The superior longitudinal fasciculus and its functional triple-network mechanisms in brooding.

Brooding, which refers to a repetitive focus on one's distress, is associated with functional connectivity within Default-Mode, Salience, and Executive-Control networks (DMN; SN; ECN), comprising the so-called "triple-network" of attention. Individual differences in brain structure that might perseverate dysfunctional connectivity of brain networks associated with brooding are less clear, however. Using diffusion and functional Magnetic Resonance Imaging, we explored multimodal relationships between brooding severity, white-matter microstructure, and resting-state functional connectivity in depressed adults (N = 32-44), and then examined whether findings directly replicated in a demographically-similar, independent sample (N = 36-45). Among the fully-replicated results, three core findings emerged. First, brooding severity is associated with functional integration and segregation of the triple-network, particularly with a Precuneal subnetwork of the DMN. Second, microstructural asymmetry of the Superior Longitudinal Fasciculus (SLF) provides a robust structural connectivity basis for brooding and may account for over 20% of its severity (Discovery: adj. R2 = 0.18; Replication: adj. R2 = 0.22; MSE = 0.06, Predictive R2 = 0.22). Finally, microstructure of the right SLF and auxiliary white-matter is associated with the functional connectivity correlates of brooding, both within and between components of the triple-network (Discovery: adj. R2 = 0.21; Replication: adj. R2 = 0.18; MSE = 0.03, Predictive R2 = 0.21-0.22). By cross-validating multimodal discovery with replication, the present findings help to reproducibly unify disparate perspectives of brooding etiology. Based on that synthesis, our study reformulates brooding as a microstructural-functional connectivity neurophenotype.

Differential sensitivity to the environment: contribution of cognitive biases and genes to psychological wellbeing.

Negative cognitive biases and genetic variation have been associated with risk of psychopathology in largely independent lines of research. Here, we discuss ways in which these dynamic fields of research might be fruitfully combined. We propose that gene by environment (G × E) interactions may be mediated by selective cognitive biases and that certain forms of genetic 'reactivity' or 'sensitivity' may represent heightened sensitivity to the learning environment in a 'for better and for worse' manner. To progress knowledge in this field, we recommend including assessments of cognitive processing biases; examining G × E interactions in 'both' negative and positive environments; experimentally manipulating the environment when possible; and moving beyond single-gene effects to assess polygenic sensitivity scores. We formulate a new methodological framework encapsulating cognitive and genetic factors in the development of both psychopathology and optimal wellbeing that holds long-term promise for the development of new personalized therapies.

5-HTTLPR and BDNF Val66Met polymorphisms moderate effects of stress on rumination.

This study examined whether polymorphisms in the serotonin transporter (SLC6A4, 5-HTTLPR) and brain-derived neurotropic factor (BDNF Val66Met, rs6265) genes moderate the relationship between life stress and rumination. Participants were a large homogenous group of healthy, unmedicated, never depressed individuals with few current symptoms of depression (N = 273). Results indicate that individuals with two short (S) alleles of the 5-HTTLPR polymorphism or two Met alleles of the BDNF Val66Met polymorphism ruminate more under conditions of life stress, compared to the other genotypes. Moreover, the accumulation of risk alleles (i.e. S and Met alleles) across genes is associated with significantly greater rumination in the context of life stress. These results suggest that both 5-HTTLPR and BDNF Val66Met moderate the relationship between life stress and rumination. These findings support the notion that variation in these genes is associated with biological sensitivity to the negative effects of stress.

Depression symptoms and cognitive control of emotion cues: a functional magnetic resonance imaging study.

Few studies have examined associations between depressive symptoms and alterations in neural systems that subserve cognitive control. Cognitive control was assessed with an exogenous cueing task using happy, sad, and neutral facial expressions as cues among women with mild to moderate symptoms of depression and a non-depressed control group while functional magnetic resonance imaging (fMRI) measured brain activity. Amygdala and medial/orbital prefrontal cortex (PFC) response to valid emotion cues did not differ as a function of depression symptoms. However, significant depression group differences were observed when task demands required cognitive control. Participants with elevated depression symptoms showed weaker activation in right and left lateral PFC and parietal regions when shifting attentional focus away from invalid emotion cues. No depression group differences were observed for invalid non-emotional cues. Findings suggest that mild to moderate depression symptoms are associated with altered function in brain regions that mediate cognitive control of emotional information.

