Dopamine and emotion processing in schizotypal anhedonia

Title from PDF of title page (University of Missouri--Columbia, viewed on Apr. 12, 2010).The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract appears in the public.pdf file.Thesis advisor: Dr. John Kerns.M.A. University of Missouri--Columbia 2009.Three studies examined emotion processing and dopamine regulation in anhedonia. In Study 1, in multiple assessments of emotional experience (e.g., naturalistic and lab contexts and social and nonsocial situations), people with elevated social anhedonia (n = 40) reported less intensity of positive affect than both controls (n = 30) and people with elevated perceptual aberration-magical ideation (n = 29). Social anhedonia was also associated with providing less emotional content when describing what it is like to experience positive situations. In contrast, both social anhedonia and perceptual aberration-magical ideation were associated with increased frequency of negative affect for their daily experiences. Moreover, social anhedonia was not associated with a decrease specifically in high-arousal emotions. In Study 2 (n = 339), social and physical anhedonia (but not perceptual aberration-magical ideation) were again associated with decreased self-reported positive affect to lab stimuli. Overall, results suggest anhedonia may be associated with a general decrease in self-reported positive affect intensity. The Val(158)Met polymorphism of the catechol-O-methyltransferase (COMT) gene has been associated with aspects of schizophrenia that are possibly related to the disorder's pathogenesis. In study 3, as a group, relatives of patients with schizophrenia who were homozygous for the val allele of the COMT polymorphism showed the highest elevations in self-reported social and physical anhedonia. Associations with the COMT polymorphism were absent in relatives of patients with bipolar disorder and control participants. Findings suggest that anhedonia is manifest in individuals who carry genetic liability for schizophrenia and is associated with the Val(158)Met polymorphism of the COMT gene.Includes bibliographical references

Multidisciplinary Consideration of Potential Pathophysiologic Mechanisms of Paradoxical Erythema with Topical Brimonidine Therapy.

Rosacea is a chronic inflammatory disease with transient and non-transient redness as key characteristics. Brimonidine is a selective α2-adrenergic receptor (AR) agonist approved for persistent facial erythema of rosacea based on significant efficacy and good safety data. The majority of patients treated with brimonidine report a benefit; however, there have been sporadic reports of worsening erythema after the initial response. A group of dermatologists, receptor physiology, and neuroimmunology scientists met to explore potential mechanisms contributing to side effects as well as differences in efficacy. We propose the following could contribute to erythema after application: (1) local inflammation and perivascular inflammatory cells with abnormally functioning ARs may lead to vasodilatation; (2) abnormal saturation and cells expressing different AR subtypes with varying ligand affinity; (3) barrier dysfunction and increased skin concentrations of brimonidine with increased actions at endothelial and presynaptic receptors, resulting in increased vasodilation; and (4) genetic predisposition and receptor polymorphism(s) leading to different smooth muscle responses. Approximately 80% of patients treated with brimonidine experience a significant improvement without erythema worsening as an adverse event. Attention to optimizing skin barrier function, setting patient expectations, and strategies to minimize potential problems may possibly reduce further the number of patients who experience side effects.FundingGalderma International S.A.S., Paris, France

Abandoned Ordnance in Libya: Threats to Civilians and Recommended Responses

In a report released in August 2012, “Explosive Situation: Qaddafi\u27s Abandoned Weapons and the Threat to Libya\u27s Civilians,” researchers from Harvard Law School\u27s International Human Rights Clinic (IHRC) examined Libya\u27s abandoned ordnance problem and its humanitarian consequences for the local population. Based on field and desk research, the report documents the threats these weapons pose, analyzes steps to address them and offers recommendations to minimize civilian harm. IHRC co-published the report with the Center for Civilians in Conflict (formerly CIVIC) and the Center for American Progress. In this article, two of the report\u27s authors summarize its 2012 findings and recommendations

Anhedonia and deficits in positive emotional experience in individuals with genetic liability for schizophrenia

There is growing evidence that anhedonia--the extent to which an individual reports pleasure or interest in social and physical stimuli--is important to the pathophysiology of schizophrenia. At the same time, some research has suggested that there are different facets of pleasure and positive affect (PA), such as liking vs. wanting (Berridge & Robinson, 1998). Previous research has not directly examined the relationship between anhedonia symptoms and measures of positive affect in relation to genetic liability to schizophrenia. This research examined people with schizophrenia and schizoaffective disorder, their first-degree relatives, and nonpsychiatric controls to assess emotion traits as potential phenotypes for anhedonia in genetic liability for schizophrenia. Multiple methods and measures were used to assess anhedonia and affective traits. There was a general lack of association between interview anhedonia and many facets of PA, coupled with a lack of group differences across PA variables. However, there was general evidence of association of self-reported anhedonia (in both probands and relatives) with many PA variables, suggesting the presence of confounding methodological variance. Significant group differences on a novel behavioral measure of effort for reward were detected. Last, results suggested that ambivalence, long considered relevant to psychosis, is more associated with affect than with liability to schizophrenia

