Brain structural and functional correlates of resilience to Bipolar Disorder

Background: Resilient adaptation can be construed in different ways, but as used here it refers to the adaptive brain changes associated with avoidance of psychopathology despite familiar risk for Bipolar Disorder (BD). Although family history of BD is associated with elevated risk of affective morbidity a significant proportion of first-degree relatives of BD patients remains free of psychopathology. Examination of brain structure and function in these individuals may inform on adaptive changes that may pre-empt disease expression. Methods: Data presented here are derived from the Vulnerability to Bipolar Disorders (VIBES) study which includes patients with BD, asymptomatic relatives and healthy controls. Participants underwent extensive investigations including brain structural (sMRI) and functional magnetic resonance imaging (fMRI). The data presented here focus on sMRI voxel-based-morphometry and on conventional and connectivity analyses of fMRI data obtained during the Stroop Colour Word Test (SCWT), a task of cognitive control during conflict resolution. All analyses were implemented in SPM (www.fil.ion.ucl.ac.uk/spm). Resilience in relatives was operationalized as the absence of clinical-range symptoms.Results: Resilient relatives of BD patients expressed structural, functional and connectivity changes reflecting the effect of genetic risk on the brain. These included increased insular volume, decreased activation within the posterior and inferior parietal regions involved in selective attention during the SCWT, and reduced fronto-insular and fronto-cingulate connectivity.Resilience was associated with increased cerebellar vermal volume and enhanced functional coupling between the dorsal and the ventral prefrontal cortex. Conclusions: Our findings suggests the presence of biological mechanisms associated with resilient adaptation of brain networks and pave the way for the identification of outcome-specific trajectories given a particular genotype

Towards a clinical staging for bipolar disorder: defining patient subtypes based on functional outcome.

BACKGROUND: The functional outcome of Bipolar Disorder (BD) is highly variable. This variability has been attributed to multiple demographic, clinical and cognitive factors. The critical next step is to identify combinations of predictors that can be used to specify prognostic subtypes, thus providing a basis for a staging classification in BD. METHODS: Latent Class Analysis was applied to multiple predictors of functional outcome in a sample of 106 remitted adults with BD. RESULTS: We identified two subtypes of patients presenting "good" (n=50; 47.6%) and "poor" (n=56; 52.4%) outcome. Episode density, level of residual depressive symptoms, estimated verbal intelligence and inhibitory control emerged as the most significant predictors of subtype membership at the p<0.05 level. Their odds ratio (OR) and confidence interval (CI) with reference to the "good" outcome group were: episode density (OR=4.622, CI 1.592-13.418), level of residual depressive symptoms (OR=1.543, CI 1.210-1.969), estimated verbal intelligence (OR=0.969; CI 0.945-0.995), and inhibitory control (OR=0.771, CI 0.656-0.907). Age, age of onset and duration of illness were comparable between prognostic groups. LIMITATIONS: The longitudinal stability or evolution of the subtypes was not tested. CONCLUSIONS: Our findings provide the first empirically derived staging classification of BD based on two underlying dimensions, one for illness severity and another for cognitive function. This approach can be further developed by expanding the dimensions included and testing the reproducibility and prospective prognostic value of the emerging classes. Developing a disease staging system for BD will allow individualised treatment planning for patients and selection of more homogeneous patient groups for research purposes

Multimodal Neuroimaging-Informed Clinical Applications in Neuropsychiatric Disorders

Recent advances in neuroimaging data acquisition and analysis hold the promise to enhance the ability to make diagnostic and prognostic predictions and perform treatment planning in neuropsychiatric disorders. Prior research using a variety of types of neuroimaging techniques has confirmed that neuropsychiatric disorders are associated with dysfunction in anatomical and functional brain circuits. We first discuss current challenges associated with the identification of reliable neuroimaging markers for diagnosis and prognosis in mood disorders and for neurosurgical treatment planning for deep brain stimulation (DBS). We then present data on the use of neuroimaging for the diagnosis and prognosis of mood disorders and for DBS treatment planning. We demonstrate how multivariate analyses of functional activation and connectivity parameters can be used to differentiate patients with bipolar disorder from those with major depressive disorder and non-affective psychosis. We also present data on connectivity parameters that mediate acute treatment response in affective and non-affective psychosis. We then focus on precision mapping of functional connectivity in native space. We describe the benefits of integrating anatomical fiber reconstruction with brain functional parameters and cortical surface measures to derive anatomically-informed connectivity metrics within the morphological context of each individual brain. We discuss how this approach may be particularly promising in psychiatry, given the clinical and etiological heterogeneity of the disorders, and particularly in treatment response prediction and planning. Precision mapping of connectivity is essential for DBS. In DBS, treatment electrodes are inserted into positions near key grey matter nodes within the circuits considered relevant to disease expression. However, targeting white matter tracts that underpin connectivity within these circuits may increase treatment efficacy and tolerability therefore relevant for effective treatment. We demonstrate how this approach can be validated in the treatment of Parkinson’s disease by identifying connectivity patterns that can be used as biomarkers for treatment planning and thus refine the traditional approach of DBS planning that uses only grey matter landmarks. Finally we describe how this approach could be used in planning DBS treatment of psychiatric disorders