Prefrontal morphology, 5-HTTLPR polymorphism and biased attention for emotional stimuli.

Biased attention for emotional stimuli has been associated with vulnerability to psychopathology. This study examines the neural substrates of biased attention. Twenty-three adult women completed high-resolution structural imaging followed by a standard behavioral measure of biased attention (i.e. spatial cueing task). Participants were also genotyped for the serotonin transporter-linked promoter region (5-HTTLPR) gene. Results indicated that lateral prefrontal cortex (lPFC) morphology was inversely associated with maintained attention for positive and negative stimuli, but only among short 5-HTTLPR allele carriers. No such associations were observed for the medial prefrontal cortex (mPFC) or the amygdala. Results from this study suggest that brain regions involved in cognitive control of emotion are also associated with attentional biases for emotion stimuli among short 5-HTTLPR allele carriers.

Evaluation of the potential genotoxicity of the phosphate binder lanthanum carbonate.

Lanthanum was evaluated for potential genotoxicity using a range of in vitro assays (as the carbonate) in the presence and absence of post-mitochondrial fraction (S9) and in vivo in three independent tests for mutagenicity and clastogenicity (as the carbonate and chloride). The drug was devoid of mutagenic activity in bacterial assays (maximum concentration 5000 microg/plate) using a range of test strains (Salmonella typhimurium TA1535, TA1537, TA1538, TA98, TA100 and TA102 and Escherichia coli WP2 uvrA and WP2 uvrA pkm101). No effects were seen in the hgprt gene mutation assay in Chinese hamster ovary cells in the presence of S9. In the absence of S9, sporadic increases in revertant numbers were not dose-related or reproducible in subsequent experiments and hence were concluded to be chance events. In an in vitro chromosome aberration assay using Chinese hamster ovary cells, chromosome damage in the presence and absence of S9 (concentration 200-5000 microg/ml) was attributed to overt cell toxicity. To confirm this, a comprehensive in vivo evaluation of the drug was performed. Negative results were obtained in two independent rodent micronucleus tests. In the first mice were given oral doses (of carbonate) up to 2000 mg/kg, in the second rats were given a single i.v. bolus injection (of chloride) up to 0.1 mg/kg. Negative results were also obtained in a rat liver unscheduled DNA synthesis assay after treatment for 28 days with i.v. bolus injections (of chloride) up to 0.1 mg/kg/day. In these in vivo studies lanthanum plasma concentrations were >3000 times higher than the steady-state peak plasma concentration observed in dialysis patients given therapeutic doses of lanthanum carbonate. It can be concluded that lanthanum is not genotoxic and that lanthanum carbonate is unlikely to present a latent hazard in therapeutic use.

Recommendations for conducting the in vivo alkaline Comet assay. 4th International Comet Assay Workshop.

The in vivo alkaline single cell gel electrophoresis assay, hereafter the Comet assay, can be used to investigate the genotoxicity of industrial chemicals, biocides, agrochemicals and pharmaceuticals. The major advantages of this assay include the relative ease of application to any tissue of interest, the detection of multiple classes of DNA damage and the generation of data at the level of the single cell. These features give the Comet assay potential advantages over other in vivo test methods, which are limited largely to proliferating cells and/or a single tissue. The Comet assay has demonstrated its reliability in many testing circumstances and is, in general, considered to be acceptable for regulatory purposes. However, despite the considerable data published on the in vivo Comet assay and the general agreement within the international scientific community over many protocol-related issues, it was felt that a document giving detailed practical guidance on the protocol required for regulatory acceptance of the assay was required. In a recent meeting held in conjunction with the 4th International Comet Assay Workshop (Ulm, Germany, 22-25 July 2001) an expert panel reviewed existing data and recent developments of the Comet assay with a view to developing such a document. This paper is intended to act as an update to the more general guidelines which were published as a result of the International Workshop on Genotoxicity Test Procedures. The recommendations are also seen as a major step towards gaining more formal regulatory acceptance of the Comet assay.