and glial numbers and cortical volume. Glial and neuronal numbers also were counted in area 3b of the somatosensory cortex in the same group of brains and were normal in all psychiatric groups. Glia affect several processes, including regulation of extracellular potassium, glucose storage and metabolism, and glutamate uptake, all of which are crucial for normal neuronal activity. We thus have identified a biological marker associated with familial mood disorders that may provide important clues regarding the pathogenesis of these common psychiatric conditions.

Comorbidity Between Major Depression and Alcohol Use Disorder From Adolescence to Adulthood

Background—Limited information exists regarding the long-term development of comorbidity between Major Depressive Disorder (MDD) and Alcohol Use Disorder (AUD; abuse/dependence). Using a representative prospective study, we examine multiple aspects pertaining to MDD+AUD comorbidity, with a focus on the relation between disorders across periods (adolescence, early adulthood, adulthood) and cumulative impairments by age 30. Method—816 participants were diagnostically interviewed at ages 16, 17, 24, and 30. Results—Rates of comorbid MDD+AUD were low in adolescence (2%), but increased in early adulthood (10%) and adulthood (7%). Rates of cumulative comorbidity were elevated (21%). Most individuals with a history of MDD or AUD had the other disorder, except for women with MDD. Prospectively, adolescent AUD predicted early adult MDD, while early adult MDD predicted adult AUD. Compared to pure disorders, MDD+AUD was associated with higher risk of alcohol dependence, suicide attempt, lower global functioning, and life dissatisfaction. Conclusions—Lifetime rates of comorbid MDD+AUD were considerably higher than in crosssectional studies. Comorbidity was partly explained by bidirectional and developmentally-specific associations and predicted selected rather than generalized impairments. Clinically, our findings emphasize the need to always carefully assess comorbidity in patients with MDD or AUD, taking into account concurrency and developmental timing.