Parvovirus 4 Infection and Clinical Outcome in High-Risk Populations

Parvovirus 4 (PARV4) is a DNA virus frequently associated with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections, but its clinical significance is unknown. We studied the prevalence of PARV4 antibodies in 2 cohorts of HIV- and HCV-infected individuals (n=469) and the correlations with disease status. We found that PARV4 infection frequently occurred in individuals exposed to bloodborne viruses (95% in HCV-HIV coinfected intravenous drug users [IDUs]). There were no correlations between PARV4 serostatus and HCV outcomes. There was, however, a significant association with early HIV-related symptoms, although because this was tightly linked to both HCV status and clinical group (IDU), the specific role of PARV4 is not yet clea

Using genealogical trees to examine admixture between modern humans and Neandertals

This thesis uses genealogical trees to identify, date, and quantify patterns of admixture between Neandertals and individual modern human populations, using a combination of high quality data and parametric methodology. Previous methods on this subject have either approximated features of trees, or inferred them indirectly. Here, genealogical trees are used directly to understand the admixture process between humans and Neandertals by extending a recently developed method named CEPHi: Coalescent Estimation of Population History. CEPHi uses recombinationally cold regions of the human genome to build genealogical trees specifying the relationships between individuals in two input populations (one Neandertal, one human), including estimated population size histories, split times, and coalescence and mutation times. Using CEPHi, a Neandertal-human population split time of &Tilde;712,000 years in the past is estimated, as well as uncovering loci introduced by Neandertal-human admixture, revealing distinct bimodal distributions of estimated coalescence times between non-African and Neandertal haplotypes. A Neandertal population history is inferred, from the time of their split with humans up to &Tilde;50,000 years ago (the fossil age), showing this archaic species to have suffered a bottleneck at this time, consistent with leaving Africa, followed by a further reduction to extinction. Contrasting African-Neandertal and Eurasian-Neandertal analyses are used to define admixture using genealogical trees, and test our procedures in CEPHi via coalescent-based simulations. This region-level definition of admixture is used to specify sets of introgressed coldspots across 13 modern human populations. These sets are compared between pairs of populations, revealing information about the possible timing of interactions between Neandertals and modern humans, and sharing of admixture events between human groups, especially with respect to the split time between European and Asian populations. Online sets of introgressed regions for each of the four continents in our dataset are provided: African, American, Asian, and European. Finally, in order to investigate the variation in time of contact between Neandertals and individual human populations, a novel method is described and implemented which dates admixture between individual human populations and Neandertals, using information from genealogical trees. Dates of admixture are estimated as ~50-60,000 years in the past in European populations, and &Tilde;80-90,000 years in the past in Asian populations, suggestive of potentially somewhat distinct histories between European and Asian populations. This method can be applied to date any set of introgressed regions, including those shared between particular populations, enabling a clearer picture of the joint evolutionary history of modern humans, Neandertals, and other archaic species

Altered Cortico-Striatal Connectivity in Offspring of Schizophrenia Patients Relative to Offspring of Bipolar Patients and Controls

Schizophrenia (SZ) and bipolar disorder (BD) share clinical features, genetic risk factors and neuroimaging abnormalities. There is evidence of disrupted connectivity in resting state networks in patients with SZ and BD and their unaffected relatives. Resting state networks are known to undergo reorganization during youth coinciding with the period of increased incidence for both disorders. We therefore focused on characterizing resting state network connectivity in youth at familial risk for SZ or BD to identify alterations arising during this period. We measured resting-state functional connectivity in a sample of 106 youth, aged 7-19 years, comprising offspring of patients with SZ (N = 27), offspring of patients with BD (N = 39) and offspring of community control parents (N = 40). We used Independent Component Analysis to assess functional connectivity within the default mode, executive control, salience and basal ganglia networks and define their relationship to grey matter volume, clinical and cognitive measures. There was no difference in connectivity within any of the networks examined between offspring of patients with BD and offspring of community controls. In contrast, offspring of patients with SZ showed reduced connectivity within the left basal ganglia network compared to control offspring, and they showed a positive correlation between connectivity in this network and grey matter volume in the left caudate. Our findings suggest that dysconnectivity in the basal ganglia network is a robust correlate of familial risk for SZ and can be detected during childhood and adolescence