Genetic network properties of the human cortex based on regional thickness and surface area measures

We examined network properties of genetic covariance between average cortical thickness (CT) and surface area (SA) within genetically-identified cortical parcellations that we previously derived from human cortical genetic maps using vertex-wise fuzzy clustering analysis with high spatial resolution. There were 24 hierarchical parcellations based on vertex-wise CT and 24 based on vertex-wise SA expansion/contraction; in both cases the 12 parcellations per hemisphere were largely symmetrical. We utilized three techniques—biometrical genetic modeling, cluster analysis, and graph theory—to examine genetic relationships and network properties within and between the 48 parcellation measures. Biometrical modeling indicated significant shared genetic covariance between size of several of the genetic parcellations. Cluster analysis suggested small distinct groupings of genetic covariance; networks highlighted several significant negative and positive genetic correlations between bilateral parcellations. Graph theoretical analysis suggested that small world, but not rich club, network properties may characterize the genetic relationships between these regional size measures. These findings suggest that cortical genetic parcellations exhibit short characteristic path lengths across a broad network of connections. This property may be protective against network failure. In contrast, previous research with structural data has observed strong rich club properties with tightly interconnected hub networks. Future studies of these genetic networks might provide powerful phenotypes for genetic studies of normal and pathological brain development, aging, and function

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

Genetics and Epigenetics of Self-Injurious Thoughts and Behaviors: Systematic Review of the Suicide Literature and Methodological Considerations

Suicide is a multifaceted and poorly understood clinical outcome, and there is an urgent need to advance research on its phenomenology and etiology. Epidemiological studies have demonstrated that suicidal behavior is heritable, suggesting that genetic and epigenetic information may serve as biomarkers for suicide risk. Here we systematically review the literature on genetic and epigenetic alterations observed in phenotypes across the full range of self-injurious thoughts and behaviors (SITB). We included 577 studies focused on genome-wide and epigenome-wide associations, candidate genes (SNP and methylation), noncoding RNAs, and histones. Convergence of specific genes is limited across units of analysis, although pathway-based analyses do indicate nervous system development and function and immunity/inflammation as potential underlying mechanisms of SITB. We provide suggestions for future work on the genetic and epigenetic correlates of SITB with a specific focus on measurement issues

Pathway-based polygene risk for severe depression implicates drug metabolism in CONVERGE.

BACKGROUND: The Psychiatric Genomics Consortium (PGC) has made major advances in the molecular etiology of MDD, confirming that MDD is highly polygenic. Pathway enrichment results from PGC meta-analyses can also be used to help inform molecular drug targets. Prior to any knowledge of molecular biomarkers for MDD, drugs targeting molecular pathways (MPs) proved successful in treating MDD. It is possible that examining polygenicity within specific MPs implicated in MDD can further refine molecular drug targets. METHODS: Using a large case-control GWAS based on low-coverage whole genome sequencing (N = 10 640) in Han Chinese women, we derived polygenic risk scores (PRS) for MDD and for MDD specific to each of over 300 MPs previously shown to be relevant to psychiatric diagnoses. We then identified sets of PRSs, accounting for critical covariates, significantly predictive of case status. RESULTS: Over and above global MDD polygenic risk, polygenic risk within the GO: 0017144 drug metabolism pathway significantly predicted recurrent depression after multiple testing correction. Secondary transcriptomic analysis suggests that among genes in this pathway, CYP2C19 (family of Cytochrome P450) and CBR1 (Carbonyl Reductase 1) might be most relevant to MDD. Within the cases, pathway-based risk was additionally associated with age at onset of MDD. CONCLUSIONS: Results indicate that pathway-based risk might inform etiology of recurrent major depression. Future research should examine whether polygenicity of the drug metabolism gene pathway has any association with clinical presentation or treatment response. We discuss limitations to the generalizability of these preliminary findings, and urge replication in future research

Medical student attitudes to patient involvement in healthcare decision-making and research

Objective: Patient involvement is used to describe the inclusion of patients as active participants in healthcare decision-making and research. This study aimed to investigate incoming year 1 medical (MBChB) students’ attitudes and opinions regarding patient involvement in this context. Methods: We established a staff–student partnership to formulate the design of an online research survey, which included Likert scale questions and three short vignette scenarios designed to probe student attitudes towards patient involvement linked to existing legal precedent. Incoming year 1 medical students (n=333) were invited to participate in the survey before formal teaching commenced. Results: Survey data (49 participants) indicate that students were broadly familiar with, and supportive of, patient involvement in medical treatment. There was least support for patient involvement in conducting (23.9%), contributing to (37.0%) or communicating research (32.6%), whereas there was unanimous support for patients choosing treatment from a selection of options (100%). Conclusion: Incoming members of the medical profession demonstrate awareness of the need to actively involve patients in healthcare decision-making but are unfamiliar with the utility and value of such involvement in research. Further empirical studies are required to examine attitudes to patient involvement in healthcare