Secondary Teachers’ Family Engagement Practices Targeting Academic Achievement for Hispanic Students

Teachers’ engagement practices with Hispanic families are contributing to the continuing disparities in academic achievement between Hispanic and other students. The purpose of this basic qualitative study was to explore secondary teachers’ perceptions about the challenges of building engagement with Hispanic families. The conceptual framework guiding the study included Epstein’s theory of overlapping spheres of influence and Yosso’s theory of cultural wealth, which together provided an ecological-social and critical race framework to ground the study’s problem, purpose, and methodology. The key research questions revolved around participants’ perceptions of (a) challenges in Hispanic family engagement, (b) family engagement practices improving student performance, and (c) family engagement practices demonstrating the activation of Hispanic families’ cultural wealth or the overlap between spheres of influence in Hispanic students’ lives. Purposive sampling was used to recruit 15 secondary level general education teachers from a medium-sized urban school district in the Northeastern United States who participated in audio recorded semistructured interviews on the virtual Zoom platform. Braun and Clarke’s 6-phase thematic analysis was used to guide the inductive thematic analysis of interview transcripts. The three final themes prevalent in the findings and that addressed the study’s three research questions were obstacles in engaging Hispanic families, inconsistent and isolated family engagement practices, and teachers as experts and value setters. A potential positive social change implication is that the study may inform teacher-parent engagement practices found to be effective in improving Hispanic student performance in the areas of academics and social-emotional functioning

Mirroring everyday clinical practice in clinical trial design: a new concept to improve the external validity of randomized double-blind placebo-controlled trials in the pharmacological treatment of major depression

Background: Randomized, double-blind, placebo-controlled trials constitute the gold standard in clinical research when testing the efficacy of new psychopharmacological interventions in the treatment of major depression. However, the blinded use of placebo has been found to influence clinical trial outcomes and may bias patient selection. Discussion: To improve clinical trial design in major depression so as to reflect clinical practice more closely we propose to present patients with a balanced view of the benefits of study participation irrespective of their assignment to placebo or active treatment. In addition every participant should be given the option to finally receive the active medication. A research agenda is outlined to evaluate the impact of the proposed changes on the efficacy of the drug to be evaluated and on the demographic and clinical characteristics of the enrollment fraction with regard to its representativeness of the eligible population. Summary: We propose a list of measures to be taken to improve the external validity of double-blind, placebocontrolled trials in major depression. The recommended changes to clinical trial design may also be relevant for other psychiatric as well as medical disorders in which expectations regarding treatment outcome may affect the outcome itself

Soap Opera Reception in Greece: Resistance, Negotiation and Viewing Position

This thesis aims to contribute to debates concerning the possibility and nature of resistance in the consumption of popular culture. I attempted to delineate the patterns through which Greek male and female viewers construct and use the meanings of domestic and foreign soap operas, in the context of their everyday life. The questions that have guided my research have been the following: how do men and women of different social backgrounds relate to soap operas of different ethnic origins? Do their discourses and practices challenge the soap opera text and its ideological currency? Do they empower them in any way? What is the role of gender, class, and national identity in this process? I conducted in depth interviews with 35 soap opera fans (19 women - 16 men) and their qualitative analysis led me to distinguish between three viewing positions, that is, the attitudes, pleasures, and practices that characterized the patterns of reception that I encountered: the aesthetic position, the position of the social observer, and the ironic distance position. Several viewers negotiated between two positions according to the social dynamics of the viewing setting and the text's ethnic origin. These positions are further analyzed in relation to gender, class and age. The marked differences in the reception of indigenous, as opposed to foreign soaps, underline the significance of ethno-cultural identity. The cultural meanings and uses of soap opera may differ substantially, depending on the social group of the viewers. The thesis concludes that resistance does not always involve oppositional readings and that it is still a useful notion to describe certain practices and discourses in television reception that take place at a personal, social and symbolic level

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors